|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences. Int J Mol Sci 2021; 22:ijms222413675. [PMID: 34948469 PMCID: PMC8708779 DOI: 10.3390/ijms222413675] [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: 11/13/2021] [Revised: 12/12/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022] Open
Abstract
Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage and repair, together with the preservation of endothelial integrity, is of crucial importance for the homeostasis of endothelium. Endothelial Progenitor Cells (EPCs) represent a heterogenous cell population, characterized by the ability to differentiate into mature endothelial cells (ECs), which contribute to vascular homeostasis, neovascularization and endothelial repair. A modification of the number and function of EPCs has been described in numerous chronic inflammatory and auto-immune conditions; however, reports that focus on the number and functions of EPCs in RA are characterized by conflicting results, and discrepancies exist among different studies. In the present review, the authors describe EPCs' role and response to RA-related endothelial modification, with the aim of illustrating current evidence regarding the level of EPCs and their function in this disease, to summarize EPCs' role as a biomarker in cardiovascular comorbidities related to RA, and finally, to discuss the modulation of EPCs secondary to RA therapy.
Collapse
|
|
3
|
Bonora BM, Albiero M, Morieri ML, Cappellari R, Amendolagine FI, Mazzucato M, Zambon A, Iori E, Avogaro A, Fadini GP. Fenofibrate increases circulating haematopoietic stem cells in people with diabetic retinopathy: a randomised, placebo-controlled trial. Diabetologia 2021; 64:2334-2344. [PMID: 34368894 DOI: 10.1007/s00125-021-05532-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/18/2021] [Indexed: 11/27/2022]
Abstract
AIM/HYPOTHESIS In two large RCTs, fenofibrate reduced the progression of diabetic retinopathy. We investigated whether fenofibrate increases circulating haematopoietic stem/progenitor cells (HSPCs), which have vascular properties and have been shown to protect from retinopathy. METHODS We conducted a 12 week parallel-group RCT comparing fenofibrate vs placebo. Patients with diabetic retinopathy and without other conditions that would affect HSPCs were enrolled at a tertiary diabetes outpatient clinic and randomised to receive fenofibrate or placebo based on a computer-generated sequence. Patients and study staff assessing the outcomes were blinded to group assignment. The primary endpoint was the change in the levels of circulating HSPCs, defined by expression of the stem cell markers CD34 and/or CD133. Secondary endpoints were the changes in endothelial progenitor cells, lipids, soluble mediators and gene expression. We used historical data on the association between HSPCs and retinopathy outcomes to estimate the effect of fenofibrate on retinopathy progression. RESULTS Forty-two participants with diabetic retinopathy were randomised and 41 completed treatment and were analysed (20 in the placebo group and 21 in the fenofibrate group). Mean age was 57.4 years, diabetes duration was 18.2 years and baseline HbA1c was 60 mmol/mol (7.6%). When compared with placebo, fenofibrate significantly increased levels of HSPCs expressing CD34 and/or CD133. CD34+ HSPCs non-significantly declined in the placebo group (mean ± SD -44.2 ± 31.6 cells/106) and significantly increased in the fenofibrate group (53.8 ± 31.1 cells/106). The placebo-subtracted increase in CD34+ HSPCs from baseline was 30% (99.3 ± 43.3 cells/106; p = 0.027) which, projected onto the relationship between HSPC levels and retinopathy outcomes, yielded an OR of retinopathy progression of 0.67 for fenofibrate vs placebo. Endothelial differentiation of CD34+ cells, estimated by the %KDR (kinase insert domain receptor) expression, was significantly reduced by fenofibrate. Fenofibrate decreased serum triacylglycerols, but the change in triacylglycerols was unrelated to the change in HSPCs. No effect was observed for endothelial progenitor cells, cytokines/chemokines (stromal-cell derived factor-1, vascular endothelial growth factor, monocyte chemoattractant protein-1) and gene expression in peripheral blood mononuclear cells. CONCLUSIONS/INTERPRETATION Fenofibrate increased HSPC levels in participants with diabetic retinopathy and this mechanism may explain why fenofibrate reduced retinopathy progression in previous studies. TRIAL REGISTRATION ClinicalTrials.gov NCT01927315.
Collapse
Affiliation(s)
- Benedetta Maria Bonora
- Department of Medicine, University of Padova, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Mattia Albiero
- Department of Medicine, University of Padova, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | | | | | | | | | - Alberto Zambon
- Department of Medicine, University of Padova, Padua, Italy
| | | | - Angelo Avogaro
- Department of Medicine, University of Padova, Padua, Italy
| | - Gian Paolo Fadini
- Department of Medicine, University of Padova, Padua, Italy.
- Veneto Institute of Molecular Medicine, Padua, Italy.
| |
Collapse
|
|
4
|
Szymanska M, Mahmood D, Yap TE, Cordeiro MF. Recent Advancements in the Medical Treatment of Diabetic Retinal Disease. Int J Mol Sci 2021; 22:ijms22179441. [PMID: 34502350 PMCID: PMC8430918 DOI: 10.3390/ijms22179441] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetic retinal disease remains one of the most common complications of diabetes mellitus (DM) and a leading cause of preventable blindness. The mainstay of management involves glycemic control, intravitreal, and laser therapy. However, intravitreal therapy commonly requires frequent hospital visits and some patients fail to achieve a significant improvement in vision. Novel and long-acting therapies targeting a range of pathways are warranted, while evidence to support optimal combinations of treatments is currently insufficient. Improved understanding of the molecular pathways involved in pathogenesis is driving the development of therapeutic agents not only targeting visible microvascular disease and metabolic derangements, but also inflammation and accelerated retinal neurodegeneration. This review summarizes the current and emerging treatments of diabetic retinal diseases and provides an insight into the future of managing this important condition.
Collapse
Affiliation(s)
- Maja Szymanska
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Daanyaal Mahmood
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Timothy E. Yap
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
| | - Maria F. Cordeiro
- The Imperial College Ophthalmic Research Group (ICORG), Imperial College London, London NW1 5QH, UK; (M.S.); (D.M.); (T.E.Y.)
- The Western Eye Hospital, Imperial College Healthcare NHS Trust (ICHNT), London NW1 5QH, UK
- Glaucoma and Retinal Neurodegeneration Group, Department of Visual Neuroscience, UCL Institute of Ophthalmology, London EC1V 9EL, UK
- Correspondence:
| |
Collapse
|
|
5
|
Endothelial Progenitor Cells Dysfunctions and Cardiometabolic Disorders: From Mechanisms to Therapeutic Approaches. Int J Mol Sci 2021; 22:ijms22136667. [PMID: 34206404 PMCID: PMC8267891 DOI: 10.3390/ijms22136667] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/10/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of several disorders, such as hypertension, central obesity, dyslipidemia, hyperglycemia, insulin resistance and non-alcoholic fatty liver disease. Despite health policies based on the promotion of physical exercise, the reduction of calorie intake and the consumption of healthy food, there is still a global rise in the incidence and prevalence of MetS in the world. This phenomenon can partly be explained by the fact that adverse events in the perinatal period can increase the susceptibility to develop cardiometabolic diseases in adulthood. Individuals born after intrauterine growth restriction (IUGR) are particularly at risk of developing cardiovascular diseases (CVD) and metabolic disorders later in life. It has been shown that alterations in the structural and functional integrity of the endothelium can lead to the development of cardiometabolic diseases. The endothelial progenitor cells (EPCs) are circulating components of the endothelium playing a major role in vascular homeostasis. An association has been found between the maintenance of endothelial structure and function by EPCs and their ability to differentiate and repair damaged endothelial tissue. In this narrative review, we explore the alterations of EPCs observed in individuals with cardiometabolic disorders, describe some mechanisms related to such dysfunction and propose some therapeutical approaches to reverse the EPCs dysfunction.
Collapse
|
|
6
|
Nensat C, Songjang W, Tohtong R, Suthiphongchai T, Phimsen S, Rattanasinganchan P, Metheenukul P, Kumphune S, Jiraviriyakul A. Porcine placenta extract improves high-glucose-induced angiogenesis impairment. BMC Complement Med Ther 2021; 21:66. [PMID: 33602182 PMCID: PMC7893890 DOI: 10.1186/s12906-021-03243-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/09/2021] [Indexed: 11/29/2022] Open
Abstract
Background High glucose (HG)-induced reactive oxygen species (ROS) overproduction impairs angiogenesis that is one pivotal factor of wound healing process. Angiogenesis impairment induces delayed wound healing, whereby it eventually leads to amputation in cases of poorly controlled diabetes with diabetic ulceration. Porcine placenta extract (PPE) is a natural waste product that comprises plenty of bioactive agents including growth factors and antioxidants. It was reported as an effective compound that prevents ROS generation. The goal of this study was to investigate the in vitro effect of PPE on HG-induced ROS-mediated angiogenesis impairment. Methods Primary endothelial cells (HUVECs) and endothelial cell line (EA.hy926) were treated with HG in the presence of PPE. The endothelial cells (ECs) viability, intracellular ROS generation, migration, and angiogenesis were determined by MTT assay, DCFDA reagent, wound healing assay, and tube formation assay, respectively. Additionally, the molecular mechanism of PPE on HG-induced angiogenesis impairment was investigated by Western blot. The angiogenic growth factor secretion was also investigated by the sandwich ELISA technique. Results HG in the presence of PPE significantly decreased intracellular ROS overproduction compared to HG alone. HG in the presence of PPE significantly increased ECs viability, migration, and angiogenesis compared to HG alone by showing recovery of PI3K/Akt/ERK1/2 activation. HG in the presence of PPE also decreased ECs apoptosis compared to HG alone by decreasing p53/Bax/cleaved caspase 9/cleaved caspase 3 levels and increasing Bcl 2 level. Conclusion PPE attenuated HG-induced intracellular ROS overproduction that improved ECs viability, proliferation, migration, and angiogenesis by showing recovery of PI3K/Akt/ERK1/2 activation and inhibition of ECs apoptosis. This study suggests PPE ameliorated HG-induced ROS-mediated angiogenesis impairment, whereby it potentially provides an alternative treatment for diabetic wounds. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-021-03243-z.
