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Athanasopoulos E, Pelagiadis I, Martimianaki G, Stratigaki M, Katzilakis N, Stiakaki E. Circulating Endothelial Progenitor Cells and Metabolic Factors in Childhood Cancer Survivors. Pediatr Blood Cancer 2025:e31771. [PMID: 40350548 DOI: 10.1002/pbc.31771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 04/12/2025] [Accepted: 04/21/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND Circulating endothelial progenitor cells (cEPCs) are known to have an active role in maintaining healthy vessel anatomy and function. The purpose of the present study was to quantify cEPCs in childhood cancer survivors after treatment completion and evaluate possible associations of their levels with metabolic disorders. METHODS Circulating EPCs isolated from peripheral blood samples from 383 children and adolescent cancer survivors diagnosed with acute lymphoblastic leukemia (ALL), lymphomas, or solid tumors (ST) were quantified 1, 3, and more than 3 years after treatment completion using flow cytometry. Their levels were compared to 200 healthy controls, and multivariate logistic regression analysis was applied to seek correlations with metabolic disorders, including hypertension, obesity, hyperglycemia, and dyslipidemia. RESULTS The levels of CD34+/CD133+/VEGFR+ and CD34+/VEGFR+ cEPCs were significantly higher in children treated for solid tumors and lymphomas compared to the ALL group. Compared to controls, both cEPCs populations were found to be increased in patients treated for ST (CD34+/CD133+/VEGFR+, p = 0.0049; CD34+/VEGFR+, p = 0.0001). Declining trends of CD34+/VEGFR+ and CD34+/CD133+/VEGFR+ levels were observed in patients treated for solid tumors and lymphomas during the first 3 years after treatment, while an increasing trend was observed in ALL patients (p = 0.01). Three years after treatment completion, all groups had cEPC levels comparable to the control group. By multivariate regression analysis, no significant differences were observed in children with metabolic disorders, including hypertension, obesity, hyperglycemia, and dyslipidemia. CONCLUSION Significant differences in cEPC levels were observed in childhood cancer survivors during the first year after treatment completion, which were comparable to healthy controls after 3 years post-treatment.
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Affiliation(s)
- Emmanouil Athanasopoulos
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
| | - Iordanis Pelagiadis
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
| | - Georgia Martimianaki
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
| | - Maria Stratigaki
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
| | - Nikolaos Katzilakis
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
| | - Eftichia Stiakaki
- Department of Pediatric Hematology-Oncology, University Hospital of Heraklion and Laboratory of Blood Diseases and Childhood Cancer Biology, Medical School University of Crete, Heraklion, Greece
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Tomić I, Zeljko I, Brizić I, Šoljić V, Ivančić I, Tomić M, Ćurlin M, Tomić D. Decreased Endothelial Progenitor Cells Are Associated with Severe Coronary Artery Disease: Insights from a Clinical Study. J Cardiovasc Dev Dis 2025; 12:132. [PMID: 40278191 PMCID: PMC12028075 DOI: 10.3390/jcdd12040132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 03/28/2025] [Accepted: 03/29/2025] [Indexed: 04/26/2025] Open
Abstract
Endothelial progenitor cells (EPCs) play a crucial role in vascular repair, and their depletion has been involved in coronary artery disease (CAD) severity. This study examines the relationship between circulating EPC levels and CAD complexity, as quantified by the Syntax Score I. A total of 85 patients undergoing coronary angiography were enrolled, with EPCs quantified using flow cytometry. EPC proportion showed a significant inverse relationship with CAD severity, measured by Syntax Score I. Additionally, we investigated EPC levels in patients presenting with acute coronary syndrome (ACS) and found that EPC depletion was more pronounced in this group compared to non-ACS patients (median EPC count: 0.35 vs. 0.61, p = 0.027). These findings suggest that lower EPC levels are indicative of more severe CAD and ACS, reinforcing their potential as biomarkers for cardiovascular risk stratification, monitoring disease advancement, and identifying patients at risk of adverse events.
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Affiliation(s)
- Ivan Tomić
- Department of Internal Medicine, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; (I.Z.); (I.B.); (M.T.)
| | - Ivan Zeljko
- Department of Internal Medicine, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; (I.Z.); (I.B.); (M.T.)
| | - Ivica Brizić
- Department of Internal Medicine, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; (I.Z.); (I.B.); (M.T.)
| | - Violeta Šoljić
- Faculty of Health Study, University of Mostar, Trg Hrvatskih Velikana 1, 88000 Mostar, Bosnia and Herzegovina; (V.Š.); (M.Ć.)
- Department of Histology and Embryology, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina
| | - Ivona Ivančić
- Faculty of Pharmacy, University of Mostar, Trg Hrvatskih Velikana 1, 88000 Mostar, Bosnia and Herzegovina;
| | - Monika Tomić
- Department of Internal Medicine, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina; (I.Z.); (I.B.); (M.T.)
| | - Marina Ćurlin
- Faculty of Health Study, University of Mostar, Trg Hrvatskih Velikana 1, 88000 Mostar, Bosnia and Herzegovina; (V.Š.); (M.Ć.)
- Department of Histology and Embryology, University Clinical Hospital Mostar, Kralja Tvrtka bb, 88000 Mostar, Bosnia and Herzegovina
| | - Domagoj Tomić
- Health Centre Široki Brijeg, Dr. Jure Grubišića 11, 88220 Široki Brijeg, Bosnia and Herzegovina;
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Efstathiou N, Koliakos G, Kantziou K, Kyriazis G, Slavakis A, Drossou V, Soubasi V. Kinetics of Circulating Progenitor Cells and Chemotactic Factors in Full-Term Neonates with Encephalopathy: Indications of Participation in the Endogenous Regenerative Process. Biomolecules 2025; 15:427. [PMID: 40149963 PMCID: PMC11940357 DOI: 10.3390/biom15030427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Revised: 02/24/2025] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
Preclinical studies have shown that progenitor cells (PCs) are mobilized toward injured tissues to ameliorate damage and contribute to regeneration. The exogenous therapeutic administration of PCs in children affected by neonatal encephalopathy (NE) is a promising, yet underreported, topic. In this prospective study, we investigated whether endogenous circulating progenitor cells (CPCs) are involved in intrinsic regeneration mechanisms following neonatal brain injury. Thirteen full-term infants with moderate/severe NE, eleven with perinatal stress, and twelve controls were enrolled. Blood samples were collected on days 1, 3, 9, 18, and 45, as well as at 8 and 24 months of life, and were analyzed with a focus on Endothelial Progenitor Cells, Haematopoietic Stem Cells, and Very Small Embryonic-Like Stem Cells, in addition to chemotactic factors (erythropoietin, IGF-1, and SDF-1). Correlations between CPCs, chemotactic factors, and brain injury were assessed using serum levels of brain injury biomarkers (S100B and neuron-specific enolase), brain MRIs, and Bayley III developmental scores. Increased brain injury biomarkers were followed by the upregulation of SDF-1 receptor and erythropoietin and, finally, by elevated CPCs. These findings suggest a potential endogenous regenerative effort, primarily observed in the moderate encephalopathy group, but this is suppressed in cases of severe brain injury. Mimicking and enhancing endogenous regeneration pathways in cases of failure-regarding cell type and timeframe-could provide a novel therapeutic model.
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Affiliation(s)
- Nikolaos Efstathiou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgios Koliakos
- Biochemistry Department, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Katerina Kantziou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Georgios Kyriazis
- Immunology Department, Pulmonary Clinic, Papanikolaou General Hospital, Aristotle University of Thessaloniki, Exohi, 57010 Thessaloniki, Greece
| | - Aristeidis Slavakis
- Biochemistry Department, Hippokration General Hospital, 54642 Thessaloniki, Greece
| | - Vasiliki Drossou
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Vasiliki Soubasi
- 1st Neonatal Clinic and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
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Tan Y, Li M, Ma X, Shi D, Liu W. Angiogenesis after acute myocardial infarction: a bibliometric -based literature review. Front Cardiovasc Med 2025; 12:1426583. [PMID: 40017521 PMCID: PMC11865093 DOI: 10.3389/fcvm.2025.1426583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 01/29/2025] [Indexed: 03/01/2025] Open
Abstract
Objective The prevalence of acute myocardial infarction, a severe ischemic cardiac disease, is on the rise annually. The establishment of coronary collateral circulation in the border zone of the infarct can effectively relieve myocardial ischemia and impede cell death, while angiogenesis can promote the formation of collateral circulation in the ischemic tissues. Over the past two decades, studies related to angiogenesis in acute myocardial infarction have increased rapidly. However, there is a lack of bibliometric studies in this particular field. Methods For this study, we employed bibliometric analysis to outline focal points and patterns in scientific and clinical research. The collection of literature was gathered using the Web of Science Core Collection database. Bibliometric and visual analysis were conducted. Knowledge maps were generated using CiteSpace and VOSviewer software. Results and conclusions With the deepening of the research, therapeutic angiogenesis will become a treatment direction for acute myocardial infarction in the future.
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Affiliation(s)
- Yu Tan
- Department of Cardiology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Li
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaojuan Ma
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dazhuo Shi
- National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wei Liu
- Department of Cardiology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China
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Huang X, Liu J, Wu X, Mo Y, Luo X, Yang Y, Yang C, Liang X, Liang R, Chen Y, Fan Z, Lu W, Chen Y, Hua Q. Remote Continuous Microinjury-Triggered Cytokines Facilitate Severe Diabetic Foot Ulcer Healing via the Ras/Raf/MEK/ERK Pathway. J Inflamm Res 2025; 18:1755-1772. [PMID: 39931169 PMCID: PMC11808219 DOI: 10.2147/jir.s493505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 01/25/2025] [Indexed: 02/13/2025] Open
Abstract
PURPOSE Microinjury can trigger in situ tissue repair. Bone transport consists of continuous microinjuries/microfracture and induces bone formation and angiogenesis. Tibial cortex transverse transport (TTT) was found to promote angiogenesis at the foot and the healing of diabetic foot ulcers (DFUs). However, the underlying mechanism remains largely unknown. METHODS We divided 72 Sprague-Dawley rats with DFUs into the control, sham, and TTT groups. Wound measurement and histology were performed to evaluate the wound healing processes. Enzyme-linked immunosorbent assay, flow cytometry, immunohistochemistry, and Western Blot were used to assess angiogenesis and the activity of endothelial progenitor cells (EPCs) and the Ras/Raf/MEK/ERK signaling pathway. RESULTS We found accelerated wound healing, improved epidermal continuity, and increased dermal thickness in the TTT group than the control and the sham groups. Higher levels of serum TGF-β1, PDGF-BB, and VEGF were detected in the TTT group. These changes were in parallel with the expression of TGF-β1, PDGF-BB, and VEGF in the foot wounds and the frequency of EPCs in both bone marrow and peripheral circulation, which implied that the secreted TGF-β1, PDGF-BB, and VEGF promote proliferation and migration of EPCs to the foot wounds. The expression of CD31+ cells, SMA-α+ cells, and the Ras/Raf/MEK/ERK pathway was higher in the TTT group than in the control and sham groups. CONCLUSION The findings showed that TTT enhanced the production of growth factors that in turn activated EPC proliferation and migration through the Ras/Raf/MEK/ERK pathway, ultimately contributing to angiogenesis and DFU healing. Based on these findings, we proposed a theory that remote continuous microinjuries can trigger the repair of target tissues (ie, microinjury-induced remote repair, MIRR). Future studies are needed to validate this theory.
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Affiliation(s)
- Xiajie Huang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-Constructed by the Province and Ministry, Guangxi Medical University, Nanning, People’s Republic of China
| | - Jie Liu
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Xiaomei Wu
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Yangzhou Mo
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Xiping Luo
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Yongge Yang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Chaoquan Yang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Xinyun Liang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Rongyuan Liang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Yeping Chen
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Zezhen Fan
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - William Lu
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Yan Chen
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
| | - Qikai Hua
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People’s Republic of China
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Gurevitz C, Zadok OIB, Leshem-Lev D, Hodeda L, Rotholz A, Kornowski R, Eisen A. Circulating Endothelial Progenitor Cells in Patients with Established Cardiovascular Disease Treated with PCSK9 Monoclonal Antibodies. Am J Prev Cardiol 2024; 20:100896. [PMID: 39649377 PMCID: PMC11625290 DOI: 10.1016/j.ajpc.2024.100896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/19/2024] [Accepted: 11/13/2024] [Indexed: 12/10/2024] Open
Abstract
Background The role of circulating endothelial progenitor cells (cEPCs) in vascular repair and their association to cardiovascular protection is well established. Objectives We examined the effect of proprotein convertase subtilisin kexin type 9 monoclonal antibodies (PCSK9 mAb) on cEPCs in adults with hypercholesterolemia and cardiovascular disease, aiming to establish a pleotropic class effect. Methods Non-interventional prospective study in patients with cardiovascular disease treated with either evolocumab or alirocumab. Patients were sampled for cEPCs at baseline, 1- and 3-months following initiation of PCSK9 mAb. cEPCs were assessed using flow cytometry by expression of CD34/CD133 and vascular endothelial growth factor receptor (VEGFR)-2, and functionally by formation of colony forming units (CFUs) and by Mitochondrial Tetrazolium (MTT) assay, indicative of cEPCs viability. Results 51 patients (median age 67 (IQR 63,74) years;63 % male, median low-density lipoprotein-cholesterol (LDL-C) 125 (102,165) mg/dL) were initiated on PCSK9 mAb therapy (evolocumab n = 22, alirocumab n = 29) for secondary prevention. Following 3-month treatment with PCSK9 mAb, there was an increase in CD34(+)VEGFR-2(+) and CD133(+)VEGFR-2(+) levels (0.50 % [IQR 0.30,1.04] to 1.36 % [0.89, 1.73], p < 0.001 and 0.57 % [0.25,0.88] to 1.18 % [0.74,1.66], p < 0.001, respectively). Functionally, increase in EPCs-CFUs was evident (0.5 [0.0,1.0] to 2.0 [1.5,2.5], p < 0.001) with concomitant increase in MTT (0.11 [0.09,0.15] to 0.17 [0.12,0.21], p < 0.001). Stratifying by PCSK9 mAb, both agents were associated with an increase in cEPCs level and function. Conclusions In hypercholesterolemic patients with cardiovascular disease treated with PCSK9 mAb, there is an increase in cEPCs levels and function from baseline levels. These findings, which persist in both evolocumab and alirocumab, might suggest a novel pleiotropic class effect.
