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Cabiati M, Vozzi F, Ceccherini E, Guiducci L, Persiani E, Gisone I, Sgalippa A, Cecchettini A, Del Ry S. Exploring Bone Morphogenetic Protein-2 and -4 mRNA Expression and Their Receptor Assessment in a Dynamic In Vitro Model of Vascular Calcification. Cells 2024; 13:2091. [PMID: 39768183 PMCID: PMC11674890 DOI: 10.3390/cells13242091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 12/10/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Vascular calcification (VC) is a dynamic, tightly regulated process driven by cellular activity and resembling the mechanisms of bone formation, with specific molecules playing pivotal roles in its progression. We aimed to investigate the involvement of the bone morphogenic proteins (BMP-2, BMP-4, BMPR-1a/1b, and BMPR-2) system in this process. Our study used an advanced in vitro model that simulates the biological environment of the vascular wall, assessing the ability of a phosphate mixture to induce the osteoblastic switch in human coronary artery smooth muscle cells (HCASMCs). METHODS HCASMCs were grown in mono- and co-culture with human coronary artery endothelial cells (HCAECs) in a double-flow bioreactor (LiveBox2 and IVTech), allowing static and dynamic conditions through a peristaltic pump. The VC was stimulated by incubation in a calcifying medium for 7 days. A BMP system Real-Time PCR was performed at the end of each experiment. RESULTS In monocultures, BMP-2 expression increased in calcified HCASMCs in static (p = 0.01) and dynamic conditions. BMP-4 and the biological receptors were expressed in all the experimental settings, increasing mainly in dynamic flow conditions. In co-cultures, we observed a marked increase in BMP-2 and BMP-4, BMPR-1a (p = 0.04 and p = 0.01, respectively), and BMPR-2 (p = 0.001) in the calcifying setting mostly in dynamic conditions. CONCLUSIONS The increase in BMP-2/4 in co-culture suggests that these genes might promote the switch towards an osteogenic-like phenotype, data also supported by the rise of both BMPR-1a and BMPR-2. Thus, our findings provide insights into the mechanisms by which dynamic co-culture modulates the BMP system activation in an environment mimicking in vivo VC's cellular and mechanical characteristics.
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Affiliation(s)
- Manuela Cabiati
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Federico Vozzi
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Elisa Ceccherini
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Letizia Guiducci
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Elisa Persiani
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Ilaria Gisone
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
| | - Agnese Sgalippa
- Health Science Interdisciplinary Center, Sant’Anna School of Advanced Studies, 56100 Pisa, Italy;
| | - Antonella Cecchettini
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
- Department of Clinical and Experimental Medicine, University of Pisa, 56100 Pisa, Italy
| | - Silvia Del Ry
- Institute of Clinical Physiology IFC-CNR, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy; (F.V.); (E.C.); (L.G.); (E.P.); (I.G.); (S.D.R.)
- Department of Clinical and Experimental Medicine, University of Pisa, 56100 Pisa, Italy
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Tóth A, Balogh E, Jeney V. In Vitro Models of Cardiovascular Calcification. Biomedicines 2024; 12:2155. [PMID: 39335668 PMCID: PMC11429067 DOI: 10.3390/biomedicines12092155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/15/2024] [Accepted: 09/21/2024] [Indexed: 09/30/2024] Open
Abstract
Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), diabetes, dyslipidemia, and hypertension in the younger population as well. Currently, there is no therapeutic approach to prevent or cure cardiovascular calcification. The pathophysiology of cardiovascular calcification is highly complex and involves osteogenic differentiation of various cell types of the cardiovascular system, such as vascular smooth muscle cells and valve interstitial cells. In vitro cellular and ex vivo tissue culture models are simple and useful tools in cardiovascular calcification research. These models contributed largely to the discoveries of the numerous calcification inducers, inhibitors, and molecular mechanisms. In this review, we provide an overview of the in vitro cell culture and the ex vivo tissue culture models applied in the research of cardiovascular calcification.