Collapse
Affiliation(s)
- Chatchai Nensat
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand.,Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand
| | - Worawat Songjang
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand.,Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand
| | - Rutaiwan Tohtong
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
| | | | - Suchada Phimsen
- Department of Biochemistry, Faculty of Medical Science, Naresuan University, Phitsanulok, 65000, Thailand
| | | | - Pornphimon Metheenukul
- Department of Veterinary Technology, Faculty of Veterinery Technology, Kasetsart University, Bangkok, 10900, Thailand
| | - Sarawut Kumphune
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand.,Biomedical Engineering Institute (BMEI), Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Arunya Jiraviriyakul
- Integrative Biomedical Research Unit (IBRU), Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand. .,Department of Medical Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, 65000, Thailand.
| |
Collapse
|
|
7
|
Liu D, Zheng W, Pan S, Liu Z. Concise review: current trends on applications of stem cells in diabetic nephropathy. Cell Death Dis 2020; 11:1000. [PMID: 33221823 PMCID: PMC7680458 DOI: 10.1038/s41419-020-03206-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy, with high prevalence, is the main cause of renal failure in diabetic patients. The strategies for treating DN are limited with not only high cost but an unsatisfied effect. Therefore, the effective treatment of DN needs to be explored urgently. In recent years, due to their self-renewal ability and multi-directional differentiation potential, stem cells have exerted therapeutic effects in many diseases, such as graft-versus-host disease, autoimmune diseases, pancreatic diseases, and even acute kidney injury. With the development of stem cell technology, stem cell-based regenerative medicine has been tried to be applied to the treatment of DN. Related stem cells include embryonic stem cells, induced pluripotent stem cells, mesenchymal cells, and endothelial progenitor cells. Undoubtedly, stem cell transplantation has achieved certain results in the treatment of DN animal models. However, stem cell therapy still remains certain thorny issues during treatment. For instance, poor engraftment and limited differentiation of stem cells caused by the diabetic microenvironment, differentiation into unwanted cell lineages, and malignant transformation or genetic aberrations of stem cells. At present, various researches on the therapeutic effects of stem cells in DN with different opinions are reported and the specific mechanism of stem cells is still unclear. We review here the potential mechanism of stem cells as new therapeutic agents in the treatment of DN. Also, we review recent findings and updated information about not only the utilization of stem cells on DN in both preclinical and clinical trials but limitations and future expectations of stem cell-based therapy for DN.
Collapse
Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Wen Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China. .,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China.
| |
Collapse
|
|
8
|
Eleftheriadou I, Dimitrakopoulou N, Kafasi N, Tentolouris A, Dimitrakopoulou A, Anastasiou IA, Mourouzis I, Jude E, Tentolouris N. Endothelial progenitor cells and peripheral neuropathy in subjects with type 2 diabetes mellitus. J Diabetes Complications 2020; 34:107517. [PMID: 31928893 DOI: 10.1016/j.jdiacomp.2019.107517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/10/2019] [Accepted: 12/28/2019] [Indexed: 01/18/2023]
Abstract
AIMS To examine for differences in circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs) in patients with and without diabetic peripheral neuropathy (DPN). METHODS A total of 105 participants were included: 50 patients with type 2 diabetes (T2DM) and DPN, 30 patients with T2DM without DPN and 25 healthy individuals. CPCs and 6 different EPCs phenotypes were assessed with flow cytometry. We also measured plasma levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor 1 (SDF-1), vascular cell adhesion protein-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM) and tumor necrosis factor a (TNFa). RESULTS No difference was observed in the number of CPCs among the 3 groups. Patients with DPN had higher numbers of all 6 EPCs phenotypes when compared with patients without DPN and higher number of 5 EPCs phenotypes when compared with healthy individuals. Plasma VEFG, VCAM-1, ICAM-1 and TNFa levels did not differ among the 3 groups. Patients with DPN had lower SDF-1 levels in comparison with healthy individuals. CONCLUSION Circulating EPCs are increased while SDF-1 levels are decreased in the presence of DPN. Our findings suggest that DPN may be associated with impaired trafficking of EPCs and impaired EPCs homing to the injured endothelium.
Collapse
Affiliation(s)
- Ioanna Eleftheriadou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece; Diabetic Foot Clinic, King's College Hospital, London, UK
| | - Natalia Dimitrakopoulou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Nikolitsa Kafasi
- Department of Immunology and Histocompatibility, Laiko General Hospital, Athens, Greece
| | - Anastasios Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | | | - Ioanna A Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Iordanis Mourouzis
- Department of Pharmacology, School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Edward Jude
- Tameside General Hospital, Ashton-Under-Lyne, Lancashire, UK
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
| |
Collapse
|
|
9
|
Hafner J, Zierfuss B, Schernthaner GH, Schmidt-Erfurth U. From the eye into the foot? Atherosclerosis 2020; 294:41-43. [DOI: 10.1016/j.atherosclerosis.2019.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 12/12/2019] [Indexed: 11/29/2022]
|
|
10
|
Rheumatoid arthritis (RA) and cardiovascular disease. Autoimmun Rev 2019; 18:679-690. [PMID: 31059840 DOI: 10.1016/j.autrev.2019.05.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 01/27/2019] [Indexed: 12/13/2022]
Abstract
Patients with rheumatoid arthritis (RA) suffer cardiovascular events 1.5-2 fold than the general population, and cardiovascular (CV) events are leading cause of death in patients with RA. It is known that patients with RA have endothelial dysfunction, related with impaired function of endothelial progenitor cells (EPCs). The mechanistic pathways leading to endothelial function are complicated, but understanding these mechanisms may open new frontiers of management and therapies to patients suffering from atherosclerosis. Inflammation is a key factor in atherosclerosis, including endothelial function, plaque stabilization and post infarct remodeling; thus, inhibition of TNF-α may affect the inflammatory burden and plaque vulnerability leading to less cardiovascular events and myocardial infarctions. An aggressive management of inflammation may lead to a significant improvement in the clinical cardiovascular outcome of patients with RA. The clinical evidence that showed a reduced risk of CV events following treatment with anti-inflammatory agents may suggest a new approach to treat atherosclerosis, i.e., inhibition of inflammation using biological medications that were primarily aimed to treat the high scale inflammation of RA and other autoimmune-inflammatory diseases, but may be useful also to prevent progression of atherosclerosis.
Collapse
|
|
11
|
Huang YC, Liao WL, Lin JM, Chen CC, Liu SP, Chen SY, Lin YN, Lei YJ, Liu HT, Chen YJ, Tsai FJ. High levels of circulating endothelial progenitor cells in patients with diabetic retinopathy are positively associated with ARHGAP22 expression. Oncotarget 2018; 9:17858-17866. [PMID: 29707151 PMCID: PMC5915159 DOI: 10.18632/oncotarget.24909] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 09/21/2017] [Indexed: 01/08/2023] Open
Abstract
Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 (ARHGAP22) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR. Fifty T2D patients with DR were recruited. Circulating EPCs were characterized as CD31+/vascular endothelial growth factor-2+/CD45dim/CD133+ and were quantified using triple staining flow cytometry. Real-time polymerase chain reaction tests were used to quantify ARHGAP22 expression. We found that T2D patients with proliferative DR had significantly lower EPC levels than those with non-proliferative DR (P = 0.028). T2D patients with EPC levels above the median value (> 4 cells/105 events) had higher levels of ARHGAP22 expression (P = 0.002). EPC levels were positively correlated with ARHGAP22 expression (r = 0.364, P = 0.009). Among T2D patients with DR, a higher expression of ARHGAP22 was associated with higher levels of EPCs. ARHGAP22 may be involved in the mobilization or active circulation of EPCs, thus contributing to neovascularization during DR development.
Collapse
Affiliation(s)
- Yu-Chuen Huang
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Wen-Ling Liao
- Center for Personalized Medicine, China Medical University Hospital, Taichung 404, Taiwan.,Graduate Institute of Integrated Medicine, China Medical University, Taichung 404, Taiwan
| | - Jane-Ming Lin
- Department of Ophthalmology, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Ching-Chu Chen
- Division of Endocrinology and Metabolism, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Shih-Ping Liu
- Center for Translational Medicine, China Medical University Hospital, Taichung 404, Taiwan.,Graduate Institute of Biomedical Science, China Medical University, Taichung 404, Taiwan.,Department of Social Work, Asia University, Taichung 413, Taiwan
| | - Shih-Yin Chen
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,School of Chinese Medicine, China Medical University, Taichung 404, Taiwan
| | - Yu-Ning Lin
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Yu-Jie Lei
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Huan-Ting Liu
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
| | - Yu-Jen Chen
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,Department of Radiation Oncology, Mackay Memorial Hospital, Taipei 104, Taiwan.,Department of Medical Research, Mackay Memorial Hospital, New Taipei City 251, Taiwan.,Institute of Traditional Medicine, National Yang-Ming University, Taipei 112, Taiwan
| | - Fuu-Jen Tsai
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan.,Children's Hospital of China Medical University, Taichung 404, Taiwan.,Department of Medical Genetics, China Medical University Hospital, Taichung 404, Taiwan.,Department of Biotechnology, Asia University, Taichung 413, Taiwan
| |
Collapse
|
|
12
|
Abstract
Endothelial progenitor cells (EPCs) promote angiogenesis and play a pivotal role in endothelial repair and re-endothelialization after vascular injury. Transient receptor potential-canonical1 (TRPC1) has been recently implied to play important roles on EPC function. Here, we studied the role of TRPC1 in regulating EPC function in vivo and in vitro. EPCs were cultured from TRPC1-knockout mice and their controls. In vitro, TRPC1 knockout reduced EPC functional activities, including migration and tube formation. Additionally, calmodulin (CaM)/endothelial nitric oxide synthase (eNOS) signaling activity were downregulated after TRPC1 knockout. Administration of CaM or eNOS inhibitor ameliorated TRPC1 knockout-reduced EPC migration and tube formation. In vivo Matrigel plug assay confirmed that TRPC1 knockout decreased formation of functional blood vessels of EPCs compared with wild-type EPCs. Taken together, these data suggest that TRPC1 is a critical regulator of angiogenesis.
Collapse
|
|
13
|
Berezin AE. Cardiac biomarkers in diabetes mellitus: New dawn for risk stratification? Diabetes Metab Syndr 2017; 11 Suppl 1:S201-S208. [PMID: 28011232 DOI: 10.1016/j.dsx.2016.12.032] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 12/12/2016] [Indexed: 12/21/2022]
Abstract
Type 2 diabetes mellitus (T2DM) remains a leading cause of cardiovascular (CV) events and diseases worldwide. The aim of the review is to summarize our knowledge regarding clinical implementation of the biomarker-based strategy of the CV risk assessment in T2DM patient population. There is large body of evidence regarding use of the cardiac biomarkers to risk stratification at higher CV risk individuals who belongs to general population and cohort with established CV disease. Although T2DM patients have higher incidence of macrovascular and microvascular CV complications than the general population, whether cardiac biomarkers would be effective to risk stratification of the T2DM is not fully understood. The role of natriuretic peptides, galectin-3, interleukins, growth differentiation factor-15, as well as biomarkers of endothelial dysfunction are widely discussed. In conclusion, future directions, which associate with discovering of novel biomarkers and their best combinations to provide additional predictive information beyond other traditional CV risk factors, are discussed.