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Affiliation(s)
- Chen Gurevitz
- Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Mount Sinai Fuster Heart Hospital, Ichan School of Medicine, New York, NY, USA
| | - Osnat Itzhaki Ben Zadok
- Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dorit Leshem-Lev
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Lital Hodeda
- Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
| | - Aviad Rotholz
- Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ran Kornowski
- Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alon Eisen
- Department of Cardiology, Rabin Medical Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Zhang J, Zheng L. The correlation between the number of endothelial progenitor cells in the peripheral blood and abdominal aortic aneurysm. Medicine (Baltimore) 2024; 103:e40722. [PMID: 39612386 PMCID: PMC11608706 DOI: 10.1097/md.0000000000040722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/08/2024] [Indexed: 12/01/2024] Open
Abstract
This study was to investigate the correlation between the number of endothelial progenitor cells (EPCs) in peripheral blood and abdominal aortic aneurysm (AAA), and provide a potential biomarker for the diagnosis and treatment monitoring of AAA. Patients with AAA evaluated in the First Affiliated Hospital of Soochow University from June 2018 to October 2018 (n = 7) were included in this study. All patients were confirmed as AAA by vascular CTA with an increase of more than 50% of the abdominal aortic diameter. Patients (n = 7) with normal abdominal aorta diameter were included as control group with matching age, sex, blood pressure, and blood sugar concentration between experimental and control groups. Mononuclear cells were collected by density gradient centrifugation, stained by CD34-FITC and CD309-PE antibodies, and analyzed by flow cytometry. The number of EPCs in the peripheral blood of patients with AAA (0.874 ± 0.129‰) was significantly lower than that in the control group (1.420 ± 0.289‰) (P < .01). The number of EPCs may be used as a potential biomarker for the diagnosis and monitoring of AAA following treatment.
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Affiliation(s)
- Jinlong Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Lei Zheng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
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Rakkar K, Kadir RRA, Othman OA, Sprigg N, Bath PM, Bayraktutan U. Comorbidities and Angiogenic Regulators Affect Endothelial Progenitor Cell Subtype Numbers in a Healthy Volunteer Control Group. Stem Cell Rev Rep 2024; 20:2336-2344. [PMID: 39186241 PMCID: PMC11554701 DOI: 10.1007/s12015-024-10777-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2024] [Indexed: 08/27/2024]
Abstract
Endothelial progenitor cells (EPCs) are stem cells that can repair injured blood vessels through neovascularisation. This is achieved through secretion of growth factors and endothelial maturation. EPC numbers and function have been studied to determine their diagnostic, prognostic and therapeutic potential in many ischaemic diseases such as stroke. However their activation homing and migration is not definitively understood in stroke patients. In this study, we profiled the non-stroke control group recruited into the Dunhill Medical Trust Endothelial Progenitor Cell Study. Demographic, clinical and plasma levels of angiogenic regulators of participants were analysed to determine if there was any correlation with EPC numbers, subtypes and function. Participants with diabetes had significantly supressed EPC numbers (CD45-CD34 + CD133 + KDR+) and CD34 + KDR + and KDR + EPC subtypes. Male participants had significantly lower EPC numbers compared to female participants and the proliferative capacity of endothelial colony forming cells significantly decreased with increasing participant age. Pro-angiogenic proteins such as granulocyte colony-stimulating factor and stromal cell-derived factor were positively correlated with both undifferentiated and endothelial-committed EPC subtype numbers (CD133+, KDR+, CD34 + CD133+, CD34 + KDR+), whereas anti-angiogenic proteins such as thrombospondin-1 showed a negative correlation with undifferentiated EPC subtypes (CD133+, CD34 + CD133+) but a positive correlation with endothelial-committed EPC subtype numbers (KDR+, CD34 + KDR+). These results show that EPC numbers and subtypes are affected by many factors and larger studies which can analyse and deconvolute the interactions between comorbidities, plasma biomarker levels and EPC are needed.
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Affiliation(s)
- Kamini Rakkar
- Translational Medical Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, NG7 2RD, UK
| | | | - Othman A Othman
- Faculty of Medicine and Health Sciences, Queen's Medical Centre, University of Nottingham, University Park, Nottingham, NG7 2UH, UK
| | - Nikola Sprigg
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- Academic Stroke, Mental Health & Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Philip M Bath
- Stroke Trials Unit, Mental Health & Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
- Academic Stroke, Mental Health & Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK
| | - Ulvi Bayraktutan
- Academic Stroke, Mental Health & Clinical Neuroscience, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK.
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Hershenson R, Nardi-Agmon I, Leshem-Lev D, Kornowski R, Eisen A. The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease. Cardiovasc Diabetol 2024; 23:386. [PMID: 39468546 PMCID: PMC11520434 DOI: 10.1186/s12933-024-02466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/10/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. METHODS A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. RESULTS Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). CONCLUSIONS Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.
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Affiliation(s)
- Roy Hershenson
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel.
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Inbar Nardi-Agmon
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Dorit Leshem-Lev
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Felsenstein Medical Research Center, Rabin Medical Center, Petah Tikva, Israel
| | - Ran Kornowski
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Alon Eisen
- Department of Cardiology, Rabin Medical Center, 39 Jabotinsky St., 49100, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Xiong W, Zhang X, Hu J, Zou X, Huang H, Qu W, Cai S, Li C, Wei Y, Zhong X, Cai Z, Huang Z. PF-PEG@ASIV-EXO Hydrogel Accelerates Diabetic Wound Healing by Ferroptosis Resistance and Promoting Angiogenesis. ACS Biomater Sci Eng 2024; 10:6263-6285. [PMID: 39311841 DOI: 10.1021/acsbiomaterials.4c00692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Astragaloside IV (ASIV) promotes the proliferation of key cells, endothelial progenitor cells (EPCs), during the wound healing process, while exosomes and hydrogels are ideal drug delivery carriers. This study aims to explore the mechanism of action of the "ROS-responsive hydrogel-engineered EPCs-targeted exosomes" composite ASIV delivery system (PF-PEG@ASIV-EXO) in diabetic wound healing. Surface markers of EPCs and PF-PEG@ASIV-EXO were detected separately. The degradation rate of PF-PEG@ASIV-EXO was assessed after coculturing with human dermal fibroblasts (HDF), immortalized human epidermal cells (HaCAT), and human EPCs, and the biocompatibility of EPCs and PF-PEG@ASIV-EXO was evaluated through exosome release and uptake. The effects of PF-PEG@ASIV-EXO on the viability, angiogenesis, ferroptosis, and mitochondria of high-glucose-treated EPCs (HS-EPCs) were investigated. A diabetic wound rat model was established, and the effects of PF-PEG@ASIV-EXO on diabetic wounds were evaluated through HE and Masson staining, as well as levels of VWF, CD31, and ferroptosis in the skin. EPCs were successfully isolated, and PF-PEG@ASIV-EXO was successfully constructed. PF-PEG@ASIV-EXO exhibited a high degradation rate within EPCs, and both EPCs and PF-PEG@ASIV-EXO showed good biocompatibility. PF-PEG@ASIV-EXO promoted the vitality and angiogenesis of EPCs, inhibited ferroptosis, and mitigated mitochondrial damage. Following treatment with PF-PEG@ASIV-EXO, the healing of diabetic rat skin accelerated, accompanied by elevated expression of VWF and CD31, and reduced ferroptosis levels. PF-PEG@ASIV-EXO hydrogel inhibits ferroptosis, promotes angiogenesis, and thereby accelerates the healing of diabetic wounds.
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Affiliation(s)
- Wu Xiong
- Department of Burns and Plastic Surgery, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
| | - Xi Zhang
- Clinical Medical School of Hunan University of Chinese Medicine, Hunan Brain Hospital, Changsha 410007, China
| | - Jinhui Hu
- Department of Breast Surgery, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
| | - Xiaoling Zou
- Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
| | - Hongyu Huang
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Wenjing Qu
- Department of Endocrinology, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, China
| | - Shimin Cai
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Chengyu Li
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Yang Wei
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xingxing Zhong
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Zhaoyang Cai
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Zixin Huang
- College of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208, China
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11
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Huang L, Ye Y, Sun Y, Zhou Z, Deng T, Liu Y, Wu R, Wang K, Yao C. LncRNA H19/miR-107 regulates endothelial progenitor cell pyroptosis and promotes flow recovery of lower extremity ischemia through targeting FADD. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167323. [PMID: 38925483 DOI: 10.1016/j.bbadis.2024.167323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 06/02/2024] [Accepted: 06/21/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Peripheral artery disease (PAD) is an ischemic disease with a rising incidence worldwide. The lncRNA H19 (H19) is enriched in endothelial progenitor cells (EPCs), and transplantation of pyroptosis-resistant H19-overexpressed EPCs (oe-H19-EPCs) may promote vasculogenesis and blood flow recovery in PAD, especially with critical limb ischemia (CLI). METHODS EPCs isolated from human peripheral blood was characterized using immunofluorescence and flow cytometry. Cell proliferation was determined with CCK8 and EdU assays. Cell migration was assessed by Transwell and wound healing assays. The angiogenic potential was evaluated using tube formation assay. The pyroptosis pathway-related protein in EPCs was detected by western blot. The binding sites of H19 and FADD on miR-107 were analyzed using Luciferase assays. In vivo, oe-H19-EPCs were transplanted into a mouse ischemic limb model, and blood flow was detected by laser Doppler imaging. The transcriptional landscape behind the therapeutic effects of oe-H19-EPCs on ischemic limbs were examined with whole transcriptome sequencing. RESULTS Overexpression of H19 in EPCs led to an increase in proliferation, migration, and tube formation abilities. These effects were mediated through pyroptosis pathway, which is regulated by the H19/miR-107/FADD axis. Transplantation of oe-H19-EPCs in a mouse ischemic limb model promoted vasculogenesis and blood flow recovery. Whole transcriptome sequencing indicated significant activation of vasculogenesis pathway in the ischemic limbs following treatment with oe-H19-EPCs. CONCLUSIONS Overexpression of H19 increases FADD level by competitively binding to miR-107, leading to enhanced proliferation, migration, vasculogenesis, and inhibition of pyroptosis in EPCs. These effects ultimately promote the recovery of blood flow in CLI.
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Affiliation(s)
- Lin Huang
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yanchen Ye
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yunhao Sun
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Zhihao Zhou
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Tang Deng
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Yunyan Liu
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Ridong Wu
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
| | - Kangjie Wang
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
| | - Chen Yao
- Division of Vascular Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510800, China; National-Guangdong Joint Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
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12
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Gold DA, Sandesara PB, Kindya B, Gold ME, Jain V, Vatsa N, Desai SR, Yadalam A, Razavi A, Elhage Hassan M, Ko YA, Liu C, Alkhoder A, Rahbar A, Hossain MS, Waller EK, Jaber WA, Nicholson WJ, Quyyumi AA. Circulating Progenitor Cells and Coronary Collaterals in Chronic Total Occlusion. Int J Cardiol 2024; 407:132104. [PMID: 38677332 PMCID: PMC11559591 DOI: 10.1016/j.ijcard.2024.132104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND The role of circulating progenitor cells (CPC) in collateral formation that occurs in the presence of chronic total occlusions (CTO) of a coronary artery is not well established. In stable patients with a CTO, we investigated whether CPC levels are associated with (a) collateral development and (b) ischemic burden, as measured by circulating high sensitivity troponin-I (hsTn-I) levels. METHODS CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34 and both CD34 and CD133 epitopes. The association between CPC counts and both Rentrop collateral grade (0, 1, 2, or 3) and hsTn-I levels were evaluated using multivariate regression analysis, after adjusting for demographic and clinical characteristics. RESULTS In 89 patients (age 65.5, 72% male, 27% Black), a higher CPC count was positively associated with a higher Rentrop collateral grade; [CD34+ adjusted odds ratio (OR) 1.49 95% confidence interval (CI) (0.95, 2.34) P = 0.082] and [CD34+/CD133+ OR 1.57 95% CI (1.05, 2.36) P = 0.028]. Every doubling of CPC counts was also associated with lower hsTn-I levels [CD34+ β -0.35 95% CI (-0.49, -0.15) P = 0.002] and [CD34+/CD133+ β -0.27 95% CI (-0.43, -0.08) P = 0.009] after adjustment. CONCLUSION Individuals with higher CPC counts have greater collateral development and lower ischemic burden in the presence of a CTO.
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Affiliation(s)
- Daniel A Gold
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Pratik B Sandesara
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Bryan Kindya
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Matthew E Gold
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Vardhmaan Jain
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Nishant Vatsa
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Shivang R Desai
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Adithya Yadalam
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Alexander Razavi
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Malika Elhage Hassan
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Yi-An Ko
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Chang Liu
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Ayman Alkhoder
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Alireza Rahbar
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Mohammad S Hossain
- Division of Hematology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Edmund K Waller
- Division of Hematology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Wissam A Jaber
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - William J Nicholson
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Arshed A Quyyumi
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
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13
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Bajaj G, Singh V, Sagar P, Gupta R, Singhal NK. Phosphoenolpyruvate carboxykinase-1 targeted siRNA promotes wound healing in type 2 diabetic mice by restoring glucose homeostasis. Int J Biol Macromol 2024; 270:132504. [PMID: 38772464 DOI: 10.1016/j.ijbiomac.2024.132504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/02/2024] [Accepted: 05/17/2024] [Indexed: 05/23/2024]
Abstract
It is well-accepted that the liver plays a vital role in the metabolism of glucose and its homeostasis. Dysregulated hepatic glucose production and utilization, leads to type 2 diabetes (T2DM). In the current study, RNA sequencing and qRT-PCR analysis of nanoformulation-treated T2DM mice (TGthr group) revealed beneficial crosstalk of PCK-1 silencing with other pathways involved in T2DM. The comparison of precise genetic expression profiles of the different experimental groups showed significantly improved hepatic glucose, fatty acid metabolism and several other T2DM-associated crucial markers after the nanoformulation treatment. As a result of these improvements, we observed a significant acceleration in wound healing and improved insulin signaling in vascular endothelial cells in the TGthr group as compared to the T2DM group. Enhanced phosphorylation of PI3K/Akt pathway proteins in the TGthr group resulted in increased angiogenesis as observed by the increased expression of endothelial cell markers (CD31, CD34) thereby improving endothelial dysfunctions in the TGthr group. Additionally, therapeutic nanoformulation has been observed to improve the inflammatory cytokine profile in the TGthr group. Overall, our results demonstrated that the synthesized therapeutic nanoformulation referred to as GPR8:PCK-1siRNA holds the potential in ameliorating hyperglycemia-associated complications such as delayed wound healing in diabetes.