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Affiliation(s)
- Andrea Tóth
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Enikő Balogh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Jeney
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
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Ramzan F, Salim A, Hussain A, Khan I. Unleashing the Healing Power of Mesenchymal Stem Cells for Osteochondral Abnormalities. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2024. [DOI: 10.1007/s40883-024-00356-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 07/25/2024] [Accepted: 08/31/2024] [Indexed: 01/11/2025]
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Napoli G, Mushtaq S, Basile P, Carella MC, De Feo D, Latorre MD, Baggiano A, Ciccone MM, Pontone G, Guaricci AI. Beyond Stress Ischemia: Unveiling the Multifaceted Nature of Coronary Vulnerable Plaques Using Cardiac Computed Tomography. J Clin Med 2024; 13:4277. [PMID: 39064316 PMCID: PMC11278082 DOI: 10.3390/jcm13144277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/04/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Historically, cardiovascular prevention has been predominantly focused on stress-induced ischemia, but recent trials have challenged this paradigm, highlighting the emerging role of vulnerable, non-flow-limiting coronary plaques, leading to a shift towards integrating plaque morphology with functional data into risk prediction models. Coronary computed tomography angiography (CCTA) represents a high-resolution, low-risk, and largely available non-invasive modality for the precise delineation of plaque composition, morphology, and inflammatory activity, further enhancing our ability to stratify high-risk plaque and predict adverse cardiovascular outcomes. Coronary artery calcium (CAC) scoring, derived from CCTA, has emerged as a promising tool for predicting future cardiovascular events in asymptomatic individuals, demonstrating incremental prognostic value beyond traditional cardiovascular risk factors in terms of myocardial infarction, stroke, and all-cause mortality. Additionally, CCTA-derived information on adverse plaque characteristics, geometric characteristics, and hemodynamic forces provides valuable insights into plaque vulnerability and seems promising in guiding revascularization strategies. Additionally, non-invasive assessments of epicardial and pericoronary adipose tissue (PCAT) further refine risk stratification, adding prognostic significance to coronary artery disease (CAD), correlating with plaque development, vulnerability, and rupture. Moreover, CT imaging not only aids in risk stratification but is now emerging as a screening tool able to monitor CAD progression and treatment efficacy over time. Thus, the integration of CAC scoring and PCAT evaluation into risk stratification algorithms, as well as the identification of high-risk plaque morphology and adverse geometric and hemodynamic characteristics, holds promising results for guiding personalized preventive interventions, helping physicians in identifying high-risk individuals earlier, tailoring lifestyle and pharmacological interventions, and improving clinical outcomes in their patients.
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Affiliation(s)
- Gianluigi Napoli
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Saima Mushtaq
- Department of Perioperative Cardiology and Cardiovascular Imaging, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy; (S.M.); (A.B.); (G.P.)
| | - Paolo Basile
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Maria Cristina Carella
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Daniele De Feo
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Michele Davide Latorre
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Andrea Baggiano
- Department of Perioperative Cardiology and Cardiovascular Imaging, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy; (S.M.); (A.B.); (G.P.)
| | - Marco Matteo Ciccone
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
| | - Gianluca Pontone
- Department of Perioperative Cardiology and Cardiovascular Imaging, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy; (S.M.); (A.B.); (G.P.)
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy
| | - Andrea Igoren Guaricci
- University Cardiologic Unit, Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Polyclinic University Hospital, 70124 Bari, Italy; (G.N.); (P.B.); (M.C.C.); (D.D.F.); (M.D.L.); (M.M.C.)
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Towler DA. Parathyroid hormone-PTH1R signaling in cardiovascular disease and homeostasis. Trends Endocrinol Metab 2024; 35:648-660. [PMID: 38429163 PMCID: PMC11233248 DOI: 10.1016/j.tem.2024.02.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 03/03/2024]
Abstract
Primary hyperparathyroidism (pHPT) afflicts our aging population with an incidence approaching 50 per 100 000 patient-years at a female:male ratio of ~3:1. Decisions surrounding surgical management are currently driven by age, hypercalcemia severity, presence of osteoporosis, renal insufficiency, or hypercalciuria with or without nephrolithiasis. Cardiovascular (CV) disease (CVD) is not systematically considered. This is notable since the parathyroid hormone (PTH) 1 receptor (PTH1R) is biologically active in the vasculature, and adjusted CV mortality risk is increased almost threefold in individuals with pHPT who do not meet contemporary recommendations for surgical cure. We provide an overview of epidemiology, pharmacology, and physiology that highlights the need to: (i) identify biomarkers that establish a healthy 'set point' for CV PTH1R signaling tone; (ii) better understand the pharmacokinetic-pharmacodynamic (PK-PD) relationships of PTH1R ligands in CV homeostasis; and (iii) incorporate CVD risk assessment into the management of hyperparathyroidism.
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Affiliation(s)
- Dwight A Towler
- Department of Internal Medicine - Endocrine Division, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, UT Southwestern Medical Center, Dallas, TX 75390, USA.