Collapse
Affiliation(s)
- Alexander E Berezin
- Private Hospital "Vita-Center", Zaporozhye, Ukraine; Internal Medicine Department, Medical University of Zaporozhye, Ukraine.
| |
Collapse
|
|
14
|
Berezin AE. Endothelial progenitor cells dysfunction and impaired tissue reparation: The missed link in diabetes mellitus development. Diabetes Metab Syndr 2017; 11:215-220. [PMID: 27578620 DOI: 10.1016/j.dsx.2016.08.007] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 08/22/2016] [Indexed: 01/08/2023]
Abstract
Diabetes mellitus (DM) is considered a leading cause of premature cardiovascular (CV) mortality and morbidity in general population and in individuals with known CV disease. Recent animal and clinical studies have shown that reduced number and weak function of endothelial progenitor cells (EPCs) may not only indicate to higher CV risk, but contribute to the impaired heart and vessels reparation in patients with DM. Moreover, EPCs having a protective impact on the vasculature may mediate the functioning of other organs and systems. Therefore, EPCs dysfunction is probably promising target for DM treatment strategy, while the role of restoring of EPCs number and functionality in CV risk diminish and reduce of DM-related complications is not fully clear. The aim of the review is summary of knowledge regarding EPCs dysfunction in DM patients.
Collapse
Affiliation(s)
- Alexander E Berezin
- State Medical University of Zaporozhye, 26, Mayakovsky av., Zaporozhye, UA, 69035, Ukraine.
| |
Collapse
|
|
15
|
The inhibitory effects of polysaccharide peptides (PsP) of Ganoderma lucidum against atherosclerosis in rats with dyslipidemia. Heart Int 2017; 12:e1-e7. [PMID: 29114382 PMCID: PMC5460693 DOI: 10.5301/heartint.5000234] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2017] [Indexed: 01/01/2023] Open
Abstract
Background Atherosclerosis occurs as a result of low-density lipoprotein (LDL) deposits oxidation. Endothelial dysfunction is an early process of atherosclerosis. Restoring endothelial lining back to normal by endothelial progenitor cells (EPCs) is critical for slowing or reversing vascular disease progression. Oxidative stress from hydrogen peroxide (H2O2) is increased in dyslipidemia so that antioxidant agent is required to prevent destruction of blood vessels. Objectives This study aims to report Ganoderma lucidum polysaccharide peptide (PsP) effects in atherogenic process by measuring H2O2 level, IL-10 level, and EPC number in blood serum, and also intima-media thickness of aorta in dyslipidemia Wistar rat model by giving them a hypercholesterol diet (HCD). Materials and methods The study was an experimental in vivo post-test with control group design. Thirty-five Wistar rats (Rattus norwegicus) were divided into five groups (normal diet group, HCD group, and hypercholesterol groups that received 50 mg/kg, 150 mg/kg, and 300 mg/kg bodyweight PsP). Results Each treatment group showed significant results for the administration of PsP using the one-way analysis of variance test (p<0.050) for the reduction of H2O2 (p = 0.003), levels of IL-10 (p = 0.027), number of EPC in the blood serum (p = 0.011), and the intima-media thickness of the aorta (p = 0.000). PsP from G. lucidum is a potent antioxidant and may prevent atherogenesis process in patients with dyslipidemia. Conclusions The optimum doses of PsP in this study is 300 mg/kg bodyweight. Further studies are required to determine the antioxidant effects of PsP G. lucidum and its benefits in the management of dyslipidemia.
Collapse
|
|
16
|
Circulating progenitor and angiogenic cell frequencies are abnormally static over pregnancy in women with preconception diabetes: A pilot study. PLoS One 2017; 12:e0172988. [PMID: 28278173 PMCID: PMC5344347 DOI: 10.1371/journal.pone.0172988] [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: 09/29/2016] [Accepted: 02/13/2017] [Indexed: 11/30/2022] Open
Abstract
Type 1 and 2 diabetes decrease the frequencies and functional capacities of circulating angiogenic cells (CAC). Diabetes also elevates gestational complications. These observations may be interrelated. We undertook pilot studies to address the hypothesis that preconception diabetes deviates known gestational increases in CACs. Cross-sectional study of type 1 diabetic, type 2 diabetic and normoglycemic pregnant women was conducted at 1st, 2nd, and 3rd trimester and compared to a 6mo postpartum surrogate baseline. Circulating progenitor cells (CPC; CD34+CD45dimSSlow) and CACs (CD34+CD45dimSSlow expressing CD133 without or with KDR) were quantified by flow cytometry and by colony assay (CFU-Hill). In pregnant normoglycemic women, CD34+CD45dimSSlow cell frequency was greater in 1st and 3rd trimester than postpartum but frequency of these cells was static over type 1 or 2 diabetic pregnancies. Type 1 and type 2 diabetic women showed CACs variance versus normal controls. Type 1 diabetic women had more total CD34+KDR+ CACs in 1st trimester and a higher ratio of CD133+KDR+ to total CD133+ cells in 1st and 2nd trimesters than control women, demonstrating an unbalance in CD133+KDR+ CACs. Type 2 diabetic women had more CD133+KDR+ CACs in 1st trimester and fewer CD133+KDR- CACs at mid-late pregnancy than normal pregnant women. Thus, pregnancy stage-specific physiological fluctuation in CPCs (CD34+) and CACs (CD133+KDR+ and CD133+KDR-) did not occur in type 1 and type 2 diabetic women. Early outgrowth colonies were stable across normal and diabetic pregnancies. Therefore, preconception diabetes blocks the normal dynamic pattern of CAC frequencies across gestation but does not alter colony growth. The differences between diabetic and typical women were seen at specific gestational stages that may be critical for initiation of the uterine vascular pathologies characterizing diabetic gestations.
Collapse
|
|
17
|
Castela A, Gomes P, Silvestre R, Guardão L, Leite L, Chilro R, Rodrigues I, Vendeira P, Virag R, Costa C. Vasculogenesis and Diabetic Erectile Dysfunction: How Relevant Is Glycemic Control? J Cell Biochem 2016; 118:82-91. [PMID: 27237706 DOI: 10.1002/jcb.25613] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 05/26/2016] [Indexed: 12/16/2022]
Abstract
Erectile dysfunction (ED) is a complication of diabetes, condition responsible for causing endothelial dysfunction (EDys) and hampering repair mechanisms. However, scarce information is available linking vasculogenesis mediated by Endothelial Progenitor Cells (EPCs) and diabetes-associated ED. Furthermore, it remains to be elucidated if glycemic control plays a role on EPCs functions, EPCs modulators, and penile vascular health. We evaluated the effects of diabetes and insulin therapy on bone marrow (BM) and circulating EPCs, testosterone, and systemic/penile Stromal Derived Factor-1 alpha (SDF-1α) expression. Male Wistar rats were divided into groups: age-matched controls, 8-weeks streptozotocin-induced type 1 diabetics, and insulin-treated 8-weeks diabetics. EPCs were identified by flow cytometry for CD34/CD133/VEGFR2/CXCR4 antigens. Systemic SDF-1α and testosterone levels were evaluated by ELISA. Penile SDF-1α protein expression was assessed, in experimental and human diabetic cavernosal samples, by immunohistochemical techniques. Diabetic animals presented a reduction of BM-derived EPCs and an increase in putative circulating endothelial cells (CECs) sloughed from vessels wall. These alterations were rescued by insulin therapy. In addition, glycemic control promoted an increase in systemic testosterone and SDF-1α levels, which were significantly decreased in animals with diabetes. SDF-1α protein expression was reduced in experimental and human cavernosal diabetic samples, an effect prevented by insulin in treated animals. Insulin administration rescued the effects of diabetes on BM function, CECs levels, testosterone, and plasmatic/penile SDF-1α protein expression. This emphasizes the importance of glycemic control in the prevention of diabetes-induced systemic and penile EDys, by the amelioration of endothelial damage, and increase in protective pathways. J. Cell. Biochem. 118: 82-91, 2017. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Angela Castela
- Faculty of Medicine, Department of Biochemistry, University of Porto, Porto, Portugal.,Institute for Molecular and Cell Biology of the University of Porto (IBMC-UP), Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Pedro Gomes
- Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal
| | - Ricardo Silvestre
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Luísa Guardão
- Animal Facility, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Liliana Leite
- Animal Facility, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Rui Chilro
- Digital University, University of Porto, Porto, Portugal
| | - Ilda Rodrigues
- Faculty of Medicine, Department of Biochemistry, University of Porto, Porto, Portugal
| | - Pedro Vendeira
- Clínica Saúde Atlântica, Clínica Urológica Vendeira, Porto, Portugal
| | - Ronald Virag
- Centre d'Explorations et Traitements de l'Impuissance, Paris, France
| | - Carla Costa
- Faculty of Medicine, Department of Biochemistry, University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
18
|
Simó-Servat O, Simó R, Hernández C. Circulating Biomarkers of Diabetic Retinopathy: An Overview Based on Physiopathology. J Diabetes Res 2016; 2016:5263798. [PMID: 27376090 PMCID: PMC4916280 DOI: 10.1155/2016/5263798] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Accepted: 05/18/2016] [Indexed: 12/21/2022] Open
Abstract
Diabetic retinopathy (DR) is the main cause of working-age adult-onset blindness. The currently available treatments for DR are applicable only at advanced stages of the disease and are associated with significant adverse effects. In early stages of DR the only therapeutic strategy that physicians can offer is a tight control of the risk factors for DR. Therefore, new pharmacological treatments for these early stages of the disease are required. In order to develop therapeutic strategies for early stages of DR new diagnostic tools are urgently needed. In this regard, circulating biomarkers could be useful to detect early disease, to identify those diabetic patients most prone to progressive worsening who ought to be followed up more often and who could obtain the most benefit from these therapies, and to monitor the effectiveness of new drugs for DR before more advanced DR stages have been reached. Research of biomarkers for DR has been mainly based on the pathogenic mechanism involved in the development of DR (i.e., AGEs, oxidative stress, endothelial dysfunction, inflammation, and proangiogenic factors). This review focuses on circulating biomarkers at both early and advanced stages that could be relevant for the prediction or detection of DR.
Collapse
Affiliation(s)
- Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
| | - Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
| |
Collapse
|
|
19
|
Sukmawati D, Tanaka R, Ito-Hirano R, Fujimura S, Hayashi A, Itoh S, Mizuno H, Daida H. The role of Notch signaling in diabetic endothelial progenitor cells dysfunction. J Diabetes Complications 2016; 30:12-20. [PMID: 26598222 DOI: 10.1016/j.jdiacomp.2015.09.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 09/06/2015] [Accepted: 09/24/2015] [Indexed: 12/24/2022]
Abstract
AIMS To investigate the role of Notch signaling pathway in vasculogenic dysfunction of diabetic EPCs (DM-EPCs). METHODS The study was performed in mice and diabetes was induced with Streptozotocin. The functional consequences of Notch pathway modulation were studied by assessment of colony forming capacity (EPC colony forming assay), EPC differentiation capacity (% of definitive EPC-CFU (dEPC-CFU)), circulating EPCs (EPC culture assay) and migrated cells (migration assay); in the presence of Notch inhibitor (γ-secretase inhibitors (GSI)) compared to control. Notch pathway and VEGF involvement in DM- EPCs were assessed by gene expression (RT-qPCR). RESULTS DM demonstrated to increase Notch pathway expression in bone marrow (BM) EPCs followed by lower EPC-CFU number, EPCs differentiation capacity, number of circulating EPCs, migrated cells and VEGF expression compared to control (p<0.05). Inhibition of Notch pathway by GSI rescued vasculogenic dysfunction in DM-EPCs as represented by increase in EPC-CFU number, differentiation capacity and number of circulating EPCs (p<0.05). CONCLUSION Our findings indicate the involvement of Notch pathway in mediating DM-EPCs dysfunction including less number of EPC-CFU, circulating EPCs and migrated cell number compared to control. Further in vitro inhibition of Notch pathway by GSI rescued DM-EPC dysfunction. Therefore targeting Notch pathway in DM may provide a target to restore DM-EPC dysfunction.