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Affiliation(s)
- Geetika Bajaj
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India; Department of Biotechnology, Panjab University, Sector 25, Chandigarh 160014, India
| | - Vishal Singh
- National Institute for Implementation Research on Non-Communicable Diseases, Jodhpur 342005, India
| | - Poonam Sagar
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Ritika Gupta
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India
| | - Nitin Kumar Singhal
- National Agri-Food Biotechnology Institute (NABI), Sector-81, S.A.S Nagar, Mohali 140306, Punjab, India.
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14
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Popa MA, Mihai CM, Șuică VI, Antohe F, Dubey RK, Leeners B, Simionescu M. Dihydrotestosterone Augments the Angiogenic and Migratory Potential of Human Endothelial Progenitor Cells by an Androgen Receptor-Dependent Mechanism. Int J Mol Sci 2024; 25:4862. [PMID: 38732080 PMCID: PMC11084206 DOI: 10.3390/ijms25094862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
Endothelial progenitor cells (EPCs) play a critical role in cardiovascular regeneration. Enhancement of their native properties would be highly beneficial to ensuring the proper functioning of the cardiovascular system. As androgens have a positive effect on the cardiovascular system, we hypothesized that dihydrotestosterone (DHT) could also influence EPC-mediated repair processes. To evaluate this hypothesis, we investigated the effects of DHT on cultured human EPCs' proliferation, viability, morphology, migration, angiogenesis, gene and protein expression, and ability to integrate into cardiac tissue. The results showed that DHT at different concentrations had no cytotoxic effect on EPCs, significantly enhanced the cell proliferation and viability and induces fast, androgen-receptor-dependent formation of capillary-like structures. DHT treatment of EPCs regulated gene expression of androgen receptors and the genes and proteins involved in cell migration and angiogenesis. Importantly, DHT stimulation promoted EPC migration and the cells' ability to adhere and integrate into murine cardiac slices, suggesting it has a role in promoting tissue regeneration. Mass spectrometry analysis further highlighted the impact of DHT on EPCs' functioning. In conclusion, DHT increases the proliferation, migration, and androgen-receptor-dependent angiogenesis of EPCs; enhances the cells' secretion of key factors involved in angiogenesis; and significantly potentiates cellular integration into heart tissue. The data offer support for potential therapeutic applications of DHT in cardiovascular regeneration and repair processes.
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Affiliation(s)
- Mirel Adrian Popa
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (M.A.P.); (C.M.M.); (V.I.Ș.); (F.A.)
| | - Cristina Maria Mihai
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (M.A.P.); (C.M.M.); (V.I.Ș.); (F.A.)
| | - Viorel Iulian Șuică
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (M.A.P.); (C.M.M.); (V.I.Ș.); (F.A.)
| | - Felicia Antohe
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (M.A.P.); (C.M.M.); (V.I.Ș.); (F.A.)
| | - Raghvendra K. Dubey
- Department for Reproductive Endocrinology, University Zurich, 8006 Zürich, Switzerland; (R.K.D.); (B.L.)
| | - Brigitte Leeners
- Department for Reproductive Endocrinology, University Zurich, 8006 Zürich, Switzerland; (R.K.D.); (B.L.)
| | - Maya Simionescu
- Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania; (M.A.P.); (C.M.M.); (V.I.Ș.); (F.A.)
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15
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Ng CY, Cheung C. Origins and functional differences of blood endothelial cells. Semin Cell Dev Biol 2024; 155:23-29. [PMID: 37202277 DOI: 10.1016/j.semcdb.2023.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/05/2023] [Accepted: 05/05/2023] [Indexed: 05/20/2023]
Abstract
The interests in blood endothelial cells arise from their therapeutic potential in vascular repair and regeneration. Our understanding of blood endothelial cells that exist in the circulation has been evolving significantly from the original concept of endothelial progenitor cells. Many studies have uncovered heterogeneities of blood endothelial subtypes where some cells express both endothelial and hematopoietic antigens, and others possess either mature or immature endothelial markers. Due to the lack of definitive cell marker identities, there have been momentums in the field to adopt a technical-oriented labeling system based on the cells' involvement in postnatal neovascularization and cell culture derivatives. Our review streamlines nomenclatures for blood endothelial subtypes and standardizes understanding of their functional differences. Broadly, we will discuss about myeloid angiogenic cells (MACs), endothelial colony-forming cells (ECFCs), blood outgrowth endothelial cells (BOECs) and circulating endothelial cells (CECs). The strategic location of blood endothelial cells confers them essential roles in supporting physiological processes. MACs exert angiogenic effects through paracrine mechanisms, while ECFCs are recruited to sites of vascular injury to participate directly in new vessel formation. BOECs are an in vitro derivative of ECFCs. CECs are shed into the bloodstream from damaged vessels, hence reflective of endothelial dysfunction. With clarity on the functional attributes of blood endothelial subtypes, we present recent advances in their applications in disease modelling, along with serving as biomarkers of vascular tissue homeostasis.
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Affiliation(s)
- Chun-Yi Ng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
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16
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Bi M, Yang K, Yu T, Wu G, Li Q. Cell-based mechanisms and strategies of co-culture system both in vivo and vitro for bone tissue engineering. Biomed Pharmacother 2023; 169:115907. [PMID: 37984308 DOI: 10.1016/j.biopha.2023.115907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 11/15/2023] [Accepted: 11/16/2023] [Indexed: 11/22/2023] Open
Abstract
The lack of a functional vascular supply has been identified as a major challenge limiting the clinical introduction of stem cell-based bone tissue engineering (BTE) for the repair of large-volume bone defects (LVBD). Various approaches have been explored to improve the vascular supply in tissue-engineered constructs, and the development of strategies that could effectively induce the establishment of a functional vascular supply has become a major goal of BTE research. One of the state-of-the-art methods is to incorporate both angiogenic and osteogenic cells in co-culture systems. This review clarifies the key concepts involved, summarises the cell types and models used to date, and systematically evaluates their performance. We also discuss the cell-to-cell communication between these two cell types and the strategies explored in BTE constructs with angiogenic and osteogenic cells to optimise their functions. In addition, we outline unresolved issues and remaining obstacles that need to be overcome for further development in this field and eventual successful repair of LVBD.
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Affiliation(s)
- Mengning Bi
- Department of Prosthetic Dentistry, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China; Department of Orthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology Shanghai, China
| | - Kaiwen Yang
- Department of Prosthetic Dentistry, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China; Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Stomatology &Shanghai Research Institute of Stomatology; National Clinical Research Center of Stomatology, Shanghai, China
| | - Tao Yu
- Department of Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Gang Wu
- Department of Oral and Maxillofacial Surgery/Pathology, Amsterdam UMC and Academic Center for Dentistry Amsterdam (ACTA), Vrije Universiteit Amsterdam (VU), Amsterdam Movement Science (AMS), Amsterdam, the Netherlands; Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam (UvA) and Vrije Universiteit Amsterdam (VU), Amsterdam, the Netherlands.
| | - Qiong Li
- Department of Prosthetic Dentistry, Stomatological Hospital and Dental School of Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China.
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17
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Zhao H, Fang L, Chen Y, Ma Y, Zhou Q, Xu S, Shuai Z, Cai G, Pan F. Could endothelial progenitor cells complement the diagnosis of inflammatory arthritis? A systematic review and meta-analysis. J Investig Med 2023; 71:929-940. [PMID: 37381710 DOI: 10.1177/10815589231182320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/30/2023]
Abstract
The objective of this meta-analysis was to systematically review existing evidence and evaluate variations in levels of circulating endothelial progenitor cells (EPCs) among individuals with psoriatic arthritis (PsA), juvenile idiopathic arthritis (JIA), and rheumatoid arthritis (RA). Relevant studies were identified through database searches, and 20 records were enrolled. We used the fixed-effect model or random-effect model to estimate the pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) in circulating EPC levels between inflammatory arthritis patients and controls. The results showed that circulating EPC levels differed among subtypes of inflammatory arthritis, with significantly lower levels in patients with RA (SMD = -0.848, 95% CI = -1.474 to -0.221, p = 0.008) and PsA (SMD = -0.791, 95% CI = -1.136 to -0.446, p < 0.001). However, no statistically significant difference was found in circulating EPC levels between patients with JIA and controls (SMD = -1.160, 95% CI = -2.578 to 0.259, p = 0.109). Subgroup analyses suggested that in patients with RA, circulating EPC levels were influenced by age, disease activity, and duration. Although many studies have investigated circulating EPC levels in patients with inflammatory arthritis, the results have been inconsistent. This meta-analysis offers a comprehensive overview of the existing evidence and emphasizes the association between levels of circulating EPCs and various types of arthritis. However, further research is needed to determine the specific mechanisms underlying the observed differences in EPC levels in different types of arthritis and to establish the clinical utility of this biomarker.
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Affiliation(s)
- Hui Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Lanlan Fang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Yuting Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Yubo Ma
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Qiang Zhou
- Department of Clinical Laboratory, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Shengqian Xu
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zongwen Shuai
- Department of Rheumatism and Immunity, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guoqi Cai
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- The Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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Benítez-Camacho J, Ballesteros A, Beltrán-Camacho L, Rojas-Torres M, Rosal-Vela A, Jimenez-Palomares M, Sanchez-Gomar I, Durán-Ruiz MC. Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications. Stem Cell Res Ther 2023; 14:324. [PMID: 37950274 PMCID: PMC10636846 DOI: 10.1186/s13287-023-03537-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 10/13/2023] [Indexed: 11/12/2023] Open
Abstract
Diabetes mellitus (DM) constitutes a chronic metabolic disease characterized by elevated levels of blood glucose which can also lead to the so-called diabetic vascular complications (DVCs), responsible for most of the morbidity, hospitalizations and death registered in these patients. Currently, different approaches to prevent or reduce DM and its DVCs have focused on reducing blood sugar levels, cholesterol management or even changes in lifestyle habits. However, even the strictest glycaemic control strategies are not always sufficient to prevent the development of DVCs, which reflects the need to identify reliable biomarkers capable of predicting further vascular complications in diabetic patients. Endothelial progenitor cells (EPCs), widely known for their potential applications in cell therapy due to their regenerative properties, may be used as differential markers in DVCs, considering that the number and functionality of these cells are affected under the pathological environments related to DM. Besides, drugs commonly used with DM patients may influence the level or behaviour of EPCs as a pleiotropic effect that could finally be decisive in the prognosis of the disease. In the current review, we have analysed the relationship between diabetes and DVCs, focusing on the potential use of EPCs as biomarkers of diabetes progression towards the development of major vascular complications. Moreover, the effects of different drugs on the number and function of EPCs have been also addressed.
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Affiliation(s)
- Josefa Benítez-Camacho
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Antonio Ballesteros
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
| | - Lucía Beltrán-Camacho
- Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
- Cell Biology, Physiology and Immunology Department, Córdoba University, Córdoba, Spain
| | - Marta Rojas-Torres
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Antonio Rosal-Vela
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Margarita Jimenez-Palomares
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Ismael Sanchez-Gomar
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain
| | - Mª Carmen Durán-Ruiz
- Biomedicine, Biotechnology and Public Health Department, Science Faculty, Cádiz University, Torre Sur. Avda. República Saharaui S/N, Polígono Río San Pedro, Puerto Real, 11519, Cádiz, Spain.
- Biomedical Research and Innovation Institute of Cadiz (INIBICA), Cádiz, Spain.
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Lee J, Sternberg H, Bignone PA, Murai J, Malik NN, West MD, Larocca D. Clonal and Scalable Endothelial Progenitor Cell Lines from Human Pluripotent Stem Cells. Biomedicines 2023; 11:2777. [PMID: 37893151 PMCID: PMC10604251 DOI: 10.3390/biomedicines11102777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/02/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Human pluripotent stem cells (hPSCs) can be used as a renewable source of endothelial cells for treating cardiovascular disease and other ischemic conditions. Here, we present the derivation and characterization of a panel of distinct clonal embryonic endothelial progenitor cells (eEPCs) lines that were differentiated from human embryonic stem cells (hESCs). The hESC line, ESI-017, was first partially differentiated to produce candidate cultures from which eEPCs were cloned. Endothelial cell identity was assessed by transcriptomic analysis, cell surface marker expression, immunocytochemical marker analysis, and functional analysis of cells and exosomes using vascular network forming assays. The transcriptome of the eEPC lines was compared to various adult endothelial lines as well as various non-endothelial cells including both adult and embryonic origins. This resulted in a variety of distinct cell lines with functional properties of endothelial cells and strong transcriptomic similarity to adult endothelial primary cell lines. The eEPC lines, however, were distinguished from adult endothelium by their novel pattern of embryonic gene expression. We demonstrated eEPC line scalability of up to 80 population doublings (pd) and stable long-term expansion of over 50 pd with stable angiogenic properties at late passage. Taken together, these data support the finding that hESC-derived clonal eEPC lines are a potential source of scalable therapeutic cells and cell products for treating cardiovascular disease. These eEPC lines offer a highly promising resource for the development of further preclinical studies aimed at therapeutic interventions.
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Affiliation(s)
- Jieun Lee
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Alameda, CA 94501, USA; (H.S.); (P.A.B.); (N.N.M.); (D.L.)
| | - Hal Sternberg
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Alameda, CA 94501, USA; (H.S.); (P.A.B.); (N.N.M.); (D.L.)
| | - Paola A. Bignone
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Alameda, CA 94501, USA; (H.S.); (P.A.B.); (N.N.M.); (D.L.)
| | - James Murai
- Advanced Cell Technology, Alameda, CA 94502, USA
| | - Nafees N. Malik
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Alameda, CA 94501, USA; (H.S.); (P.A.B.); (N.N.M.); (D.L.)
| | | | - Dana Larocca
- AgeX Therapeutics, Inc., 1101 Marina Village Parkway, Alameda, CA 94501, USA; (H.S.); (P.A.B.); (N.N.M.); (D.L.)
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Xia X, Li G, Dong Q, Wang JW, Kim JE. Endothelial progenitor cells as an emerging cardiovascular risk factor in the field of food and nutrition research: advances and challenges. Crit Rev Food Sci Nutr 2023; 64:12166-12183. [PMID: 37599627 DOI: 10.1080/10408398.2023.2248506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2023]
Abstract
Dietary modifications can help prevent many cardiovascular disease (CVD) events. Endothelial progenitor cells (EPCs) actively contribute to cardiovascular system maintenance and could function as surrogate markers for evaluating improvement in cardiovascular health resulting from nutritional interventions. This review summarizes the latest research progress on the impact of food and nutrients on EPCs, drawing on evidence from human, animal, and in vitro studies. Additionally, current trends and challenges faced in the field are highlighted. Findings from studies examining cells as EPCs are generally consistent, demonstrating that a healthy diet, such as the Mediterranean diet or a supervised diet for overweight people, specific foods like olive oil, fruit, vegetables, red wine, tea, chia, and nutraceuticals, and certain nutrients such as polyphenols, unsaturated fats, inorganic nitrate, and vitamins, generally promote higher EPC numbers and enhanced EPC function. Conversely, an unhealthy diet, such as one high in sugar substitutes, salt, or fructose, impairs EPC function. Research on outgrowth EPCs has revealed that various pathways are involved in the modulation effects of food and nutrients. The potential of EPCs as a biomarker for assessing the effectiveness of nutritional interventions in preventing CVDs is immense, while further clarification on definition and characterization of EPCs is required.
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Affiliation(s)
- Xuejuan Xia
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
- Department of Food Science & Technology, Faculty of Science, National University of Singapore, Singapore
| | - Guannan Li
- State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass, Southwest University, Chongqing, China
| | - Qingli Dong
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cardiovascular Research Institute, National University Health Systems, Centre for Translational Medicine, Singapore
- Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jung Eun Kim
- Department of Food Science & Technology, Faculty of Science, National University of Singapore, Singapore
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Lim HJ, Jang WB, Rethineswaran VK, Choi J, Lee EJ, Park S, Jeong Y, Ha JS, Yun J, Choi YJ, Hong YJ, Kwon SM. StemRegenin-1 Attenuates Endothelial Progenitor Cell Senescence by Regulating the AhR Pathway-Mediated CYP1A1 and ROS Generation. Cells 2023; 12:2005. [PMID: 37566085 PMCID: PMC10417434 DOI: 10.3390/cells12152005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/04/2023] [Accepted: 08/04/2023] [Indexed: 08/12/2023] Open
Abstract
Endothelial progenitor cell (EPC)-based stem cell therapy is a promising therapeutic strategy for vascular diseases. However, continuous in vitro expansion for clinical studies induces the loss of EPC functionality due to aging. In this study, we investigated the effects of StemRegenin-1 (SR-1), an antagonist of aryl hydrocarbon receptor (AhR), on replicative senescence in EPCs. We found that SR-1 maintained the expression of EPC surface markers, including stem cell markers, such as CD34, c-Kit, and CXCR4. Moreover, SR-1 long-term-treated EPCs preserved their characteristics. Subsequently, we demonstrated that SR-1 showed that aging phenotypes were reduced through senescence-associated phenotypes, such as β-galactosidase activity, SMP30, p21, p53, and senescence-associated secretory phenotype (SASP). SR-1 treatment also increased the proliferation, migration, and tube-forming capacity of senescent EPCs. SR-1 inhibited the AhR-mediated cytochrome P450 (CYP)1A1 expression, reactive-oxygen species (ROS) production, and DNA damage under oxidative stress conditions in EPCs. Furthermore, as a result of CYP1A1-induced ROS inhibition, it was found that accumulated intracellular ROS were decreased in senescent EPCs. Finally, an in vivo Matrigel plug assay demonstrated drastically enhanced blood vessel formation via SR-1-treated EPCs. In summary, our results suggest that SR-1 contributes to the protection of EPCs against cellular senescence.
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Affiliation(s)
- Hye Ji Lim
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Woong Bi Jang
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Vinoth Kumar Rethineswaran
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jaewoo Choi
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Eun Ji Lee
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Sangmi Park
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Yeoreum Jeong
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jong Seong Ha
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Jisoo Yun
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
| | - Young Jin Choi
- Department of Hemato-Oncology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea;
| | - Young Joon Hong
- Department of Cardiology, Chonnam National University School of Medicine, Chonnam National University Hospital, Gwangju 61469, Republic of Korea
| | - Sang-Mo Kwon
- Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; (H.J.L.); (W.B.J.); (V.K.R.); (J.C.); (E.J.L.); (S.P.); (Y.J.); (J.S.H.); (J.Y.)
- Convergence Stem Cell Research Center, Pusan National University, Yangsan 50612, Republic of Korea
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Efstathiou N, Soubasi V, Koliakos G, Kantziou K, Kyriazis G, Slavakis A, Dermentzoglou V, Michalettou I, Drosou-Agakidou V. Beyond brain injury biomarkers: chemoattractants and circulating progenitor cells as biomarkers of endogenous rehabilitation effort in preterm neonates with encephalopathy. Front Pediatr 2023; 11:1151787. [PMID: 37292373 PMCID: PMC10244884 DOI: 10.3389/fped.2023.1151787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 04/26/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction Preclinical work and studies in adults have shown that endogenous regeneration efforts that involve mobilization of progenitor cells take place after brain injury. However, kinetics of endogenous circulating progenitor cells (CPCs) in preterm neonates is not well described, particularly their possible role regarding brain injury and regeneration. We aimed to assess the kinetics of CPCs in neonates with encephalopathy of prematurity in relation to brain injury biomarkers, chemoattractants and relevant antenatal and postanal clinical factors, in an effort to outline the related pathophysiology. Materials and methods 47 preterm neonates (of 28-33 weeks GA) were enrolled: 31 newborns with no or minimal brain injury (grade I IVH) and 16 prematures with encephalopathy (grade III or IV IVH, PVL or infarct). Peripheral blood samples obtained on days 1, 3, 9, 18 and 45 after birth were analyzed using flow cytometry, focusing on EPCs (early and late Endothelial Progenitor Cells), HSCs (Hematopoietic Stem Cells) and VSELs (Very Small Embryonic-Like Stem Cells). At the same time-points serum levels of S100B, Neuron-specific Enolase (NSE), Erythropoietin (EPO), Insulin-like growth factor-1 (IGF-1) and SDF-1 were also measured. Neonates were assessed postnatally with brain MRI, and with Bayley III developmental test at 2 years of corrected age. Results Preterms with brain injury proved to have significant increase of S100B and NSE, followed by increase of EPO and enhanced mobilization mainly of HSCs, eEPCs and lEPCs. IGF-1 was rather decreased in this group of neonates. IGF-1 and most CPCs were intense decreased in cases of antenatal or postnatal inflammation. S100B and NSE correlated with neuroimaging and language scale in Bayley III test, providing good prognostic ability. Conclusion The observed pattern of CPCs' mobilization and its association with neurotrophic factors following preterm brain injury indicate the existence of an endogenous brain regeneration process. Kinetics of different biomarkers and associations with clinical factors contribute to the understanding of the related pathophysiology and might help to early discriminate neonates with adverse outcome. Timely appropriate enhancement of the endogenous regeneration effort, when it is suppressed and insufficient, using neurotrophic factors and exogenous progenitor cells might be a powerful therapeutic strategy in the future to restore brain damage and improve the neurodevelopmental outcome in premature infants with brain injury.
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Affiliation(s)
- N. Efstathiou
- 1st Neonatal Department and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - V. Soubasi
- 2nd Neonatal Department and NICU, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - G. Koliakos
- Biochemistry Department, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - K. Kantziou
- 1st Neonatal Department and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - G. Kyriazis
- Immunology Laboratory, Pulmonology Department, Papanikolaou General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A. Slavakis
- Biochemistry Department, Hippokration General Hospital, Thessaloniki, Greece
| | - V. Dermentzoglou
- Child Radiologist, Radiology Department, Agia Sofia Pediatric Hospital, Athens, Greece
| | - I. Michalettou
- Child Occupational Τherapist, Hippokration General Hospital, Thessaloniki, Greece
| | - V. Drosou-Agakidou
- 1st Neonatal Department and NICU, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Arikan G, Turan V, Kurekeken M, Goksoy HS, Dogusan Z. Autologous bone marrow-derived nucleated cell (aBMNC) transplantation improves endometrial function in patients with refractory Asherman's syndrome or with thin and dysfunctional endometrium. J Assist Reprod Genet 2023; 40:1163-1171. [PMID: 36662355 PMCID: PMC10239402 DOI: 10.1007/s10815-023-02727-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 01/11/2023] [Indexed: 01/21/2023] Open
Abstract
PURPOSE The purpose was to evaluate the effect of intrauterine injection of aBMNC on the endometrial function in patients with refractory Asherman's syndrome (AS) and/or thin and dysfunctional endometrium (TE). STUDY DESIGN This is a prospective, experimental, non-controlled study MATERIAL AND METHODS: The study was carried out between December 2018 and December 2020 on 20 patients, who were of age < 45 years and had oligo/amenorrhea and primary infertility due to refractory AS and/or TE. One hundred ml BM was extracted. aBMNC cells were separated according to generic volume reduction protocol by using the Cell Separation System SEPAX S-100 table top centrifuge system. We have evaluated CD34+, mononuclear cell (MNC), and total nucleated cell (TNC) counts. The transplantation aBMNC was performed by two intrauterine injections at an interval of one week, transvaginally into the endometrial-myometrial junction by an ovum aspiration needle. Midcyclic endometrial thickness (ET) and gestations after transplantation were evaluated. RESULTS The mean TNC, MNC, and CD34+ cells were 11.55 ± 4.7 × 108, 3.85 ± 2.01 × 108, and 7.00 ± 2.88 × 106 at first injection, respectively, and 6.85 ± 2.67 × 108, 2.04 ± 1.11 × 108, and 3.44 ± 1.31 × 106 at second injection, respectively. The maximum posttransplantation ET was significantly higher than the maximum pretransplantation ET: 2.97 ± 0.48 vs. 5.76 ± 1.19 (mean ± standard deviation, p < 0.01). Twelve patients had frozen-thaw embryo transfers after the study. In 42% (n = 5 of 12) of the patients, pregnancy was achieved. One of the five patients delivered a healthy baby at term. CONCLUSIONS Autologous BMNC transplantation may contribute to endometrial function in patients with AS and/or TE.
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Affiliation(s)
- Gurkan Arikan
- Department of Obstetrics and Gynecology, Altinbaş University, Medical Park Bahçelievler Hospital, Kültür Sok. No. 1 E5 Yolu, 34160 Bahçelievler, Istanbul, Turkey.
| | - Volkan Turan
- Department of Obstetrics and Gynecology, Altinbaş University, Medical Park Bahçelievler Hospital, Kültür Sok. No. 1 E5 Yolu, 34160 Bahçelievler, Istanbul, Turkey
- Istanbul Health and Technology University, Faculty of Medicine, Istanbul, Turkey
| | - Meryem Kurekeken
- Department of Obstetrics and Gynecology, Altinbaş University, Medical Park Bahçelievler Hospital, Kültür Sok. No. 1 E5 Yolu, 34160 Bahçelievler, Istanbul, Turkey
- Reproductive Medicine and Infertility Center, Hisar Intercontinental Hospital, Istanbul, Turkey
| | - Hasan Sami Goksoy
- Department of Hematology, Yeni Yuzyil University Gaziosmanpaşa Hospital, Istanbul, Turkey
| | - Zeynep Dogusan
- Bone Marrow Transplantation Center, Yeni Yuzyil University Gaziosmanpaşa Hospital, Istanbul, Turkey
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Meyer N, Vu TH, Brodowski L, Schröder-Heurich B, von Kaisenberg C, von Versen-Höynck F. Fetal endothelial colony-forming cell impairment after maternal kidney transplantation. Pediatr Res 2023; 93:810-817. [PMID: 35732823 PMCID: PMC10033415 DOI: 10.1038/s41390-022-02165-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 05/17/2022] [Accepted: 06/04/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Successful pregnancies are nowadays possible after kidney transplantation but are associated with a higher incidence of maternal and fetal complications. Immunosuppressive therapy causes cardiovascular side effects but must be maintained during pregnancy. Little is known about the consequences of maternal kidney transplantation on offspring's endothelial health. Endothelial colony forming cells (ECFCs) represent a highly proliferative subtype of endothelial progenitor cells and are crucial for vascular homeostasis, repair and neovascularization. Therefore, we investigated whether maternal kidney transplantation affects fetal ECFCs' characteristics. METHODS ECFCs were isolated from umbilical cord blood of uncomplicated and post-kidney-transplant pregnancies and analyzed for their functional abilities with proliferation, cell migration, centrosome orientation and angiogenesis assays. Further, ECFCs from uncomplicated pregnancies were exposed to either umbilical cord serum from uncomplicated or post-kidney-transplant pregnancies. RESULTS Post-kidney-transplant ECFCs showed significantly less proliferation, less migration and less angiogenesis compared to control ECFCs. The presence of post-kidney-transplant umbilical cord serum led to similar functional aberrations of ECFCs from uncomplicated pregnancies. CONCLUSIONS These pilot data demonstrate differences in ECFCs' biological characteristics in offspring of women after kidney transplantation. Further studies are needed to monitor offspring's long-term cardiovascular development and to assess possible causal relationships with immunosuppressants, uremia and maternal cardiovascular alterations. IMPACT Pregnancy after kidney transplantation has become more common in the past years but is associated with higher complications for mother and offspring. Little is known of the impact of maternal kidney transplantation and the mandatory immunosuppressive therapy on offspring vascular development. In this study we are the first to address and detect an impairment of endothelial progenitor cell function in offspring of kidney-transplanted mothers. Serum from post-transplant pregnancies also causes negative effects on ECFCs' function. Clinical studies should focus on long-term monitoring of offspring's cardiovascular health.
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Affiliation(s)
- Nadia Meyer
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
| | - Thu Huong Vu
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
| | - Lars Brodowski
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
| | - Bianca Schröder-Heurich
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
| | - Constantin von Kaisenberg
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany
| | - Frauke von Versen-Höynck
- Gynecology Research Unit, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany.
- Department of Obstetrics and Gynecology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625, Hannover, Germany.