Collapse
Affiliation(s)
- Dewi Sukmawati
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan; Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan; Department of Histology, Faculty of Medicine, Universitas Indonesia, Jakarta, Jalan Salemba Raya No. 6 Jakarta Pusat, 10430, Indonesia.
| | - Rica Tanaka
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Rie Ito-Hirano
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Satoshi Fujimura
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Ayato Hayashi
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Seigo Itoh
- Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Hiroshi Mizuno
- Department of Plastic Reconstructive Surgery, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| | - Hiroyuki Daida
- Department of Cardiovascular Medicine, Juntendo University, School of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113-8421, Japan.
| |
Collapse
|
|
20
|
Rigato M, Bittante C, Albiero M, Avogaro A, Fadini GP. Circulating Progenitor Cell Count Predicts Microvascular Outcomes in Type 2 Diabetic Patients. J Clin Endocrinol Metab 2015; 100:2666-72. [PMID: 25942480 DOI: 10.1210/jc.2015-1687] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
CONTEXT Diabetes reduces the levels of circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs), which promote vascular repair and are inversely correlated with cardiovascular risk. OBJECTIVE The objective of the study was to test whether CPC/EPC levels predict onset/progression of microangiopathy in a cohort of type 2 diabetic (T2D) patients. DESIGN This was a pseudoprospective study with a 3.9-year follow-up. SETTING The study was conducted at a tertial referral diabetes outpatient clinic. PATIENTS A total of 187 T2D patients having a baseline determination of CPCs/EPCs participated in the study. INTERVENTION Baseline data on demographics, anthropometrics, concomitant risk factors, diabetic complications, and medications were collected. MAIN OUTCOME MEASURE Onset or progression of microangiopathy was assessed at follow-up compared with baseline. RESULTS New onset or progression of microalbuminuria, chronic kidney disease, retinopathy, and neuropathy occurred in 70 patients (9.5%/y). After controlling the false discovery rate, baseline CD34(+) CPCs and EPCs were significantly lower in patients with onset/progression of microalbuminuria and any microangiopathy. Patients with baseline CD34(+) CPC or CD133(+)/kinase insert domain-containing receptor(+)/EPC levels below the median were more likely to experience worsening microangiopathy than those with high cell levels. Independently from confounders, including age, sex, glycated hemoglobin, and diabetes duration, CD34(+) cells predicted onset/progression of microalbuminuria, retinopathy, and any microangiopathy in false discovery rate-adjusted analyses. A low CD34(+) cell count limited the beneficial effects of renin-angiotensin system blockers on microalbuminuria progression. CONCLUSIONS Levels of circulating (endothelial) progenitor cells predict microvascular outcomes in T2D. Together with previous studies showing an association with cardiovascular events, these data indicate that CPCs/EPCs represent biomarkers of the global complication burden in diabetes.
Collapse
Affiliation(s)
- Mauro Rigato
- Division of Metabolic Diseases, Department of Medicine (M.R., C.B., M.A., A.A., G.P.F.), University of Padova, 35128 Padova, Italy; and Venetian Institute of Molecular Medicine (A.A., G.P.F.), 35128 Padova, Italy
| | - Cristina Bittante
- Division of Metabolic Diseases, Department of Medicine (M.R., C.B., M.A., A.A., G.P.F.), University of Padova, 35128 Padova, Italy; and Venetian Institute of Molecular Medicine (A.A., G.P.F.), 35128 Padova, Italy
| | - Mattia Albiero
- Division of Metabolic Diseases, Department of Medicine (M.R., C.B., M.A., A.A., G.P.F.), University of Padova, 35128 Padova, Italy; and Venetian Institute of Molecular Medicine (A.A., G.P.F.), 35128 Padova, Italy
| | - Angelo Avogaro
- Division of Metabolic Diseases, Department of Medicine (M.R., C.B., M.A., A.A., G.P.F.), University of Padova, 35128 Padova, Italy; and Venetian Institute of Molecular Medicine (A.A., G.P.F.), 35128 Padova, Italy
| | - Gian Paolo Fadini
- Division of Metabolic Diseases, Department of Medicine (M.R., C.B., M.A., A.A., G.P.F.), University of Padova, 35128 Padova, Italy; and Venetian Institute of Molecular Medicine (A.A., G.P.F.), 35128 Padova, Italy
| |
Collapse
|
|
21
|
Kachamakova-Trojanowska N, Bukowska-Strakova K, Zukowska M, Dulak J, Jozkowicz A. The real face of endothelial progenitor cells - Circulating angiogenic cells as endothelial prognostic marker? Pharmacol Rep 2015; 67:793-802. [PMID: 26321283 DOI: 10.1016/j.pharep.2015.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 05/18/2015] [Accepted: 05/19/2015] [Indexed: 02/08/2023]
Abstract
Endothelial progenitor cells (EPCs) have been extensively studied for almost 19 years now and were considered as a potential marker for endothelial regeneration ability. On the other hand, circulating endothelial cells (CEC) were studied as biomarker for endothelial injury. Yet, in the literature, there is also huge incoherency in regards to terminology and protocols used. This results in misleading conclusions on the role of so called "EPCs", especially in the clinical field. The discrepancies are mainly due to strong phenotypic overlap between EPCs and circulating angiogenic cells (CAC), therefore changes in "EPC" terminology have been suggested. Other factors leading to inconsistent results are varied definitions of the studied populations and the lack of universal data reporting, which could strongly affect data interpretation. The current review is focused on controversies concerning the use of "EPCs"/CAC and CEC as putative endothelial diagnostic markers.
Collapse
Affiliation(s)
- Neli Kachamakova-Trojanowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Karolina Bukowska-Strakova
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Monika Zukowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Jozef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Alicja Jozkowicz
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| |
Collapse
|
|
22
|
Circulating Dipeptidyl Peptidase-4 Activity is Associated with Diabetic Retinopathy in Type 1 Diabetic Patients. Eur J Ophthalmol 2015; 25:328-32. [DOI: 10.5301/ejo.5000547] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2014] [Indexed: 01/28/2023]
Abstract
Purpose Diabetic retinopathy (DR) is the most frequent complication among patients with type 1 diabetes mellitus (T1DM). Dipeptidyl peptidase–4 (DPP4) is a protease with elevated activity in patients with T1DM. Several studies indicate that DPP4 inhibitors might have beneficial effect on nonproliferative retinopathy (NPR) development as well as on its progression to proliferative retinopathy (PR). We aimed to explore the relationship between serum DPP4 activity and DR in patients with T1DM. Methods This cross-sectional study recruited 44 patients with T1DM. The DPP4 activity was measured by colorimetric assay in a microplate reader. Photodocumented retinopathy status was made according to the EURODIAB protocol. Results A total of 28 (63.6%) patients were men, mean age 45.36 years, diabetes duration 23.71 years, glycated hemoglobin A1c (HbA1c) 7.4%. Patients were stratified into 2 groups according to retinopathy prevalence. Group 1 comprised 14 (31.85%) patients with DR absence while the second group consisted of 30 (68.15%) patients with both PR and NPR. Group 1 had lower fasting serum DPP4 activity (25.85 vs 33.84 U/L, p<0.001) when compared to the second group. In the binary logistic regression model adjusted for age, sex, diabetes duration, and HbA1c level, DPP4 activity was associated with DR prevalence (odds ratio 1.887 [1.073-3.321]). Conclusions Serum DPP4 activity may be independently associated with both DR types in patients with T1DM. Further study is warranted to elucidate whether there is an association between DPP4 activity and DR severity and/or progression.
Collapse
|
|
23
|
Gandica Y, Schwarz T, Oliveira O, Travasso RDM. Hypoxia in vascular networks: a complex system approach to unravel the diabetic paradox. PLoS One 2014; 9:e113165. [PMID: 25409306 PMCID: PMC4237512 DOI: 10.1371/journal.pone.0113165] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 10/20/2014] [Indexed: 01/30/2023] Open
Abstract
In this work we model the extent of hypoxia in the diabetic retina as a function of the area affected by vessel disruption. We find two regimes that differ on the ratio between the area of disrupted vasculature and the area of tissue in hypoxia. In the first regime the hypoxia is localized in the vicinity of the vascular disruption, while in the second regime there is a generalized hypoxia in the affected tissue. The transition between these two regimes occurs when the tissue area affected by individual sites of vessel damage is on the order of the square of the characteristic irrigation length in the tissue (the maximum distance that an irrigated point in the tissue is from an existing vessel). We observe that very high levels of hypoxia are correlated with the rupture of larger vessels in the retina, and with smaller radii of individual sites of vessel damage. Based on this property of vascular networks, we propose a novel mechanism for the transition between the nonproliferative and the proliferative stages in diabetic retinopathy.