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Wiessman M, Kheifets M, Schamroth Pravda N, Leshem Lev D, Ziv E, Kornowski R, Spectre G, Perl L. Thrombogenicity and endothelial progenitor cells function during Acute myocardial infarction - comparison of Prasugrel versus Ticagrelor. J Thromb Thrombolysis 2023; 55:407-414. [PMID: 36598739 PMCID: PMC9811044 DOI: 10.1007/s11239-022-02759-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Thrombin generation (TG), platelet function and circulating endothelial progenitor cells (EPCs) have an important role in the pathophysiology of coronary artery disease (CAD). To date, the effect of novel P2Y12 inhibitors on these aspects has mostly been studied in the sub-acute phase following myocardial infarction. OBJECTIVES Comparing the effects of prasugrel and ticagrelor on TG and EPCs in the acute phase of ST-segment elevation myocardial infarction (STEMI). METHODS STEMI patients were randomized to either ticagrelor or prasugrel treatment. TG, platelet reactivity and EPCs were evaluated prior to P2Y12 inhibitor loading dose (T0), and one day following (T1). RESULTS Between December 2018 - July 2021, 83 consecutive STEMI patients were randomized to ticagrelor (N = 42) or prasugrel (N = 41) treatment. No differences were observed at T0 for all measurements. P2Y12 reactivity units (PRU) at T1 did not differ as well (prasugrel 13.2 [5.5-20.8] vs. ticagrelor 15.8 [4.0-26.3], p = 0.40). At T1, prasugrel was a significantly more potent TG inhibitor, with longer lag time to TG initiation (7.7 ± 7.5 vs. 3.9 ± 2.1 min, p < 0.01), longer time to peak (14.1 ± 12.6 vs. 8.3 ± 9.7 min, p = 0.03) and a lower endogenous thrombin potential (AUC 2186.1 ± 1123.1 vs. 3362.5 ± 2108.5 nM, p < 0.01). Furthermore, EPCs measured by percentage of cells expressing CD34 (2.6 ± 4.1 vs. 1.1 ± 1.1, p = 0.01) and CD133 (2.3 ± 1.8 vs. 1.4 ± 1.5, p = 0.01) and number of colony forming units (CFU, 2.1 ± 1.5 vs. 1.1 ± 1.0, p < 0.01) were significantly higher in the prasugrel group. CONCLUSION Among STEMI patients, prasugrel as compared to ticagrelor was associated with more potent TG inhibition and improved EPCs count and function.
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Affiliation(s)
- Maya Wiessman
- grid.413156.40000 0004 0575 344XDepartment of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Ze’ev Jabotinsky St, 4941492 Petach Tikva, Israel ,grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mark Kheifets
- grid.413156.40000 0004 0575 344XDepartment of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Ze’ev Jabotinsky St, 4941492 Petach Tikva, Israel ,grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Nili Schamroth Pravda
- grid.413156.40000 0004 0575 344XDepartment of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Ze’ev Jabotinsky St, 4941492 Petach Tikva, Israel ,grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dorit Leshem Lev
- grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ,grid.413156.40000 0004 0575 344XFelsenstein Research Center, Rabin Medical Center, Petah-Tikva, Israel
| | - Eti Ziv
- grid.413156.40000 0004 0575 344XThrombosis and Haemostasis Unit, Institute of Hematology, Rabin Medical Center, Beilinson Campus, Petah-Tikva, Israel
| | - Ran Kornowski
- grid.413156.40000 0004 0575 344XDepartment of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Ze’ev Jabotinsky St, 4941492 Petach Tikva, Israel ,grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ,grid.413156.40000 0004 0575 344XFelsenstein Research Center, Rabin Medical Center, Petah-Tikva, Israel
| | - Galia Spectre
- grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ,grid.413156.40000 0004 0575 344XThrombosis and Haemostasis Unit, Institute of Hematology, Rabin Medical Center, Beilinson Campus, Petah-Tikva, Israel
| | - Leor Perl
- grid.413156.40000 0004 0575 344XDepartment of Cardiology, Rabin Medical Center, Beilinson Campus, 39 Ze’ev Jabotinsky St, 4941492 Petach Tikva, Israel ,grid.12136.370000 0004 1937 0546The Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel ,grid.413156.40000 0004 0575 344XFelsenstein Research Center, Rabin Medical Center, Petah-Tikva, Israel
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The Long Telling Story of "Endothelial Progenitor Cells": Where Are We at Now? Cells 2022; 12:cells12010112. [PMID: 36611906 PMCID: PMC9819021 DOI: 10.3390/cells12010112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/21/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
Endothelial progenitor cells (EPCs): The name embodies years of research and clinical expectations, but where are we now? Do these cells really represent the El Dorado of regenerative medicine? Here, past and recent literature about this eclectic, still unknown and therefore fascinating cell population will be discussed. This review will take the reader through a temporal journey that, from the first discovery, will pass through years of research devoted to attempts at their definition and understanding their biology in health and disease, ending with the most recent evidence about their pathobiological role in cardiovascular disease and their recent applications in regenerative medicine.
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Guo J, Huang X, Dou L, Yan M, Shen T, Tang W, Li J. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 2022; 7:391. [PMID: 36522308 PMCID: PMC9755275 DOI: 10.1038/s41392-022-01251-0] [Citation(s) in RCA: 548] [Impact Index Per Article: 182.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/03/2022] [Accepted: 11/10/2022] [Indexed: 12/23/2022] Open
Abstract
Aging is a gradual and irreversible pathophysiological process. It presents with declines in tissue and cell functions and significant increases in the risks of various aging-related diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic diseases, musculoskeletal diseases, and immune system diseases. Although the development of modern medicine has promoted human health and greatly extended life expectancy, with the aging of society, a variety of chronic diseases have gradually become the most important causes of disability and death in elderly individuals. Current research on aging focuses on elucidating how various endogenous and exogenous stresses (such as genomic instability, telomere dysfunction, epigenetic alterations, loss of proteostasis, compromise of autophagy, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing) participate in the regulation of aging. Furthermore, thorough research on the pathogenesis of aging to identify interventions that promote health and longevity (such as caloric restriction, microbiota transplantation, and nutritional intervention) and clinical treatment methods for aging-related diseases (depletion of senescent cells, stem cell therapy, antioxidative and anti-inflammatory treatments, and hormone replacement therapy) could decrease the incidence and development of aging-related diseases and in turn promote healthy aging and longevity.
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Affiliation(s)
- Jun Guo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Xiuqing Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Lin Dou
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Mingjing Yan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Weiqing Tang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, 100730, China.
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Banovic M, Poglajen G, Vrtovec B, Ristic A. Contemporary Challenges of Regenerative Therapy in Patients with Ischemic and Non-Ischemic Heart Failure. J Cardiovasc Dev Dis 2022; 9:jcdd9120429. [PMID: 36547426 PMCID: PMC9783726 DOI: 10.3390/jcdd9120429] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/11/2022] [Accepted: 10/26/2022] [Indexed: 12/02/2022] Open
Abstract
It has now been almost 20 years since first clinical trials of stem cell therapy for heart repair were initiated. While initial preclinical data were promising and suggested that stem cells may be able to directly restore a diseased myocardium, this was never unequivocally confirmed in the clinical setting. Clinical trials of cell therapy did show the process to be feasible and safe. However, the clinical benefits of this treatment modality in patients with ischemic and non-ischemic heart failure have not been consistently confirmed. What is more, in the rapidly developing field of stem cell therapy in patients with heart failure, relevant questions regarding clinical trials' protocol streamlining, optimal patient selection, stem cell type and dose, and the mode of cell delivery remain largely unanswered. Recently, novel approaches to myocardial regeneration, including the use of pluripotent and allogeneic stem cells and cell-free therapeutic approaches, have been proposed. Thus, in this review, we aim to outline current knowledge and highlight contemporary challenges and dilemmas in clinical aspects of stem cell and regenerative therapy in patients with chronic ischemic and non-ischemic heart failure.
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Affiliation(s)
- Marko Banovic
- Cardiology Department, University Clinical Center of Serbia, 11000 Beograd, Serbia
- Belgrade Medical School, 11000 Belgrade, Serbia
- Correspondence: (M.B.); (G.P.)
| | - Gregor Poglajen
- Advanced Heart Failure and Transplantation Center, Department of Cardiology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Medical Faculty Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
- Correspondence: (M.B.); (G.P.)
| | - Bojan Vrtovec
- Advanced Heart Failure and Transplantation Center, Department of Cardiology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
- Department of Internal Medicine, Medical Faculty Ljubljana, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Arsen Ristic
- Cardiology Department, University Clinical Center of Serbia, 11000 Beograd, Serbia
- Belgrade Medical School, 11000 Belgrade, Serbia
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Abstract
Endothelial colony-forming cells (ECFCs) are progenitor cells that can give rise to colonies of highly proliferative vascular endothelial cells (ECs) with clonal expansion and in vivo blood vessel-forming potential. More than two decades ago, the identification of ECFCs in human peripheral blood created tremendous opportunities as having a clinically accessible source of autologous ECs could facilitate meaningful therapies with the potential to impact multiple vascular diseases. Nevertheless, until recently, the field of endothelial progenitor cells has been plagued with ambiguities and controversies, and reaching a consensus on the definition of ECFCs has not been straightforward. Moreover, although the basic phenotypical and functional characteristics of cultured ECFCs are now well established, some fundamental questions such as the origin of ECFCs and their physiological roles in health and disease remain incompletely understood. Here, I highlight some critical studies that have shaped our current understanding of ECFCs in humans. Insights into the biological attributes of ECFCs are essential for facilitating the clinical translation of their therapeutic potential.
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Affiliation(s)
- Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
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30
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Liraglutide Improves the Angiogenic Capability of EPC and Promotes Ischemic Angiogenesis in Mice under Diabetic Conditions through an Nrf2-Dependent Mechanism. Cells 2022; 11:cells11233821. [PMID: 36497087 PMCID: PMC9736458 DOI: 10.3390/cells11233821] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/17/2022] [Accepted: 10/24/2022] [Indexed: 12/05/2022] Open
Abstract
The impairment in endothelial progenitor cell (EPC) functions results in dysregulation of vascular homeostasis and dysfunction of the endothelium under diabetic conditions. Improving EPC function has been considered as a promising strategy for ameliorating diabetic vascular complications. Liraglutide has been widely used as a therapeutic agent for diabetes. However, the effects and mechanisms of liraglutide on EPC dysfunction remain unclear. The capability of liraglutide in promoting blood perfusion and angiogenesis under diabetic conditions was evaluated in the hind limb ischemia model of diabetic mice. The effect of liraglutide on the angiogenic function of EPC was evaluated by cell scratch recovery assay, tube formation assay, and nitric oxide production. RNA sequencing was performed to assess the underlying mechanisms. Liraglutide enhanced blood perfusion and angiogenesis in the ischemic hindlimb of db/db mice and streptozotocin-induced type 1 diabetic mice. Additionally, liraglutide improved tube formation, cell migration, and nitric oxide production of high glucose (HG)-treated EPC. Assessment of liraglutide target pathways revealed a network of genes involved in antioxidant activity. Further mechanism study showed that liraglutide decreased the production of reactive oxygen species and increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 deficiency attenuated the beneficial effects of liraglutide on improving EPC function and promoting ischemic angiogenesis under diabetic conditions. Moreover, liraglutide activates Nrf2 through an AKT/GSK3β/Fyn pathway, and inhibiting this pathway abolished liraglutide-induced Nrf2 activation and EPC function improvement. Overall, these results suggest that Liraglutide represents therapeutic potential in promoting EPC function and ameliorating ischemic angiogenesis under diabetic conditions, and these beneficial effects relied on Nrf2 activation.
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31
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Kim YW, Zara G, Kang H, Branciamore S, O'Meally D, Feng Y, Kuan CY, Luo Y, Nelson MS, Brummer AB, Rockne R, Chen ZB, Zheng Y, Cardoso AA, Carlesso N. Integration of single-cell transcriptomes and biological function reveals distinct behavioral patterns in bone marrow endothelium. Nat Commun 2022; 13:7235. [PMID: 36433940 PMCID: PMC9700769 DOI: 10.1038/s41467-022-34425-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 10/25/2022] [Indexed: 11/27/2022] Open
Abstract
Heterogeneity of endothelial cell (EC) populations reflects their diverse functions in maintaining tissue's homeostasis. However, their phenotypic, molecular, and functional properties are not entirely mapped. We use the Tie2-CreERT2;Rosa26-tdTomato reporter mouse to trace, profile, and cultivate primary ECs from different organs. As paradigm platform, we use this strategy to study bone marrow endothelial cells (BMECs). Single-cell mRNA sequencing of primary BMECs reveals that their diversity and native molecular signatures is transitorily preserved in an ex vivo culture that conserves key cell-to-cell microenvironment interactions. Macrophages sustain BMEC cellular diversity and expansion and preserve sinusoidal-like BMECs ex vivo. Endomucin expression discriminates BMECs in populations exhibiting mutually exclusive properties and distinct sinusoidal/arterial and tip/stalk signatures. In contrast to arterial-like, sinusoidal-like BMECs are short-lived, form 2D-networks, contribute to in vivo angiogenesis, and support hematopoietic stem/progenitor cells in vitro. This platform can be extended to other organs' ECs to decode mechanistic information and explore therapeutics.
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Affiliation(s)
- Young-Woong Kim
- Department of Stem Cell Biology and Regenerative Medicine, Gehr Family Center for Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.
- Center for Genome Engineering, Institute for Basic Science, Yuseong-gu, Daejeon, 34126, Republic of Korea.
| | - Greta Zara
- Department of Stem Cell Biology and Regenerative Medicine, Gehr Family Center for Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - HyunJun Kang
- Department of Stem Cell Biology and Regenerative Medicine, Gehr Family Center for Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Sergio Branciamore
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Denis O'Meally
- Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Yuxin Feng
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Chia-Yi Kuan
- Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia School of Medicine, Charlottesville, VA, 22908, USA
| | - Yingjun Luo
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Michael S Nelson
- Light Microscopy Core, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Alex B Brummer
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
- Department of Physics and Astronomy, College of Charleston, Charleston, SC, 29424, USA
| | - Russell Rockne
- Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Zhen Bouman Chen
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Duarte, USA
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Angelo A Cardoso
- Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
- Irell and Manella Graduate School of Biological Sciences, Duarte, USA
| | - Nadia Carlesso
- Department of Stem Cell Biology and Regenerative Medicine, Gehr Family Center for Leukemia Research, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA.
- Irell and Manella Graduate School of Biological Sciences, Duarte, USA.