Collapse
Affiliation(s)
- Yérali Gandica
- Center for Computational Physics, Department of Physics, University of Coimbra, Coimbra, Portugal
| | - Tobias Schwarz
- Center for Computational Physics, Department of Physics, University of Coimbra, Coimbra, Portugal
- Heinz-Brandt-Schule, Berlin, Germany
| | - Orlando Oliveira
- Center for Computational Physics, Department of Physics, University of Coimbra, Coimbra, Portugal
| | - Rui D. M. Travasso
- Center for Computational Physics, Department of Physics, University of Coimbra, Coimbra, Portugal
- Center of Ophthalmology and Vision Sciences(COCV), Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- * E-mail:
| |
Collapse
|
|
24
|
Balaiya S, Grant MB, Priluck J, Chalam KV. Growth factors/chemokines in diabetic vitreous and aqueous alter the function of bone marrow-derived progenitor (CD34⁺) cells in humans. Am J Physiol Endocrinol Metab 2014; 307:E695-702. [PMID: 25159325 PMCID: PMC4200305 DOI: 10.1152/ajpendo.00253.2014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Ocular ischemic microenvironment plays a critical role in the progression of diabetic retinopathy (DR). In this study, we investigated the effect of vitreous and aqueous obtained from proliferative DR patients on the function of CD34⁺ cells derived from healthy humans. Human CD34⁺ cells were incubated with vitreous or aqueous of subjects with PDR. After incubation, cell migration of CD34⁺ was evaluated with CXCL12. Intracellular levels of nitric oxide (NO) were measured with DAF-FM. Tube formation assay was used to evaluate the effect of treated CD34⁺ cells on in vitro angiogenesis. Angiogenic protein array and mass spectrometry (MS) were performed to ascertain the factors secreted by healthy nondiabetic CD34⁺ cells exposed to diabetic vitreous or aqueous. PDR vitreous/aqueous reduced migration of CD34⁺ cells (672.45 ± 42.1/736.75 ± 101.7 AFU; P < 0.01) and attenuated intracellular NO levels (182 ± 1.4/184.5 ± 6.3 AFU, P = 0.002). Pretreatment with PDR vitreous suppressed tube formation of human retinal endothelial cells (64 ± 1.6 vs. 80 ± 2.5). CD34⁺ exposed to PDR vitreous resulted in the increased expression of CXCL4 and serpin F1, whereas CD34⁺ exposed to PDR aqueous showed increased expression of CXCL4, serpin F1, and endothelin-1 (ET-1). MS analysis of CD34⁺ (exposed to PDR vitreous) expressed J56 gene segment, isoform 2 of SPARC-related modular calcium-binding protein 2, isoform 1 of uncharacterized protein c1 orf167, integrin α-M, and 40s ribosomal protein s21. Exposure of healthy nondiabetic CD34⁺ cells to PDR vitreous and aqueous resulted in decreased migration, reduced generation of NO, and altered paracrine secretory function. Our results suggest that the contribution of CD34⁺ cells to the aberrant neovascularization observed in PDR is driven more by the proangiogenic effects of the retinal cells rather than the influence of the vitreous.
Collapse
Affiliation(s)
- Sankarathi Balaiya
- Department of Ophthalmology, University of Florida College of Medicine, Jacksonville, Florida; and
| | - Maria B Grant
- Eugene and Marilyn Glick Eye Institute, Indiana University, Indianapolis, Indiana
| | - Joshua Priluck
- Department of Ophthalmology, University of Florida College of Medicine, Jacksonville, Florida; and
| | - Kakarla V Chalam
- Department of Ophthalmology, University of Florida College of Medicine, Jacksonville, Florida; and
| |
Collapse
|
|
25
|
Ghanian Z, Maleki S, Park S, Sorenson CM, Sheibani N, Ranji M. Organ specific optical imaging of mitochondrial redox state in a rodent model of hereditary hemorrhagic telangiectasia-1. JOURNAL OF BIOPHOTONICS 2014; 7:799-809. [PMID: 23740865 PMCID: PMC4324470 DOI: 10.1002/jbio.201300033] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2013] [Revised: 04/24/2013] [Accepted: 05/13/2013] [Indexed: 05/09/2023]
Abstract
Hereditary Hemorrhagic Telangiectasia-1 (HHT-1) is a vascular disease caused by mutations in the endoglin (Eng)/CD105 gene. The objective of this study was to quantify the oxidative state of a rodent model of HHT-1 using an optical imaging technique. We used a cryofluorescence imaging instrument to quantitatively assess tissue metabolism in this model. Mitochondrial redox ratio (FAD/NADH), FAD RR, was used as a quantitative marker of the metabolic status and was examined in the kidneys, and eyes of wild-type and Eng +/- mice. Kidneys and eyes from wild-type P21, 6W, and 10M old mice showed, respectively, a 9% (±2), 24% (±0.4), 15% (±1), and 23% (±4), 33% (±0.6), and 30% (±2) change in the mean FAD RR compared to Eng +/- mice at the same age. Thus, endoglin haploinsufficiency is associated with less oxidative stress in various organs and mitigation of angiogenesis.
Collapse
Affiliation(s)
- Zahra Ghanian
- Department of Electrical Engineering, University of Wisconsin Milwaukee, Milwaukee, WI, USA
| | - Sepideh Maleki
- Department of Electrical Engineering, University of Wisconsin Milwaukee, Milwaukee, WI, USA
| | - SunYoung Park
- Departments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Christine M. Sorenson
- Departments of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Nader Sheibani
- Departments of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Mahsa Ranji
- Department of Electrical Engineering, University of Wisconsin Milwaukee, Milwaukee, WI, USA
| |
Collapse
|
|
26
|
Lee PSS, Poh KK. Endothelial progenitor cells in cardiovascular diseases. World J Stem Cells 2014; 6:355-366. [PMID: 25126384 PMCID: PMC4131276 DOI: 10.4252/wjsc.v6.i3.355] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2013] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells (EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vasculogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk factors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardiovascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evaluate the challenges facing EPC research and how these may be overcome.
Collapse
|
|
27
|
António N, Soares A, Fernandes R, Soares F, Lopes A, Carvalheiro T, Paiva A, Providência LA, Gonçalves L, Fontes Ribeiro C. Endothelial progenitor cells in diabetic patients with myocardial infarction - can statins improve their function? Eur J Pharmacol 2014; 741:25-36. [PMID: 25066111 DOI: 10.1016/j.ejphar.2014.07.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Revised: 07/07/2014] [Accepted: 07/09/2014] [Indexed: 11/26/2022]
Abstract
The effect of statins on endothelial progenitor cells (EPCs) function derived from diabetic patients (DMpts) with acute myocardial infarction (AMI) is unknown. In this study we assess the response of early and late EPCs from diabetic versus non-diabetic patients (NDMpts) with AMI to statins. EPCs were obtained from 10 diabetic and 10 age-matched non-diabetic male patients with AMI. For each patient, cultures of early and late EPCs were performed under 4 different conditions: normal glucose concentration (control); high glucose concentration; normal glucose concentration with atorvastatin supplementation and normal glucose concentration with pravastatin supplementation. To compare the effect of these treatments on EPC function in DMpts versus NDMpts, we performed in vitro: EPC colony-forming units (CFU) assay; cell cycle analysis; viability assessment and expression of the surface markers CXCR4, CD133, CD34 and KDR. Under control conditions, CFU numbers were reduced in DMpts-derived EPCs when compared to those of NDMpts (1.4±0.8 vs 2.6±1.2 CFU/well, P=0.021). When early EPCs from DMpts were cultured in the presence of statins, CFU capacity was restored, surmounting that of NDMpts under control conditions. Statins significantly improved viability of early EPCs and delayed the onset of late EPCs senescence, even in cells from DMpts. In addition, statins induced approximately a 2-fold increase in the proportion of late EPCs in S-phase of the cell cycle (P<0.05). Statins have a beneficial effect on both early and late EPCs from DMpts with AMI. Despite the functional impairment of EPCs from DMpts, they exhibit similar responsiveness to statins as equivalent cells from NDMpts.
Collapse
Affiliation(s)
- Natália António
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal; Cardiology Department, University Hospital Center of Coimbra, Portugal.
| | - Ana Soares
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal; Center of Ophthalmology and Vision Sciences, Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Portugal
| | - Rosa Fernandes
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal; Center of Ophthalmology and Vision Sciences, Institute for Biomedical Imaging and Life Science, Faculty of Medicine, University of Coimbra, Portugal
| | - Francisco Soares
- Cardiology Department, University Hospital Center of Coimbra, Portugal
| | - Ana Lopes
- Blood and Transplantation Center of Coimbra, Portuguese Institute of Blood and Transplantation, Coimbra, Portugal
| | - Tiago Carvalheiro
- Blood and Transplantation Center of Coimbra, Portuguese Institute of Blood and Transplantation, Coimbra, Portugal
| | - Artur Paiva
- Blood and Transplantation Center of Coimbra, Portuguese Institute of Blood and Transplantation, Coimbra, Portugal
| | | | - Lino Gonçalves
- Cardiology Department, University Hospital Center of Coimbra, Portugal
| | - Carlos Fontes Ribeiro
- Laboratory of Pharmacology and Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Portugal
| |
Collapse
|
|
28
|
Lois N, McCarter RV, O’Neill C, Medina RJ, Stitt AW. Endothelial progenitor cells in diabetic retinopathy. Front Endocrinol (Lausanne) 2014; 5:44. [PMID: 24782825 PMCID: PMC3988370 DOI: 10.3389/fendo.2014.00044] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 03/21/2014] [Indexed: 12/30/2022] Open
Abstract
Diabetic retinopathy (DR) is a leading cause of visual impairment worldwide. Patients with DR may irreversibly lose sight as a result of the development of diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR); retinal blood vessel dysfunction and degeneration plays an essential role in their pathogenesis. Although new treatments have been recently introduced for DME, including intravitreal vascular endothelial growth factor inhibitors (anti-VEGFs) and steroids, a high proportion of patients (~40-50%) do not respond to these therapies. Furthermore, for people with PDR, laser photocoagulation remains a mainstay therapy despite this being an inherently destructive procedure. Endothelial progenitor cells (EPCs) are a low-frequency population of circulating cells known to be recruited to sites of vessel damage and tissue ischemia where they promote vascular healing and re-perfusion. A growing body of evidence suggests that the number and function of EPCs are altered in patients with varying degrees of diabetes duration, metabolic control, and in the presence or absence of DR. Although there are no clear-cut outcomes from these clinical studies, there is mounting evidence that some EPC sub-types may be involved in the pathogenesis of DR and may also serve as biomarkers for disease progression and stratification. Moreover, some EPC sub-types have considerable potential as therapeutic modalities for DME and PDR in the context of cell therapy. This study presents basic clinical concepts of DR and combines this with a general insight on EPCs and their relation to future directions in understanding and treating this important diabetic complication.
Collapse
Affiliation(s)
- Noemi Lois
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Belfast, UK
| | - Rachel V. McCarter
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Belfast, UK
| | - Christina O’Neill
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Belfast, UK
| | - Reinhold J. Medina
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Belfast, UK
| | - Alan W. Stitt
- Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Science, Queen’s University Belfast, Royal Victoria Hospital, Belfast, UK
| |
Collapse
|
|
29
|
Liao YF, Feng Y, Chen LL, Zeng TS, Yu F, Hu LJ. Coronary heart disease risk equivalence in diabetes and arterial diseases characterized by endothelial function and endothelial progenitor cell. J Diabetes Complications 2014; 28:214-8. [PMID: 24332936 DOI: 10.1016/j.jdiacomp.2013.09.009] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Revised: 09/24/2013] [Accepted: 09/26/2013] [Indexed: 10/26/2022]
Abstract
AIMS Peripheral Arterial Disease (PAD), Carotid Artery Disease (CAD), and Type 2 Diabetes Mellitus (DM) were considered as "Coronary Heart Disease (CHD) risk equivalents". Vascular endothelial dysfunction was recognized as an early event in the development of atherosclerosis. Involved in neovasculogenesis and maintenance of vascular homeostasis, endothelial progenitor cell (EPC) has been considered as a biological marker of cardiovascular disease. The purpose of this study was to assess the CHD risk equivalents concept by investigating the endothelial function and circulating EPC number in patients with CHD, PAD, CAD and T2DM. METHODS There were four groups in the study: CHD (n = 19), AD [PAD and CAD (n = 17)], DM (n = 21) and healthy controls (HC, n = 20). PAD and CAD were assessed by ultrasonography. Coronal artery angiography was used to identify CHD. The diagnosis of T2DM was based on oral glucose tolerance test and medical history. Vascular endothelial function was assessed by flow-mediated brachial artery dilatation (FMD). Circulating EPC was quantified by flow cytometry. RESULTS The circulating EPC numbers in four groups were CHD, 973 ± 96; AD, 1048 ± 97; T2DM, 1210 ± 125; HC, 1649 ± 112 cells/ml. There were no significant differences in circulating EPC numbers between CHD and AD groups (P > 0.05). Compared with CHD or AD group, T2DM group was associated with a slight increase in circulating EPC numbers (P < 0.05). The results of FMD were almost similar to the circulating EPC numbers(CHD, 4.06 ± 0.54; AD, 3.90 ± 0.48; DM, 3.85 ± 0.57; HC, 5.52 ± 0.67%)except that there was no significant difference among the CHD, AD and T2DM groups (P > 0.05). Age, glycosylated hemoglobin, low density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI) and medical history were the independent risk factors of circulating EPC number in all the patients (P < 0.05). Age, total cholesterol, BMI and medical history were the independent risk factors of FMD in all of the patients (P<0.05). CONCLUSIONS The results of this study supported the equivalents hypothesis and revealed that "CHD risk equivalents" were characterized by the consistent physiological changes of blood vessels in angiogenesis, repairing ability and endothelial function.
Collapse
Affiliation(s)
- Yun-fei Liao
- Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Feng
- Department of Orthopedics, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Lu-Lu Chen
- Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
| | - Tian-shu Zeng
- Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Yu
- Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Li-jun Hu
- Department of Ultrasound Diagnosis, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| |
Collapse
|
|
30
|
Barthelmes D, Zhu L, Shen W, Gillies MC, Irhimeh MR. Differential gene expression in Lin-/VEGF-R2+ bone marrow-derived endothelial progenitor cells isolated from diabetic mice. Cardiovasc Diabetol 2014; 13:42. [PMID: 24521356 PMCID: PMC3926942 DOI: 10.1186/1475-2840-13-42] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 02/03/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Diabetes is known to impair the number and function of endothelial progenitor cells in the circulation, causing structural and functional alterations in the micro- and macro-vasculature. The aim of this study was to identify early diabetes-related changes in the expression of genes that have been reported to be closely involved in endothelial progenitor cell migration and function. METHODS Based on review of current literature, this study examined the expression level of 35 genes that are known to be involved in endothelial progenitor cell migration and function in magnetically sorted Lin-/VEGF-R2+ endothelial progenitor cells obtained from the bone marrow of Akita mice in the early stages of diabetes (18 weeks) using RT-PCR and Western blotting. We used the Shapiro-Wilk and D'Agostino & Pearson Omnibus tests to assess normality. Differences between groups were evaluated by Student's t-test for normally distributed data (including Welch correction in cases of unequal variances) or Mann-Whitney test for not normally distributed data. RESULTS We observed a significant increase in the number of Lin-/VEGF-R2+ endothelial progenitor cells within the bone marrow in diabetic mice compared with non-diabetic mice. Two genes, SDF-1 and SELE, were significantly differentially expressed in diabetic Lin-/VEGF-R2+ endothelial progenitor cells and six other genes, CAV1, eNOS, CLDN5, NANOG, OCLN and BDNF, showed very low levels of expression in diabetic Lin-/VEGF-R2+ progenitor cells. CONCLUSION Low SDF-1 expression may contribute to the dysfunctional mobilization of bone marrow Lin-/VEGF-R2+ endothelial progenitor cells, which may contribute to microvascular injury in early diabetes.
Collapse
Affiliation(s)
| | | | | | | | - Mohammad R Irhimeh
- Save Sight Institute, Level 1, South Block Sydney Hospital and Sydney Eye Hospital, Central Clinical School, The University of Sydney, 8 Macquarie Street, Sydney, NSW 2000, Australia.
| |
Collapse
|
|
31
|
Fadini GP. A reappraisal of the role of circulating (progenitor) cells in the pathobiology of diabetic complications. Diabetologia 2014; 57:4-15. [PMID: 24173366 DOI: 10.1007/s00125-013-3087-6] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 10/01/2013] [Indexed: 01/10/2023]
Abstract
Traditionally, the development of diabetic complications has been attributed to the biochemical pathways driving hyperglycaemic cell damage, while reparatory mechanisms have been long overlooked. A more comprehensive view of the balance between damage and repair suggests that an impaired regenerative capacity of bone marrow (BM)-derived cells strongly contributes to defective re-endothelisation and neoangiogenesis in diabetes. Although recent technological advances have redefined the biology and function of endothelial progenitor cells (EPCs), interest in BM-derived vasculotropic cells in the setting of diabetes and its complications remains high. Several circulating cell types of haematopoietic and non-haematopoietic origin are affected by diabetes and are potentially involved in the pathobiology of chronic complications. In addition to classical EPCs, these include circulating (pro-)angiogenic cells, polarised monocytes/macrophages (M1 and M2), myeloid calcifying cells and smooth muscle progenitor cells, having disparate roles in vascular biology. In parallel with the study of elusive progenitor cell phenotypes, it has been recognised that diabetes induces a profound remodelling of the BM stem cell niche. The alteration of circulating (progenitor) cells in the BM is now believed to be the link among distant end-organ complications. The field is rapidly evolving and interest is shifting from specific cell populations to the complex network of interactions that orchestrate trafficking of circulating vasculotropic cells.
Collapse
Affiliation(s)
- G P Fadini
- Department of Medicine, University Hospital of Padova, University of Padova, Via Giustiniani, 2, 35100, Padova, Italy,
| |
Collapse
|
|
32
|
Alba AC, Lalonde SD, Rao V, Walter SD, Guyatt GH, Ross HJ. Changes in circulating progenitor cells are associated with outcome in heart failure patients: a longitudinal study. Can J Cardiol 2013; 29:1657-64. [PMID: 24054922 DOI: 10.1016/j.cjca.2013.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 06/04/2013] [Accepted: 06/18/2013] [Indexed: 10/26/2022] Open
Abstract
BACKGROUND Circulating progenitor cells (CPCs) are involved in the process of endothelial repair and are a prognostic factor in cardiovascular diseases. We evaluated the association between serial measurements of CPCs and functional capacity and outcomes in heart failure (HF). METHODS We included 156 consecutive consenting ambulatory HF patients (left ventricular ejection fraction < 40%). We evaluated CPCs and functional capacity (peak VO2) every 6 months for up to 2 years. CPCs were measured as early-outgrowth colony-forming units (EO-CFUs) and circulating CD34+, VEGFR2+ and/or CD133+ cells. We recorded mortality, HF hospital admissions, transplant, and ventricular assist device. RESULTS The mean age was 55 ± 15 years. A decrease in CD34+VEGFR2+ cells was independently associated with increased functional capacity; a 10-cell decrease in CD34+VEGFR2+ cells was associated with an increase of 0.2 mL/kg/min in peak VO2 (P < 0.05). We found an interaction effect (P = 0.02) between EO-CFUs and diabetes: in patients without diabetes, a 10-EO-CFU increase was independently associated with increased peak VO2 of 0.28 mL/kg/min (P = 0.01), and in patients with diabetes, a decrease in EO-CFUs was associated with an increased peak VO2 (P < 0.05). Higher EO-CFUs were associated with reduced mortality (hazard ratio, 0.25; 95% confidence interval, 0.09-0.69). CONCLUSIONS We noted differential relations between CPCs and outcomes in patients with vs without diabetes. Higher EO-CFUs and lower CD34+VEGFR2+ cells were associated with improved functional capacity and reduced mortality in nondiabetic patients. In patients with diabetes, lower EO-CFUs were associated with improved functional capacity. The basis for these differences requires further examination.
Collapse
Affiliation(s)
- Ana C Alba
- Heart Failure/Transplant Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
| | | | | | | | | | | |
Collapse
|
|
33
|
Hazra S, Jarajapu YPR, Stepps V, Caballero S, Thinschmidt JS, Sautina L, Bengtsson N, LiCalzi S, Dominguez J, Kern TS, Segal MS, Ash JD, Saban DR, Bartelmez SH, Grant MB. Long-term type 1 diabetes influences haematopoietic stem cells by reducing vascular repair potential and increasing inflammatory monocyte generation in a murine model. Diabetologia 2013; 56:644-53. [PMID: 23192694 PMCID: PMC3773610 DOI: 10.1007/s00125-012-2781-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2012] [Accepted: 10/23/2012] [Indexed: 12/15/2022]
Abstract
AIMS/HYPOTHESIS We sought to determine the impact of long-standing type 1 diabetes on haematopoietic stem/progenitor cell (HSC) number and function and to examine the impact of modulating glycoprotein (GP)130 receptor in these cells. METHODS Wild-type, gp130(-/-) and GFP chimeric mice were treated with streptozotocin to induce type 1 diabetes. Bone marrow (BM)-derived cells were used for colony-formation assay, quantification of side population (SP) cells, examination of gene expression, nitric oxide measurement and migration studies. Endothelial progenitor cells (EPCs), a population of vascular precursors derived from HSCs, were compared in diabetic and control mice. Cytokines were measured in BM supernatant fractions by ELISA and protein array. Flow cytometry was performed on enzymatically dissociated retina from gfp(+) chimeric mice and used to assess BM cell recruitment to the retina, kidney and blood. RESULTS BM cells from the 12-month-diabetic mice showed reduced colony-forming ability, depletion of SP-HSCs with a proportional increase in SP-HSCs residing in hypoxic regions of BM, decreased EPC numbers, and reduced eNos (also known as Nos3) but increased iNos (also known as Nos2) and oxidative stress-related genes. BM supernatant fraction showed increased cytokines, GP130 ligands and monocyte/macrophage stimulating factor. Retina, kidney and peripheral blood showed increased numbers of CD11b(+)/CD45(hi)/ CCR2(+)/Ly6C(hi) inflammatory monocytes. Diabetic gp130(-/-) mice were protected from development of diabetes-induced changes in their HSCs. CONCLUSIONS/INTERPRETATION The BM microenvironment of type 1 diabetic mice can lead to changes in haematopoiesis, with generation of more monocytes and fewer EPCs contributing to development of microvascular complications. Inhibition of GP130 activation may serve as a therapeutic strategy to improve the key aspects of this dysfunction.