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Lemmer D, Schmidt J, Kummer K, Lemmer B, Wrede A, Seitz C, Balcarek P, Schwarze K, Müller GA, Patschan D, Patschan S. Impairment of muscular endothelial cell regeneration in dermatomyositis. Front Neurol 2022; 13:952699. [PMID: 36330424 PMCID: PMC9623165 DOI: 10.3389/fneur.2022.952699] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 09/01/2022] [Indexed: 11/22/2022] Open
Abstract
Background and aim Inflammatory myopathies are heterogeneous in terms of etiology, (immuno)pathology, and clinical findings. Endothelial cell injury, as it occurs in DM, is a common feature of numerous inflammatory and non-inflammatory vascular diseases. Vascular regeneration is mediated by both local and blood-derived mechanisms, such as the mobilization and activation of so-called proangiogenic cells (PACs) or early endothelial progenitor cells (eEPCs). The current study aimed to evaluate parameters of eEPC integrity in dermatomyositis (DM), compared to necrotizing myopathy (NM) and to non-myopathic controls. Methods Blood samples from DM and NM patients were compared to non-myositis controls and analyzed for the following parameters: circulating CD133+/VEGFR-2+ cells, number of colony-forming unit endothelial cells (CFU-ECs), concentrations of angiopoietin 1, vascular endothelial growth factor (VEGF), and CXCL-16. Muscle biopsies from DM and NM subjects underwent immunofluorescence analysis for CXCR6, nestin, and CD31 (PECAM-1). Finally, myotubes, derived from healthy donors, were stimulated with serum samples from DM and NM patients, subsequently followed by RT-PCR for the following candidates: IL-1β, IL-6, nestin, and CD31. Results Seventeen (17) DM patients, 7 NM patients, and 40 non-myositis controls were included. CD133+/VEGFR-2+ cells did not differ between the groups. Both DM and NM patients showed lower CFU-ECs than controls. In DM, intramuscular CD31 abundances were significantly reduced, which indicated vascular rarefaction. Muscular CXCR6 was elevated in both diseases. Circulating CXCL-16 was higher in DM and NM in contrast, compared to controls. Serum from patients with DM but not NM induced a profound upregulation of mRNS expression of CD31 and IL-6 in cultured myotubes. Conclusion Our study demonstrates the loss of intramuscular microvessels in DM, accompanied by endothelial activation in DM and NM. Vascular regeneration was impaired in DM and NM. The findings suggest a role for inflammation-associated vascular damage in the pathogenesis of DM.
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Affiliation(s)
- D. Lemmer
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
- Immanuel Krankenhaus Berlin, Medical Center of Rheumatology Berlin-Buch, Berlin, Germany
| | - J. Schmidt
- Department of Neurology and Pain Treatment, Immanuel Klinik Rüdersdorf, University Hospital of the Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Germany
- Department of Neurology, Neuromuscular Center, University Medical Center Göttingen, Göttingen, Germany
| | - K. Kummer
- Department of Neurology, Neuromuscular Center, University Medical Center Göttingen, Göttingen, Germany
| | - B. Lemmer
- Department of Physics, Georg-August-University Göttingen, Göttingen, Germany
| | - A. Wrede
- Department of Neuropathology, University Medical Center Göttingen, Göttingen, Germany
| | - C. Seitz
- Department of Dermatology, Allergology and Venereology, University Medical Center Göttingen, Göttingen, Germany
| | - P. Balcarek
- Department of Trauma Surgery, Orthopedics and Plastic Surgery, University Medical Center Göttingen, Göttingen, Germany
- Arcus Klinik, Pforzheim, Germany
| | - K. Schwarze
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
| | - G. A. Müller
- Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany
| | - D. Patschan
- Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Germany
- Department of Medicine 1, Cardiology, Angiology, and Nephrology, University Hospital Brandenburg of the Brandenburg Medical School Theodor Fontane, Branderburg, Germany
| | - S. Patschan
- Faculty of Health Sciences Brandenburg, Brandenburg Medical School Theodor Fontane, Rüdersdorf bei Berlin, Germany
- Department of Medicine 1, Cardiology, Angiology, and Nephrology, University Hospital Brandenburg of the Brandenburg Medical School Theodor Fontane, Branderburg, Germany
- *Correspondence: S. Patschan
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Rudnicka-Drożak E, Drożak P, Mizerski G, Drożak M. Endothelial Progenitor Cells in Neurovascular Disorders—A Comprehensive Overview of the Current State of Knowledge. Biomedicines 2022; 10:biomedicines10102616. [PMID: 36289878 PMCID: PMC9599182 DOI: 10.3390/biomedicines10102616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/11/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer’s disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer’s disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy.
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Affiliation(s)
- Ewa Rudnicka-Drożak
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Paulina Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
- Correspondence: ; Tel.: +48-669-084-455
| | - Grzegorz Mizerski
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Martyna Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
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Dai X, Wang K, Fan J, Liu H, Fan X, Lin Q, Chen Y, Chen H, Li Y, Liu H, Chen O, Chen J, Li X, Ren D, Li J, Conklin DJ, Wintergerst KA, Li Y, Cai L, Deng Z, Yan X, Tan Y. Nrf2 transcriptional upregulation of IDH2 to tune mitochondrial dynamics and rescue angiogenic function of diabetic EPCs. Redox Biol 2022; 56:102449. [PMID: 36063728 PMCID: PMC9463384 DOI: 10.1016/j.redox.2022.102449] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 07/30/2022] [Accepted: 08/15/2022] [Indexed: 01/11/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are reduced in number and impaired in function in diabetic patients. Whether and how Nrf2 regulates the function of diabetic EPCs remains unclear. In this study, we found that the expression of Nrf2 and its downstream genes were decreased in EPCs from both diabetic patients and db/db mice. Survival ability and angiogenic function of EPCs from diabetic patients and db/db mice also were impaired. Gain- and loss-of-function studies, respectively, showed that knockdown of Nrf2 increased apoptosis and impaired tube formation in EPCs from healthy donors and wild-type mice, while Nrf2 overexpression decreased apoptosis and rescued tube formation in EPCs from diabetic patients and db/db mice. Additionally, proangiogenic function of Nrf2-manipulated mouse EPCs was validated in db/db mice with hind limb ischemia. Mechanistic studies demonstrated that diabetes induced mitochondrial fragmentation and dysfunction of EPCs by dysregulating the abundance of proteins controlling mitochondrial dynamics; upregulating Nrf2 expression attenuated diabetes-induced mitochondrial fragmentation and dysfunction and rectified the abundance of proteins controlling mitochondrial dynamics. Further RNA-sequencing analysis demonstrated that Nrf2 specifically upregulated the transcription of isocitrate dehydrogenase 2 (IDH2), a key enzyme regulating tricarboxylic acid cycle and mitochondrial function. Overexpression of IDH2 rectified Nrf2 knockdown- or diabetes-induced mitochondrial fragmentation and EPC dysfunction. In a therapeutic approach, supplementation of an Nrf2 activator sulforaphane enhanced angiogenesis and blood perfusion recovery in db/db mice with hind limb ischemia. Collectively, these findings indicate that Nrf2 is a potential therapeutic target for improving diabetic EPC function. Thus, elevating Nrf2 expression enhances EPC resistance to diabetes-induced oxidative damage and improves therapeutic efficacy of EPCs in treating diabetic limb ischemia likely via transcriptional upregulating IDH2 expression and improving mitochondrial function of diabetic EPCs.
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Affiliation(s)
- Xiaozhen Dai
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China; Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Kai Wang
- Department of Pediatrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiawei Fan
- School of Biosciences and Technology, Chengdu Medical College, Chengdu, Sichuan, China
| | - Hanjie Liu
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Xia Fan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Lin
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Yuhang Chen
- School of Laboratory Medicine, Chengdu Medical College, Chengdu, China
| | - Hu Chen
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Yao Li
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Hairong Liu
- The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Oscar Chen
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Jing Chen
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA
| | - Xiaohong Li
- Kentucky IDeA Network for Biomedical Research Excellence Bioinformatics Core, University of Louisville, Louisville, KY, USA
| | - Di Ren
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Ji Li
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Daniel J Conklin
- Department of Medicine and Diabetes and Obesity Center, University of Louisville, Louisville, KY, USA
| | - Kupper A Wintergerst
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA; Division of Endocrinology, Department of Pediatrics, University of Louisville, Norton Children's Hospital, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Norton Children's Hospital, Louisville, KY, USA
| | - Yu Li
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Lu Cai
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Norton Children's Hospital, Louisville, KY, USA
| | - Zhongbin Deng
- Department of Surgery, Division of Immunotherapy, University of Louisville, Louisville, KY, USA
| | - Xiaoqing Yan
- Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
| | - Yi Tan
- Pediatric Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA; Wendy L. Novak Diabetes Care Center, Norton Children's Hospital, Louisville, KY, USA.
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Zhang L, Zhang X, Zhong X, Fan M, Wang G, Shi W, Xie R, Wei Y, Zhang H, Meng X, Wang Y, Ma Y. Soluble Flt-1 in AMI Patients Serum Inhibits Angiogenesis of Endothelial Progenitor Cells by Suppressing Akt and Erk’s Activity. BIOLOGY 2022; 11:biology11081194. [PMID: 36009821 PMCID: PMC9404789 DOI: 10.3390/biology11081194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 07/27/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022]
Abstract
Simple Summary Acute myocardial infarction (AMI) is the leading cause of mortality in the world. Endothelial progenitor cells (EPCs) exert important roles in the recovery of collateral circulation via angiogenesis. In this study, we studied the characteristics of EPCs isolated from the peripheral blood of AMI patients and healthy subjects. We found that the number of EPCs increased in AMI patients and exhibited faster migration compared to healthy subjects. However, no difference in angiogenic activity was observed in EPCs between AMI patients and healthy subjects. Interestingly, the serum level of sFlt-1 was elevated in AMI patients. Further analysis demonstrated that sFlt-1 inhibited EPCs angiogenesis in vitro by inhibiting the Akt and Erk signaling pathways. In conclusion, our study uncovered that EPCs increased in quantity, but their angiogenesis activity was inhibited by serum sFlt-1 in AMI patients. Abstract In acute myocardial infarction (AMI), endothelial progenitor cells (EPCs) are essential for the recovery of collateral circulation via angiogenesis. Clinical research has shown that the poor prognosis of the patients with AMI is closely associated with the cell quantity and function of EPCs. Whether there are differences in the biological features of EPCs from AMI patients and healthy subjects is worth exploring. In this study, EPCs were isolated from human peripheral blood and identified as late-stage EPCs by flow cytometry, immunofluorescence, and blood vessel formation assay. Compared to healthy subjects, AMI patients had more EPCs in the peripheral blood compared to healthy subjects. In addition, EPCs from AMI patients exhibited higher migration ability in the transwell assay compared to EPCs from healthy subjects. However, no difference in the angiogenesis of EPCs was observed between AMI patients and healthy subjects. Further studies revealed that soluble vascular endothelial growth factor receptor 1 (sFlt-1) in the serum of AMI patients was involved in the inhibition of EPCs angiogenesis by suppressing the Akt and Erk pathways. In conclusion, this study demonstrated that elevated serum sFlt-1 inhibits angiogenesis of EPC in AMI patients. Our findings uncover a pathogenic role of sFlt-1 in AMI.
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Affiliation(s)
- Lijie Zhang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Xingkun Zhang
- Henan Key Laboratory of Coronary Heart Disease Control & Prevention, Department of Cardiology, Central China Fuwai Hospital, Zhengzhou 450003, China
- Department of Cardiology, Henan Provincial People’s Hospital, Zhengzhou 451450, China
| | - Xiaoming Zhong
- Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng 475000, China
| | - Mengya Fan
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Guoliang Wang
- Department of Cardiovascular, the First Affiliated Hospital of Henan University, Kaifeng 475004, China
| | - Wei Shi
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Ran Xie
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Yinxiang Wei
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Hailong Zhang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
| | - Xiangxu Meng
- Department of Cardiovascular, the First Affiliated Hospital of Henan University, Kaifeng 475004, China
| | - Yaohui Wang
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
- Correspondence: (Y.W.); (Y.M.)
| | - Yuanfang Ma
- Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, Henan University, Kaifeng 475004, China
- Correspondence: (Y.W.); (Y.M.)
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Lyall GK, Birk GK, Harris E, Ferguson C, Riches-Suman K, Kearney MT, Porter KE, Birch KM. Efficacy of interval exercise training to improve vascular health in sedentary postmenopausal females. Physiol Rep 2022; 10:e15441. [PMID: 35986498 PMCID: PMC9391601 DOI: 10.14814/phy2.15441] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Menopause represents a turning point where vascular damage begins to outweigh reparative processes, leading to increased cardiovascular disease (CVD) risk. Exercise training reduces CVD risk in postmenopausal females via improvements in traditional risk factors and direct changes to the vasculature. We assessed the effect of moderate (MODERATE-IT) versus heavy (HEAVY-IT) intensity interval exercise training upon markers of cardiovascular health and vascular repair in postmenopausal females. METHODS Twenty-seven healthy postmenopausal females (56 ± 4 yr) were assigned to 12 weeks of either MODERATE-IT or HEAVY-IT, twice per week. MODERATE-IT consisted of 10s work, and 10s active recovery repeated for 30 min. HEAVY-IT comprised 30s work, and 30s active recovery repeated for 21 ± 2 min. Endothelial function (flow-mediated dilation), arterial stiffness (pulse wave velocity), and V̇O2peak were assessed pre-training and post-training. Blood samples were obtained pre-training and post-training for enumeration of circulating angiogenic cells (CACs), culture of CACs, and lipoprotein profile. RESULTS V̇O2peak increased 2.4 ± 2.8 ml/kg/min following HEAVY-IT only (p < 0.05). Brachial blood pressure and endothelial function were unchanged with exercise training (p > 0.05). Peripheral pulse wave velocity reduced 8% with exercise training, irrespective of intensity (p < 0.05). Exercise training had no effect on lipoprotein profile or endothelin-1 (p > 0.05). CAC adhesion to vascular smooth muscle cells (VSMC) increased 30 min post plating following MODERATE-IT only (p < 0.05). CONCLUSIONS HEAVY-IT was more effective at increasing V̇O2peak in postmenopausal females. The ability of CACs to adhere to VSMC improved following MODERATE-IT but not HEAVY-IT. Interval training had the same effect on endothelial function (no change) and arterial stiffness (reduced), regardless of exercise intensity.