Collapse
Affiliation(s)
- S. Hazra
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - Y. P. R. Jarajapu
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - V. Stepps
- BetaStem Therapeutics Inc, San Francisco, CA, USA
| | - S. Caballero
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - J. S. Thinschmidt
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - L. Sautina
- Division of Nephrology/Department of Medicine, University of Florida, Gainesville, FL, USA
| | - N. Bengtsson
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - S. LiCalzi
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - J. Dominguez
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| | - T. S. Kern
- Case Western Reserve University and Louis Stokes Veterans Administration Hospital, Cleveland, OH, USA
| | - M. S. Segal
- Division of Nephrology/Department of Medicine, University of Florida, Gainesville, FL, USA
| | - J. D. Ash
- University of Oklahoma, Oklahoma City, OK, USA
| | - D. R. Saban
- Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA
| | | | - M. B. Grant
- Pharmacology & Therapeutics, University of Florida, 1600 SW Archer Road, Academic Research Building, PO 100267, Gainesville, FL 32610-0267, USA
| |
Collapse
|
|
34
|
Schiavon M, Fadini GP, Lunardi F, Agostini C, Boscaro E, Calabrese F, Marulli G, Rea F. Increased tissue endothelial progenitor cells in end-stage lung diseases with pulmonary hypertension. J Heart Lung Transplant 2013; 31:1025-30. [PMID: 22884387 DOI: 10.1016/j.healun.2012.06.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Revised: 05/23/2012] [Accepted: 06/06/2012] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Diffuse lung diseases promote the development of vascular changes and pulmonary hypertension (PH). Endothelial progenitor cells (EPCs) seem to be involved in pulmonary vascular remodeling. We evaluated circulating and intra-pulmonary EPCs in end-stage lung diseases in relation to pulmonary arterial pressure (PAP). METHODS The study included 19 patients affected by different end-stage lung diseases, with or without PH. Six lung donors were considered as control group. EPCs were measured in blood samples taken at the time of transplant from pulmonary arteries and veins (by flow cytometry) as well as in lung specimen sections (by confocal microscopy) and expressed as percentage of total number of cells. RESULTS The amount of EPC in lung specimens was significantly different according to type of disease (p = 0.001). Specifically, a higher number of EPCs was detected in idiopathic pulmonary hypertension and idiopathic pulmonary fibrosis with high (> 25 mm Hg) mean PAP (p = 0.03 for both) compared with chronic obstructive pulmonary disease and control group. There was a direct correlation between intrapulmonary EPCs and PAP. According to receiver operating characteristic curve analysis, the presence of > 3% EPCs had a 91% sensitivity and 93% specificity in identifying high mean PAP. There were no differences in circulating arterial or venous EPCs among groups. CONCLUSIONS Intra-pulmonary EPCs are increased in lung diseases with high PAP, suggesting that EPCs may contribute to vascular remodeling in end-stage pulmonary disease.
Collapse
Affiliation(s)
- Marco Schiavon
- Department of Cardio-Thoracic and Vascular Sciences, University of Padua, Padua, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Menegazzo L, Albiero M, Avogaro A, Fadini GP. Endothelial progenitor cells in diabetes mellitus. Biofactors 2012; 38:194-202. [PMID: 22488933 DOI: 10.1002/biof.1016] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Accepted: 03/10/2012] [Indexed: 12/13/2022]
Abstract
Diabetes mellitus is associated with an increased risk of cardiovascular disease due to its negative impact on the vascular endothelium. The damaged endothelium is repaired by resident cells also through the contribution of a population of circulating cells derived from bone marrow. These cells, termed endothelial progenitor cells (EPCs) are involved in maintaining endothelial homeostasis and contributes to the formation of new blood vessels with a process called postnatal vasculogenesis. The mechanisms whereby these cells allow for protection of the cardiovascular system are still unclear; nevertheless, consistent evidences have shown that impairment and reduction of EPCs are hallmark features of type 1 and type 2 diabetes. Therefore, EPC alterations might have a pathogenic role in diabetic complications, thus becoming a potential therapeutic target. In this review, EPC alterations will be examined in the context of macrovascular and microvascular complications of diabetes, highlighting their roles and functions in the progression of the disease.
Collapse
|
|
36
|
Fadini GP, Avogaro A. It is all in the blood: the multifaceted contribution of circulating progenitor cells in diabetic complications. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:742976. [PMID: 22548049 PMCID: PMC3324138 DOI: 10.1155/2012/742976] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Accepted: 01/27/2012] [Indexed: 12/21/2022]
Abstract
Diabetes mellitus (DM) is a worldwide growing disease and represents a huge social and healthcare problem owing to the burden of its complications. Micro- and macrovascular diabetic complications arise from excess damage through well-known biochemical pathways. Interestingly, microangiopathy hits the bone marrow (BM) microenvironment with features similar to retinopathy, nephropathy and neuropathy. The BM represents a reservoir of progenitor cells for multiple lineages, not limited to the hematopoietic system and including endothelial cells, smooth muscle cells, cardiomyocytes, and osteogenic cells. All these multiple progenitor cell lineages are profoundly altered in the setting of diabetes in humans and animal models. Reduction of endothelial progenitor cells (EPCs) along with excess smooth muscle progenitor (SMP) and osteoprogenitor cells creates an imbalance that promote the development of micro- and macroangiopathy. Finally, an excess generation of BM-derived fusogenic cells has been found to contribute to diabetic complications in animal models. Taken together, a growing amount of literature attributes to circulating progenitor cells a multi-faceted role in the pathophysiology of DM, setting a novel scenario that puts BM and the blood at the centre of the stage.
Collapse
Affiliation(s)
- Gian Paolo Fadini
- Department of Medicine, University of Padua, 35100 Padua, Italy
- Laboratory of Experimental Diabetology, Venetian Institute of Molecular Medicine (VIMM), 35100 Padua, Italy
| | - Angelo Avogaro
- Department of Medicine, University of Padua, 35100 Padua, Italy
| |
Collapse
|
|
37
|
Benoit E, O'Donnell TF, Patel AN. Safety and efficacy of autologous cell therapy in critical limb ischemia: a systematic review. Cell Transplant 2012; 22:545-62. [PMID: 22490340 DOI: 10.3727/096368912x636777] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Researchers have accumulated a decade of experience with autologous cell therapy in the treatment of critical limb ischemia (CLI). We conducted a systematic review of clinical trials in the literature to determine the safety and efficacy of cell therapy in CLI. We searched the literature for clinical trials of autologous cell therapy in CLI, including observational series of five or more patients to accrue a large pool of patients for safety analysis. Safety analysis included evaluation of death, cancer, unregulated angiogenesis, and procedural adverse events such as bleeding. Efficacy analysis included the clinical endpoints amputation and death as well as functional and surrogate endpoints. We identified 45 clinical trials, including seven RCTs, and 1,272 patients who received cell therapy. The overall adverse event rate was low (4.2%). Cell therapy patients did not have a higher mortality rate than control patients and demonstrated no increase in cancer incidence when analyzed against population rates. With regard to efficacy, cell therapy patients had a significantly lower amputation rate than control patients (OR 0.36, p = 0.0004). Cell therapy also demonstrated efficacy in a variety of functional and surrogate outcomes. Clinical trials differed in the proportion of patients with risk factors for clinical outcomes, and these influenced rates of amputation and death. Cell therapy presents a favorable safety profile with a low adverse event rate and no increase in severe events such as mortality and cancer and treatment with cell therapy decreases the risk of amputation. Cell therapy has a positive benefit-to-risk ratio in CLI and may be a valuable treatment option, particularly for those challenging patients who cannot undergo arterial reconstruction.
Collapse
Affiliation(s)
- Eric Benoit
- Department of Surgery, Tufts Medical Center, Boston, MA, USA
| | | | | |
Collapse
|
|
38
|
Grisar JC, Haddad F, Gomari FA, Wu JC. Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent. Biomark Med 2012; 5:731-44. [PMID: 22103609 DOI: 10.2217/bmm.11.92] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The discovery of endothelial progenitor cells in the 1990s challenged the paradigm of angiogenesis by showing that cells derived from hematopoietic stem cells are capable of forming new blood vessels even in the absence of a pre-existing vessel network, a process termed vasculogenesis. Since then, the majority of studies in the field have found a strong association between circulating endothelial progenitor cells and cardiovascular risk. Several studies have also reported that inflammation influences the mobilization and differentiation of endothelial progenitor cells. In this review, we discuss the emerging role of endothelial progenitor cells as biomarkers of cardiovascular disease as well as the interplay between inflammation and endothelial progenitor cell biology. We will also review the challenges in the field of endothelial progenitor cell-based therapy.
Collapse
Affiliation(s)
- Johannes C Grisar
- Department of Medicine, Division of Immunology & Rheumatology, Stanford School of Medicine, 265 Campus Drive, Stanford, CA 94305-5454, USA
| | | | | | | |
Collapse
|
|
39
|
Procalcific phenotypic drift of circulating progenitor cells in type 2 diabetes with coronary artery disease. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:921685. [PMID: 22474430 PMCID: PMC3299316 DOI: 10.1155/2012/921685] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Accepted: 12/21/2011] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus (DM) alters circulating progenitor cells relevant for the pathophysiology of coronary artery disease (CAD). While endothelial progenitor cells (EPCs) are reduced, there is no data on procalcific polarization of circulating progenitors, which may contribute to vascular calcification in these patients. In a cohort of 107 subjects with and without DM and CAD, we analyzed the pro-calcific versus endothelial differentiation status of circulating CD34+ progenitor cells. Endothelial commitment was determined by expression of VEGFR-2 (KDR) and pro-calcific polarization by expression of osteocalcin (OC) and bone alkaline phosphatase (BAP). We found that DM patients had significantly higher expression of OC and BAP on circulating CD34+ cells than control subjects, especially in the presence of CAD. In patients with DM and CAD, the ratio of OC/KDR, BAP/KDR, and OC+BAP/KDR was about 3-fold increased than in other groups. EPCs cultured from DM patients with CAD occasionally formed structures highly suggestive of calcified nodules, and the expression of osteogenic markers by EPCs from control subjects was significantly increased in response to the toll-like receptor agonist LPS. In conclusion, circulating progenitor cells of diabetic patients show a phenotypic drift toward a pro-calcific phenotype that may be driven by inflammatory signals.
Collapse
|
|
40
|
Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP. Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care 2011; 34 Suppl 2:S285-90. [PMID: 21525470 PMCID: PMC3632194 DOI: 10.2337/dc11-s239] [Citation(s) in RCA: 334] [Impact Index Per Article: 23.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Angelo Avogaro
- Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy.
| | | | | | | | | |
Collapse
|
|
41
|
Affiliation(s)
- Gian Paolo Fadini
- Department of Clinical and Experimental Medicine, Metabolic Division, University of Padova, Medical School-Padova, Italy.
| |
Collapse
|
|
42
|
Jung KH, Chu K, Lee ST, Bahn JJ, Kim JH, Kim M, Lee SK, Roh JK. Risk of Macrovascular Complications in Type 2 Diabetes Mellitus: Endothelial Microparticle Profiles. Cerebrovasc Dis 2011; 31:485-93. [DOI: 10.1159/000324383] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 01/11/2011] [Indexed: 01/21/2023] Open
|
|
43
|
Villalvilla A, Fernández-Durango R. [Endothelial progenitor cells: their possible potential in cell therapy for ischemic retina]. ACTA ACUST UNITED AC 2010; 85:291-3. [PMID: 21167435 DOI: 10.1016/j.oftal.2010.10.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 09/10/2010] [Indexed: 11/28/2022]
|
|
44
|
Fadini GP, Agostini C, Boscaro E, Avogaro A. Mechanisms and significance of progenitor cell reduction in the metabolic syndrome. Metab Syndr Relat Disord 2010; 7:5-10. [PMID: 19183074 DOI: 10.1089/met.2008.0067] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Bone marrow-derived progenitor cells are involved in the homeostasis of the cardiovascular system through differentiation into endothelium, smooth muscle, and cardiomyocytes. Alterations of these extremely plastic cells have been recognized as both markers of cardiovascular risk and pathophysiological links between risk factors and development of atherosclerosis. Metabolic syndrome, as a cluster of well-defined cardiovascular risk factors, represents a strong predictor of cardiovascular events and death. Moreover, components of the syndrome interact with one another and synergistically increase this risk. Here we describe all metabolic syndrome components as being characterized by alterations in circulating progenitor cells, especially endothelial cells. We also highlight how endothelial progenitors may mediate the interactions between cardiometabolic risk factors in a complex interplay and discuss potential implications for prevention and therapy.
Collapse
Affiliation(s)
- Gian Paolo Fadini
- Department of Clinical and Experimental Medicine, University of Padova, Medical School, Padova, Italy.
| | | | | | | |
Collapse
|
|
45
|
Abstract
Diabetes mellitus increases cardiovascular risk through its negative impact on vascular endothelium. Although glucotoxicity and lipotoxicity account for endothelial cell damage, endothelial repair is also affected by diabetes. Endothelial progenitor cells (EPCs) are involved in the maintenance of endothelial homoeostasis and in the process of new vessel formation. For these reasons, EPCs are thought to have a protective impact within the cardiovascular system. In addition, EPCs appear to modulate the functioning of other organs, providing neurotropic signals and promoting repair of the glomerular endothelium. The exact mechanisms by which EPCs provide cardiovascular protection are unknown and the definition of EPCs is not standardized. Notwithstanding these limitations, the literature consistently indicates that EPCs are altered in type 1 and type 2 diabetes and in virtually all diabetic complications. Moreover, experimental models suggest that EPC-based therapies might help prevent or reverse the features of end-organ complications. This identifies EPCs as having a novel pathogenic role in diabetes and being a potential therapeutic target. Several ways of favourably modulating EPCs have been identified, including lifestyle intervention, commonly used medications and cell-based approaches. Herein, we provide a comprehensive overview of EPC pathophysiology and the potential for EPC modulation in diabetes.
Collapse
Affiliation(s)
- G P Fadini
- Department of Clinical and Experimental Medicine, Division of Metabolic Diseases, University of Padova, Medical School, Padova, Italy.
| | | |
Collapse
|
|
46
|
Liao YF, Chen LL, Zeng TS, Li YM, Fan Yu, Hu LJ, Ling Yue. Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes. Vasc Med 2010; 15:279-85. [PMID: 20511292 DOI: 10.1177/1358863x10367537] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Vascular endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetes (T2DM). Circulating endothelial progenitor cell (EPC) is involved in the neovasculogenesis and maintenance of vascular homeostasis, whose impairment may have an important role in the pathogenesis of diabetic vasculopathy. This study was performed to investigate the relationship between vascular endothelial function and circulating EPC number in T2DM. A total of 46 newly diagnosed T2DM patients (DM group) and 51 healthy subjects (NG group) were recruited. Metformin was administered to all patients for 16 weeks. Endothelial function was assessed by flow-mediated brachial artery dilatation (FMD). EPC was defined by CD45( low)/CD34(+)/VEGFR2(+) and quantified by flow cytometry. The EPC number in the DM group was significantly lower than that in the NG group (p < 0.001), and improved markedly after treatment (p < 0.001). The results of FMD were consistent with EPC variations among the three groups (p < 0.001). In multivariate regression analysis, the EPC number was an independent risk factor for FMD at baseline (p < 0.05). The absolute changes of EPC number showed significant correlation with the changes of FMD before and after treatment (r = 0.63, p < 0.001). This study demonstrated that the circulating EPC number was related to endothelial function and could be considered as a surrogate biological marker of endothelial function for T2DM.
Collapse
Affiliation(s)
- Yun-Fei Liao
- Department of Endocrinology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Tan K, Lessieur E, Cutler A, Nerone P, Vasanji A, Asosingh K, Erzurum S, Anand-Apte B. Impaired function of circulating CD34(+) CD45(-) cells in patients with proliferative diabetic retinopathy. Exp Eye Res 2010; 91:229-37. [PMID: 20493838 DOI: 10.1016/j.exer.2010.05.012] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2010] [Revised: 05/13/2010] [Accepted: 05/14/2010] [Indexed: 02/03/2023]
Abstract
Proliferative diabetic retinopathy is a consequence of retinal ischemia due to capillary occlusion resulting from damage to the retinal microvascular endothelium. Recent evidence suggests that high levels of bone-marrow derived circulating endothelial progenitor cells (EPCs) contribute to the pathological neovascularization of ischemic tissues and are a critical risk factor for the development of these complications. In the absence of a consensus definition of a circulating EPC and its surface markers in humans we evaluated the functional properties of CD34(+) CD45(-) endothelial colony forming cells (ECFCs) in patients with proliferative diabetic retinopathy (PDR). Higher levels of circulating CD34(+) CD45(-) cells were observed in patients with PDR compared to controls. However, ECFCs from patients with PDR were impaired in their ability to migrate towards SDF-1 and human serum, incorporate into and form vascular tubes with human retinal endothelial cells. The results from these pilot studies suggest that ECFCs from patients with PDR are mobilized into the circulation but may be unable to migrate and repair damaged capillary endothelium. This suggests that ECFCs may be a potential therapeutic target in the prevention and treatment of diabetic vascular complications.
Collapse
Affiliation(s)
- Kevin Tan
- Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Bhatwadekar AD, Shaw LC, Grant MB. Promise of endothelial progenitor cell for treatment of diabetic retinopathy. Expert Rev Endocrinol Metab 2010; 5:29-37. [PMID: 23678364 PMCID: PMC3652409 DOI: 10.1586/eem.09.75] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Progressive obliteration of the retinal microvessels is a characteristic of diabetic retinopathy. The resultant retinal ischemia leads to sight-threatening neovascularization and macular edema. Bone marrow-derived endothelial progenitor cells play a critical role in vascular maintenance and repair and forms the basis of cellular therapy for revascularization of ischemic myocardium and ischemic limbs. Emerging studies show potential of these cells in revascularization of ischemic retina and this review summarizes this possibility. We also report current pharmacological options to correct diabetes-associated defects in endothelial progenitor cells for their therapeutic transfer.
Collapse
Affiliation(s)
- Ashay D Bhatwadekar
- Dept of Pharmacology and Therapeutics, University of Florida, 1600 SW Archer Road Gainesville, FL 32610-0267, USA Tel.: + 1 352 392 9006 Fax: + 1 352 392 9696
| | - Lynn C Shaw
- Dept of Pharmacology and Therapeutics, University of Florida, 1600 SW Archer Road Gainesville, FL 32610-0267, USA Tel.: + 1 352 392 8020 Fax: + 1 352 392 9696
| | - Maria B Grant
- Author for correspondence Department of Pharmacology and Therapeutics, University of Florida, 1600 SW Archer Road Gainesville, FL 32610-0267, USA Tel: + 1 352 846 0978 Fax: + 1 352 392 9696
| |
Collapse
|
|
49
|
Liu X, Li Y, Liu Y, Luo Y, Wang D, Annex BH, Goldschmidt-Clermont PJ. Endothelial progenitor cells (EPCs) mobilized and activated by neurotrophic factors may contribute to pathologic neovascularization in diabetic retinopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2009; 176:504-15. [PMID: 19948824 DOI: 10.2353/ajpath.2010.081152] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Diabetic retinopathy is characterized by pathological retinal neovascularization. Accumulating evidence has indicated that high levels of circulating endothelial progenitor cells (EPCs) are an important risk factor for neovascularization. Paradoxically, the reduction and dysfunction of circulating EPCs has been extensively reported in diabetic patients. We hypothesized that EPCs are differentially altered in the various vasculopathic complications of diabetes mellitus, exhibiting distinct behaviors in terms of angiogenic response to ischemia and growth factors and potentially playing a potent role in motivating vascular precursors to induce pathological neovascularization. Circulating levels of EPCs from diabetic retinopathy patients were analyzed by flow cytometry and by counting EPC colony-forming units, and serum levels of neurotrophic factors were measured by enzyme-linked immunosorbent assay. We found increased levels of nerve growth factor and brain-derived neurotrophic factor in the blood of diabetic retinopathy patients; this increase was correlated with the levels of circulating EPCs. In addition, we demonstrated that retinal cells released neurotrophic factors under hypoxic conditions to enhance EPC activity in vitro and to increase angiogenesis in a mouse ischemic hindlimb model. These results suggest that neurotrophic factors may induce neoangiogenesis through EPC activation, leading to the pathological retinal neovascularization. Thus, we propose that neovascularization in the ischemic retina might be regulated by overexpression of neurotrophic factors.
Collapse
Affiliation(s)
- Xialin Liu
- Zhongshan Ophthalmic Center, State Key Laboratory of Ophthalmology, Sun Yat-sen University, Guangzhou 510060, China.
| | | | | | | | | | | | | |
Collapse
|
|
50
|
Avogaro A, Fadini GP. Role of endothelial progenitor cells in diabetes mellitus. Expert Rev Endocrinol Metab 2009; 4:575-589. [PMID: 30780783 DOI: 10.1586/eem.09.49] [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] [Indexed: 11/08/2022]
Abstract
Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in endothelial healing and angiogenesis. EPCs are considered an integrated component of the cardiovascular system, which promotes vascular health. Derangement of EPC biology in diabetes has been hailed as a novel concept in the pathogenesis of micro- and macro-vascular complications. Additionally, EPCs are considered to be disease biomarkers, as they provide an index of cardiovascular risk. The mechanisms leading to EPC dysfunction in diabetes may include defective mobilization from bone marrow to peripheral blood and reduced half-life. Hyperglycemia is considered the major determinant of microvascular complications, while other mechanisms concur to increase the risk of cardiovascular disease in diabetic patients. EPCs may represent a novel pathophysiological connection to understand development and progression of diabetic complications.
Collapse
Affiliation(s)
- Angelo Avogaro
- a Dipartimento di Medicina Clinica e Sperimentale, Cattedra di Malattie del Metabolismo, Università di Padova, Via Giustiniani 2, 35128 Padova, Italy.
| | - Gian Paolo Fadini
- b Dipartimento di Medicina clinica e Sperimentale, Cattedra di Malattie del Metabolismo, Università di Padova, Via Giustiniani 2, 35128 Padova, Italy.
| |
Collapse
|