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Affiliation(s)
- Gemma K Lyall
- School of Biomedical Sciences, Faculty of Biological Sciences and Multidisciplinary, Cardiovascular Research Centre, University of Leeds, Leeds, UK
| | - Gurpreet K Birk
- IVS Ltd, Vascular Ultrasound, Royal Oldham Hospital, Oldham, UK.,Vascular Ultrasound, Radiology, Leeds General Infirmary, Leeds, UK
| | - Emma Harris
- School of Human and Health Sciences, Centre for Applied Research in Health, University of Huddersfield, Huddersfield, UK
| | - Carrie Ferguson
- Institute of Respiratory Medicine and Exercise Physiology, Rehabilitation Clinical Trials Center, Division of Respiratory and Critical Care Physiology and Medicine, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA
| | | | - Mark T Kearney
- Leeds Institute of Cardiovascular and Metabolic Medicine & Multidisciplinary, Cardiovascular Research Centre, University of Leeds, Leeds, UK
| | - Karen E Porter
- Leeds Institute of Cardiovascular and Metabolic Medicine & Multidisciplinary, Cardiovascular Research Centre, University of Leeds, Leeds, UK
| | - Karen M Birch
- School of Biomedical Sciences, Faculty of Biological Sciences and Multidisciplinary, Cardiovascular Research Centre, University of Leeds, Leeds, UK
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Characterization of Endothelial Progenitor Cell: Past, Present, and Future. Int J Mol Sci 2022; 23:ijms23147697. [PMID: 35887039 PMCID: PMC9318195 DOI: 10.3390/ijms23147697] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/04/2022] [Accepted: 07/09/2022] [Indexed: 02/05/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are currently being studied as candidate cell sources for revascularization strategies. Despite these promising results, widespread clinical acceptance of EPCs for clinical therapies remains hampered by several challenges. The challenges and issues surrounding the use of EPCs and the current paradigm being developed to improve the harvest efficiency and functionality of EPCs for application in regenerative medicine are discussed. It has been observed that controversies have emerged regarding the isolation techniques and classification and origin of EPCs. This manuscript attempts to highlight the concept of EPCs in a sequential manner, from the initial discovery to the present (origin, sources of EPCs, isolation, and identification techniques). Human and murine EPC marker diversity is also discussed. Additionally, this manuscript is aimed at summarizing our current and future prospects regarding the crosstalk of EPCs with the biology of hematopoietic cells and culture techniques in the context of regeneration-associated cells (RACs).
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Short WD, Steen E, Kaul A, Wang X, Olutoye OO, Vangapandu HV, Templeman N, Blum AJ, Moles CM, Narmoneva DA, Crombleholme TM, Butte MJ, Bollyky PL, Keswani SG, Balaji S. IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3. FASEB J 2022; 36:e22298. [PMID: 35670763 PMCID: PMC9796147 DOI: 10.1096/fj.201901024rr] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 03/08/2022] [Accepted: 03/23/2022] [Indexed: 01/02/2023]
Abstract
Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL-10 in dermal wounds promotes regenerative tissue repair via STAT3-dependent regulation of fibroblast-specific hyaluronan synthesis. However, IL-10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin-specific STAT3 knockdown mice were studied to determine IL-10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3-dependent. We show that IL-10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re-epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C-X-C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL-10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL-10-conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL-10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re-epithelialization.
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Affiliation(s)
- Walker D. Short
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Emily Steen
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Aditya Kaul
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Xinyi Wang
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Oluyinka O. Olutoye
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Hima V. Vangapandu
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Natalie Templeman
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Alexander J. Blum
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Chad M. Moles
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Daria A. Narmoneva
- Biomedical EngineeringDepartment of Biomedical, Chemical and Environmental EngineeringCollege of Engineering and Applied SciencesUniversity of CincinnatiCincinnatiOhioUSA
| | - Timothy M. Crombleholme
- Division of Pediatric General Thoracic and Fetal SurgeryConnecticut Children’s HospitalUniversity of Connecticut School of MedicineFarmingtonConnecticutUSA,Fetal Care Center DallasDallasTexasUSA
| | - Manish J. Butte
- Division of ImmunologyAllergy, and RheumatologyDepartments of Pediatrics and Microbiology, Immunology, and Molecular GeneticsUniversity of California Los AngelesLos AngelesCaliforniaUSA
| | - Paul L. Bollyky
- Division of Infectious DiseasesDepartment of MedicineStanford University School of MedicineStanfordCaliforniaUSA
| | - Sundeep G. Keswani
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
| | - Swathi Balaji
- Division of Pediatric SurgeryDepartment of SurgeryTexas Children's Hospital and Baylor College of MedicineHoustonTexasUSA
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Costa A, Pasquinelli G. Air Pollution Exposure Induces Vascular Injury and Hampers Endothelial Repair by Altering Progenitor and Stem Cells Functionality. Front Cell Dev Biol 2022; 10:897831. [PMID: 35712669 PMCID: PMC9197257 DOI: 10.3389/fcell.2022.897831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/20/2022] [Indexed: 11/13/2022] Open
Abstract
Extensive evidence indicates an association of air pollution exposure with an increased risk of cardiovascular disease (CVD) development. Fine particulate matter (PM) represents one of the main components of urban pollution, but the mechanisms by which it exerts adverse effects on cardiovascular system remain partially unknown and under investigation. The alteration of endothelial functions and inflammation are among the earliest pathophysiological impacts of environmental exposure on the cardiovascular system and represent critical mediators of PM-induced injury. In this context, endothelial stem/progenitor cells (EPCs) play an important role in vascular homeostasis, endothelial reparative capacity, and vasomotor functionality modulation. Several studies indicate the impairment of EPCs' vascular reparative capacity due to PM exposure. Since a central source of EPCs is bone marrow (BM), their number and function could be related to the population and functional status of stem cells (SCs) of this district. In this review, we provide an overview of the potential mechanisms by which PM exposure hinders vascular repair by the alteration of progenitor and stem cells' functionality.
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Affiliation(s)
- Alice Costa
- Laboratory of Clinical Pathology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy
| | - Gianandrea Pasquinelli
- Laboratory of Clinical Pathology, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.,IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
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Ribieras AJ, Ortiz YY, Li Y, Huerta CT, Le N, Shao H, Vazquez-Padron RI, Liu ZJ, Velazquez OC. E-Selectin/AAV2/2 Gene Therapy Alters Angiogenesis and Inflammatory Gene Profiles in Mouse Gangrene Model. Front Cardiovasc Med 2022; 9:929466. [PMID: 35783833 PMCID: PMC9243393 DOI: 10.3389/fcvm.2022.929466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/26/2022] [Indexed: 11/13/2022] Open
Abstract
For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. E-selectin/AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limb-threatening ischemia.
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Affiliation(s)
- Antoine J. Ribieras
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Yulexi Y. Ortiz
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Yan Li
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Carlos T. Huerta
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Nga Le
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Hongwei Shao
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Roberto I. Vazquez-Padron
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Zhao-Jun Liu
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- Zhao-Jun Liu
| | - Omaida C. Velazquez
- Division of Vascular Surgery, DeWitt Daughtry Family Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Vascular Biology Institute, University of Miami Miller School of Medicine, Miami, FL, United States
- *Correspondence: Omaida C. Velazquez
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Bochenek ML, Gogiraju R, Großmann S, Krug J, Orth J, Reyda S, Georgiadis GS, Spronk H, Konstantinides S, Münzel T, Griffin JH, Wild PS, Espinola-Klein C, Ruf W, Schäfer K. EPCR-PAR1 biased signaling regulates perfusion recovery and neovascularization in peripheral ischemia. JCI Insight 2022; 7:157701. [PMID: 35700057 PMCID: PMC9431695 DOI: 10.1172/jci.insight.157701] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 06/08/2022] [Indexed: 11/17/2022] Open
Abstract
Blood clot formation initiates ischemic events, but coagulation roles during postischemic tissue repair are poorly understood. The endothelial protein C receptor (EPCR) regulates coagulation, as well as immune and vascular signaling, by protease activated receptors (PARs). Here, we show that endothelial EPCR-PAR1 signaling supports reperfusion and neovascularization in hindlimb ischemia in mice. Whereas deletion of PAR2 or PAR4 did not impair angiogenesis, EPCR and PAR1 deficiency or PAR1 resistance to cleavage by activated protein C caused markedly reduced postischemic reperfusion in vivo and angiogenesis in vitro. These findings were corroborated by biased PAR1 agonism in isolated primary endothelial cells. Loss of EPCR-PAR1 signaling upregulated hemoglobin expression and reduced endothelial nitric oxide (NO) bioavailability. Defective angiogenic sprouting was rescued by the NO donor DETA-NO, whereas NO scavenging increased hemoglobin and mesenchymal marker expression in human and mouse endothelial cells. Vascular specimens from patients with ischemic peripheral artery disease exhibited increased hemoglobin expression, and soluble EPCR and NO levels were reduced in plasma. Our data implicate endothelial EPCR-PAR1 signaling in the hypoxic response of endothelial cells and identify suppression of hemoglobin expression as an unexpected link between coagulation signaling, preservation of endothelial cell NO bioavailability, support of neovascularization, and prevention of fibrosis.
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Affiliation(s)
- Magdalena L Bochenek
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | | | - Stefanie Großmann
- Department of Cardiology, University Medical Center Mainz, Mainz, Germany
| | - Janina Krug
- Department of Cardiology, University Medical Center Mainz, Mainz, Germany
| | - Jennifer Orth
- Department of Cardiology, University Medical Center Mainz, Mainz, Germany
| | - Sabine Reyda
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | - George S Georgiadis
- Department of Vascular Surgery, University Hospital of Alexandroupolis, Alexandroupolis, Greece
| | - Henri Spronk
- CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, Netherlands
| | | | - Thomas Münzel
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | - John H Griffin
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United States of America
| | - Philipp S Wild
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | | | - Wolfram Ruf
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
| | - Katrin Schäfer
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany
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Chen K, Li Y, Xu L, Qian Y, Liu N, Zhou C, Liu J, Zhou L, Xu Z, Jia R, Ge YZ. Comprehensive insight into endothelial progenitor cell-derived extracellular vesicles as a promising candidate for disease treatment. Stem Cell Res Ther 2022; 13:238. [PMID: 35672766 PMCID: PMC9172199 DOI: 10.1186/s13287-022-02921-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Accepted: 05/29/2022] [Indexed: 12/21/2022] Open
Abstract
Endothelial progenitor cells (EPCs), which are a type of stem cell, have been found to have strong angiogenic and tissue repair capabilities. Extracellular vesicles (EVs) contain many effective components, such as cellular proteins, microRNAs, messenger RNAs, and long noncoding RNAs, and can be secreted by different cell types. The functions of EVs depend mainly on their parent cells. Many researchers have conducted functional studies of EPC-derived EVs (EPC-EVs) and showed that they exhibit therapeutic effects on many diseases, such as cardiovascular disease, acute kidney injury, acute lung injury, and sepsis. In this review article, we comprehensively summarized the biogenesis and functions of EPCs and EVs and the potent role of EPC-EVs in the treatment of various diseases. Furthermore, the current problems and future prospects have been discussed, and further studies are needed to compare the therapeutic effects of EVs derived from various stem cells, which will contribute to the accelerated translation of these applications in a clinical setting.
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Affiliation(s)
- Ke Chen
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yang Li
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Luwei Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Yiguan Qian
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ning Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Changcheng Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Jingyu Liu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Liuhua Zhou
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Zheng Xu
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China
| | - Ruipeng Jia
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
| | - Yu-Zheng Ge
- Department of Urology, Nanjing First Hospital, Nanjing Medical University, No. 68 Changle Road, Nanjing, 210006, Jiangsu, People's Republic of China.
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Pelliccia F, Zimarino M, De Luca G, Viceconte N, Tanzilli G, De Caterina R. Endothelial Progenitor Cells in Coronary Artery Disease: From Bench to Bedside. Stem Cells Transl Med 2022; 11:451-460. [PMID: 35365823 PMCID: PMC9154346 DOI: 10.1093/stcltm/szac010] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 02/04/2022] [Indexed: 11/14/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are a heterogeneous group of cells present in peripheral blood at various stages of endothelial differentiation. EPCs have been extensively investigated in patients with coronary artery disease (CAD), with controversial findings both on their role in atherosclerosis progression and in the process of neointimal growth after a percutaneous coronary intervention (PCI). Despite nearly 2 decades of experimental and clinical investigations, however, the significance of EPCs in clinical practice remains unclear and poorly understood. This review provides an update on the role of EPCs in the most common clinical scenarios that are experienced by cardiologists managing patients with CAD. We here summarize the main findings on the association of EPCs with cardiovascular risk factors, coronary atherosclerosis, and myocardial ischemia. We then discuss the potential effects of EPCs in post-PCI in-stent restenosis, as well as most recent findings with EPC-coated stents. Based on the mounting evidence of the relationship between levels of EPCs and several different adverse cardiovascular events, EPCs are emerging as novel predictive biomarkers of long-term outcomes in patients with CAD.
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Affiliation(s)
| | - Marco Zimarino
- Institute of Cardiology, “G. d’Annunzio” University, Chieti, Italy
- Cath Lab, SS. Annunziata Hospital, Chieti, Italy
| | - Giuseppe De Luca
- Division of Cardiology, Azienda Ospedaliero-Universitaria Maggiore della Carità, Università del Piemonte Orientale, Novara, Italy
| | - Nicola Viceconte
- Department of Cardiovascular Sciences, Sapienza University, Rome, Italy
| | - Gaetano Tanzilli
- Department of Cardiovascular Sciences, Sapienza University, Rome, Italy
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Huang H, Huang W. Regulation of Endothelial Progenitor Cell Functions in Ischemic Heart Disease: New Therapeutic Targets for Cardiac Remodeling and Repair. Front Cardiovasc Med 2022; 9:896782. [PMID: 35677696 PMCID: PMC9167961 DOI: 10.3389/fcvm.2022.896782] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/02/2022] [Indexed: 12/16/2022] Open
Abstract
Ischemic heart disease (IHD) is the leading cause of morbidity and mortality worldwide. Ischemia and hypoxia following myocardial infarction (MI) cause subsequent cardiomyocyte (CM) loss, cardiac remodeling, and heart failure. Endothelial progenitor cells (EPCs) are involved in vasculogenesis, angiogenesis and paracrine effects and thus have important clinical value in alternative processes for repairing damaged hearts. In fact, this study showed that the endogenous repair of EPCs may not be limited to a single cell type. EPC interactions with cardiac cell populations and mesenchymal stem cells (MSCs) in ischemic heart disease can attenuate cardiac inflammation and oxidative stress in a microenvironment, regulate cell survival and apoptosis, nourish CMs, enhance mature neovascularization, alleviate adverse ventricular remodeling after infarction and enhance ventricular function. In this review, we introduce the definition and discuss the origin and biological characteristics of EPCs and summarize the mechanisms of EPC recruitment in ischemic heart disease. We focus on the crosstalk between EPCs and endothelial cells (ECs), smooth muscle cells (SMCs), CMs, cardiac fibroblasts (CFs), cardiac progenitor cells (CPCs), and MSCs during cardiac remodeling and repair. Finally, we discuss the translation of EPC therapy to the clinic and treatment strategies.
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Assuncao-Jr AN, Rochitte CE, Kwong RY, Wolff Gowdak LH, Krieger JE, Jerosch-Herold M. Bone Marrow Cells Improve Coronary Flow Reserve in Ischemic Nonrevascularized Myocardium: A MiHeart/IHD Quantitative Perfusion CMR Substudy. JACC Cardiovasc Imaging 2022; 15:812-824. [PMID: 35512954 DOI: 10.1016/j.jcmg.2021.12.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 12/20/2021] [Accepted: 12/23/2021] [Indexed: 01/05/2023]
Abstract
OBJECTIVES This study investigated whether intramyocardial bone marrow-derived hematopoietic progenitor cells (BMCs) increase coronary flow reserve (CFR) in ischemic myocardial regions where direct revascularization was unsuitable. BACKGROUND Patients with diffuse coronary artery disease frequently undergo incomplete myocardial revascularization, which increases their risk for future adverse cardiovascular outcomes. The residual regional ischemia related to both untreated epicardial lesions and small vessel disease usually contributes to the disease burden. METHODS The MiHeart/IHD study randomized patients with diffuse coronary artery disease undergoing incomplete coronary artery bypass grafting to receive BMCs or placebo in ischemic myocardial regions. After the procedure, 78 patients underwent cardiovascular magnetic resonance (CMR) at 1, 6, and 12 months and were included in this cardiac magnetic resonance substudy with perfusion quantification. Segments were classified as target (injected), adjacent (surrounding the injection site), and remote from injection site. RESULTS Of 1,248 segments, 269 were target (22%), 397 (32%) adjacent, and 582 (46%) remote. The target had significantly lower CFR at baseline (1.40 ± 0.79 vs 1.64 ± 0.89 in adjacent and 1.79 ± 0.79 in remote; both P < 0.05). BMCs significantly increased CFR in target and adjacent segments at 6 and 12 months compared with placebo. In target regions, there was a progressive treatment effect (27.1% at 6 months, P = 0.037, 42.2% at 12 months, P = 0.001). In the adjacent segments, CFR increased by 21.8% (P = 0.023) at 6 months, which persisted until 12 months (22.6%; P = 0.022). Remote segments in both the BMC and placebo groups experienced similar improvements in CFR (not significant at 12 months compared with baseline). CONCLUSIONS BMCs, injected in severely ischemic regions unsuitable for direct revascularization, led to the largest CFR improvements, which progressed up to 12 months, compared with smaller but persistent CFR changes in adjacent and no improvement in remote segments.
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Affiliation(s)
| | | | - Raymond Y Kwong
- Division of Cardiovascular Medicine and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - José Eduardo Krieger
- Heart Institute (InCor), University of São Paulo Medical School, Säo Paulo, Brazil.
| | - Michael Jerosch-Herold
- Division of Cardiovascular Medicine and Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Aschacher T, Aschacher O, Schmidt K, Enzmann FK, Eichmair E, Winkler B, Arnold Z, Nagel F, Podesser BK, Mitterbauer A, Messner B, Grabenwöger M, Laufer G, Ehrlich MP, Bergmann M. The Role of Telocytes and Telocyte-Derived Exosomes in the Development of Thoracic Aortic Aneurysm. Int J Mol Sci 2022; 23:ijms23094730. [PMID: 35563123 PMCID: PMC9099883 DOI: 10.3390/ijms23094730] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/22/2022] [Accepted: 04/23/2022] [Indexed: 11/28/2022] Open
Abstract
A hallmark of thoracic aortic aneurysms (TAA) is the degenerative remodeling of aortic wall, which leads to progressive aortic dilatation and resulting in an increased risk for aortic dissection or rupture. Telocytes (TCs), a distinct type of interstitial cells described in many tissues and organs, were recently observed in the aortic wall, and studies showed the potential regulation of smooth muscle cell (SMC) homeostasis by TC-released shed vesicles. The purpose of the present work was to study the functions of TCs in medial degeneration of TAA. During aneurysmal formation an increase of aortic TCs was identified in human surgical specimens of TAA-patients, compared to healthy thoracic aortic (HTA)-tissue. We found the presence of epithelial progenitor cells in the adventitial layer, which showed increased infiltration in TAA samples. For functional analysis, HTA- and TAA-telocytes were isolated, characterized, and compared by their protein levels, mRNA- and miRNA-expression profiles. We detected TC and TC-released exosomes near SMCs. TAA-TC-exosomes showed a significant increase of the SMC-related dedifferentiation markers KLF-4-, VEGF-A-, and PDGF-A-protein levels, as well as miRNA-expression levels of miR-146a, miR-221 and miR-222. SMCs treated with TAA-TC-exosomes developed a dedifferentiation-phenotype. In conclusion, the study shows for the first time that TCs are involved in development of TAA and could play a crucial role in SMC phenotype switching by release of extracellular vesicles.
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Affiliation(s)
- Thomas Aschacher
- Department of Cardiovascular Surgery, Clinic Floridsdorf and Karl Landsteiner Institute for Cardio-Vascular Research, 1210 Vienna, Austria; (B.W.); (Z.A.); (M.G.)
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria; (E.E.); (B.M.); (G.L.); (M.P.E.)
- Correspondence: ; Tel.: +43-1-277-00-74316
| | - Olivia Aschacher
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, 1090 Vienna, Austria;
| | - Katy Schmidt
- Center for Anatomy and Cell Biology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Florian K. Enzmann
- Department of Vascular Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Eva Eichmair
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria; (E.E.); (B.M.); (G.L.); (M.P.E.)
| | - Bernhard Winkler
- Department of Cardiovascular Surgery, Clinic Floridsdorf and Karl Landsteiner Institute for Cardio-Vascular Research, 1210 Vienna, Austria; (B.W.); (Z.A.); (M.G.)
| | - Zsuzsanna Arnold
- Department of Cardiovascular Surgery, Clinic Floridsdorf and Karl Landsteiner Institute for Cardio-Vascular Research, 1210 Vienna, Austria; (B.W.); (Z.A.); (M.G.)
| | - Felix Nagel
- Department of Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria; (F.N.); (B.K.P.)
| | - Bruno K. Podesser
- Department of Biomedical Research, Medical University of Vienna, 1090 Vienna, Austria; (F.N.); (B.K.P.)
| | - Andreas Mitterbauer
- Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria; (A.M.); (M.B.)
| | - Barbara Messner
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria; (E.E.); (B.M.); (G.L.); (M.P.E.)
| | - Martin Grabenwöger
- Department of Cardiovascular Surgery, Clinic Floridsdorf and Karl Landsteiner Institute for Cardio-Vascular Research, 1210 Vienna, Austria; (B.W.); (Z.A.); (M.G.)
| | - Günther Laufer
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria; (E.E.); (B.M.); (G.L.); (M.P.E.)
| | - Marek P. Ehrlich
- Department of Cardiac Surgery, Medical University of Vienna, 1090 Vienna, Austria; (E.E.); (B.M.); (G.L.); (M.P.E.)
| | - Michael Bergmann
- Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria; (A.M.); (M.B.)
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MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways. Genes (Basel) 2022; 13:genes13040665. [PMID: 35456471 PMCID: PMC9027908 DOI: 10.3390/genes13040665] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/07/2022] [Accepted: 04/07/2022] [Indexed: 02/04/2023] Open
Abstract
Background. Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant genetic disorder characterized by life-threatening vascular dysplasia. Myeloid angiogenic cells (MACs), alternatively called early endothelial progenitor cells or circulating angiogenic cells, do not directly incorporate into developing blood vessels, but augment angiogenesis in a paracrine manner. MAC dysfunction has been reported in HHT. MicroRNAs (miRNAs) regulate cellular function by modulating gene expression post-transcriptionally. To date, the role of miRNAs in HHT MAC dysfunction has not been documented. Objective. The goal of this study was to comparatively profile miRNAs in HHT patient and control MACs to identify dysregulated miRNAs that may be responsible for the observed MAC dysfunction in HHT. Methodology/Results. Twenty-three dysregulated miRNAs (twenty-one upregulated and two downregulated) in HHT MACs were identified with a TaqMan miRNA microarray. Pathway enrichment analysis showed that the dysregulated miRNAs were significantly enriched in pathways involved in HHT pathogenesis, such as the transforming growth factor β (TGFβ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Hippo signalling pathways. Furthermore, miR-132-3p was determined to be significantly reduced in HHT MACs compared with controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis revealed that miR-132-3p is significantly enriched in the TGFβ and PI3K/AKT signalling pathways, targeting SMAD4, an effector of the TGFβ signalling pathway and RASA1, a negative regulator of the PI3K/AKT signalling pathway, respectively. Conclusion. MiRNA dysregulation, specifically reduced expression of miR-132-3p, in HHT MACs was identified. The dysregulated miRNAs are significantly enriched in the TGFβ, PI3K/AKT, and Hippo signalling pathways. These data suggest that alteration in miRNA expression may impair these pathways and contribute to MAC dysfunction in HHT.
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Han X, Zhang G, Chen G, Wu Y, Xu T, Xu H, Liu B, Zhou Y. Buyang Huanwu Decoction promotes angiogenesis in myocardial infarction through suppression of PTEN and activation of the PI3K/Akt signalling pathway. JOURNAL OF ETHNOPHARMACOLOGY 2022; 287:114929. [PMID: 34952189 DOI: 10.1016/j.jep.2021.114929] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/07/2021] [Accepted: 12/16/2021] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Myocardial infarction (MI) is the most severe subtype of coronary artery disease. Recent studies have demonstrated that the repair process and prognosis of MI are closely related to microcirculatory function in myocardial tissue. Buyang Huanwu Decoction (BYHWD) has shown great potential in the treatment of MI. However, the effects and mechanisms of BYHWD on angiogenesis post-MI remain unclear. AIM OF THE STUDY The study aimed to explore the promotion of angiogenesis by BYHWD post-MI and the potential mechanisms in vivo and in vitro. MATERIALS AND METHODS MI in mice was induced by permanent ligature of the coronary artery. The sample was divided into sham, model, and BYHWD treatment groups. After four weeks, the effects of BYHWD treatment on cardiac function were evaluated by echocardiography and HE and Masson staining. Angiogenesis was detected by CD 31 immunofluorescence staining in vivo. Then, various databases were searched to identify the corresponding targets of BYHWD in order to explore the molecular mechanisms underlying its effects in MI. Moreover, Western blot and immunohistochemistry were employed to measure the PTEN/PI3K/Akt/GSK3β signalling pathway and VEGFA expression in MI mice. Finally, the effects of BYHWD on cell angiogenesis and the activation of the PTEN/PI3K/Akt/GSK3β pathway in primary HUVECs were investigated. Overexpression of PTEN was achieved by an adenovirus vector encoding PTEN. RESULTS BYHWD significantly promoted angiogenesis and improved cardiac function in MI mice. Target prediction analysis suggested that BYHWD ameliorates MI via the PI3K/Akt pathway. BYHWD promoted angiogenesis post-MI by suppressing PTEN and activating the PI3K/Akt/GSK3β signalling pathway in vivo and in vitro. Moreover, the effects of BYHWD on HUVEC angiogenesis and the expression of PI3K/Akt/GSK3β signalling pathway-associated proteins were partially abrogated by the overexpression of PTEN. CONCLUSION Collectively, this study demonstrates that BYHWD exerts cardioprotective effects against MI by targeting angiogenesis. These effects are related to suppressing PTEN and activating the PI3K/Akt/GSK3β signalling pathway by BYHWD.
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Affiliation(s)
- Xin Han
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Guoyong Zhang
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Guanghong Chen
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Yuting Wu
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Tong Xu
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Honglin Xu
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China
| | - Bin Liu
- Department of Traditional Chinese Medicine (Institute of Integration of Traditional and Western Medicine of Guangzhou Medical University, State Key Laboratory of Respiratory Disease), The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 510260, China.
| | - Yingchun Zhou
- School of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Nanfang Hospital (ZengCheng Branch), Southern Medical University, Guangzhou, 510515, China.
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Ferentinos P, Tsakirides C, Swainson M, Davison A, Martyn-St James M, Ispoglou T. The impact of different forms of exercise on circulating endothelial progenitor cells in cardiovascular and metabolic disease. Eur J Appl Physiol 2022. [PMID: 35022875 DOI: 10.1007/s00421-021-04876-1.pmid:35022875;pmcid:pmc8927049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2023]
Abstract
UNLABELLED Circulating endothelial progenitor cells (EPCs) contribute to vascular repair and their monitoring could have prognostic clinical value. Exercise is often prescribed for the management of cardiometabolic diseases, however, it is not fully understood how it regulates EPCs. OBJECTIVES to systematically examine the acute and chronic effects of different exercise modalities on circulating EPCs in patients with cardiovascular and metabolic disease. METHODS Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. RESULTS six electronic databases and reference lists of eligible studies were searched to April 2021. Thirty-six trials met the inclusion criteria including 1731 participants. Acute trials: in chronic heart failure (CHF), EPC mobilisation was acutely increased after high intensity interval or moderate intensity continuous exercise training, while findings were inconclusive after a cardiopulmonary cycling exercise test. Maximal exercise tests acutely increased EPCs in ischaemic or revascularized coronary artery disease (CAD) patients. In peripheral arterial disease (PAD), EPC levels increased up to 24 h post-exercise. In patients with compromised metabolic health, EPC mobilisation was blunted after a single exercise session. Chronic trials: in CHF and acute coronary syndrome, moderate intensity continuous protocols, with or without resistance exercise or calisthenics, increased EPCs irrespective of EPC identification phenotype. Findings were equivocal in CAD regardless of exercise mode, while in severe PAD disease EPCs increased. High intensity interval training increased EPCs in hypertensive metabolic syndrome and heart failure reduced ejection fraction. CONCLUSION the clinical condition and exercise modality influence the degree of EPC mobilisation and magnitude of EPC increases in the long term.
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Affiliation(s)
| | | | - Michelle Swainson
- Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
| | - Adam Davison
- Flow Cytometry Facility, Leeds Institute of Cancer and Pathology St James's University Hospital, University of Leeds, Leeds, UK
- Cytec Biosciences B.V, Amsterdam, The Netherlands
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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