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Kalanski S, Pradhan S, Hon A, Xia Y, Safvati N, Rivera JC, Lu M, Demer LL, Tintut Y. Effects of Empagliflozin on Vascular and Skeletal Mineralization in Hyperlipidemic Mice. Vascul Pharmacol 2024; 155:107376. [PMID: 38692418 PMCID: PMC12077419 DOI: 10.1016/j.vph.2024.107376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/08/2024] [Accepted: 04/28/2024] [Indexed: 05/03/2024]
Abstract
Cardiovascular disease and osteoporosis, major causes of morbidity and mortality, are associated with hyperlipidemia. Recent studies show that empagliflozin (EMPA), an inhibitor of sodium-glucose cotransporter-2 (SGLT2), improves cardiovascular health. In preclinical animal studies, EMPA mitigates vascular calcification in the males but its effects in the females are not known. Thus, we used female mice to test the effects of EMPA on calcification in the artery wall, cardiac function, and skeletal bone. By serial in vivo microCT imaging, we followed the progression of aortic calcification and bone mineral density in young and older female Apoe-/- mice fed a high-fat diet with or without EMPA. The two different age groups were used to compare early vs. advanced stages of aortic calcification. Results show that EMPA treatment increased urine glucose levels. Aortic calcium content increased in both the controls and the EMPA-treated mice, and EMPA did not affect progression of aortic calcium content in both young and older mice. However, 3-D segmentation analysis of aortic calcium deposits on microCT images revealed that EMPA-treated mice had significantly less surface area and volume of calcified deposits as well as fewer numbers of deposits than the control mice. To test for direct effects on vascular cell calcification, we treated murine aortic smooth muscle cells with EMPA, and results showed a slight inhibition of alkaline phosphatase activity and inflammatory matrix calcification. As for skeletal bone, EMPA-treated mice had significantly lower BMD than the controls in both the lumbar vertebrae and femoral bones in both young and older mice. The findings suggest that, in hyperlipidemic female mice, unlike males, SGLT2 inhibition with empagliflozin does not mitigate progression of aortic calcification and may even lower skeletal bone density.
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Affiliation(s)
- Sophia Kalanski
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Stuti Pradhan
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Andy Hon
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Yuxuan Xia
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Nora Safvati
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Juan Carlos Rivera
- Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, California, USA
| | - Mimi Lu
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA
| | - Linda L Demer
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA; Department of Physiology, University of California, Los Angeles, Los Angeles, California, USA
| | - Yin Tintut
- Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, California, USA; Department of Physiology, University of California, Los Angeles, Los Angeles, California, USA; Department of Orthopaedic Surgery, University of California, Los Angeles, Los Angeles, California, USA.
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Xie Y, Lin T, Jin Y, Berezowitz AG, Wang XL, Lu J, Cai Y, Guzman RJ. Smooth muscle cell-specific matrix metalloproteinase 3 deletion reduces osteogenic transformation and medial artery calcification. Cardiovasc Res 2024; 120:658-670. [PMID: 38454645 PMCID: PMC11074797 DOI: 10.1093/cvr/cvae035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 11/30/2023] [Accepted: 12/12/2023] [Indexed: 03/09/2024] Open
Abstract
AIMS Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification. METHODS AND RESULTS We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries in patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process. CONCLUSION These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD.
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Affiliation(s)
- Yangzhouyun Xie
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA
| | - Tonghui Lin
- Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA
| | - Ying Jin
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA
| | - Alexa G Berezowitz
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA
| | - Xue-Lin Wang
- Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA
| | - Jinny Lu
- Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA
| | - Yujun Cai
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA
- Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA
| | - Raul J Guzman
- Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Yale University School of Medicine, 330 Cedar St., BB 204, New Haven, CT 06510, USA
- Division of Vascular and Endovascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 0221, USA
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Bonello JP, Tse MY, Robinson TJG, Bardana DD, Waldman SD, Pang SC. Expression of Chondrogenic Potential Markers in Cultured Chondrocytes from the Human Knee Joint. Cartilage 2024:19476035241241930. [PMID: 38616342 PMCID: PMC11569588 DOI: 10.1177/19476035241241930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/18/2024] [Accepted: 03/07/2024] [Indexed: 04/16/2024] Open
Abstract
OBJECTIVES While substantial progress has been made in engineering cartilaginous constructs for animal models, further research is needed to translate these methodologies for human applications. Evidence suggests that cultured autologous chondrocytes undergo changes in phenotype and gene expression, thereby affecting their proliferation and differentiation capacity. This study was designed to evaluate the expression of chondrogenic markers in cultured human articular chondrocytes from passages 3 (P3) and 7 (P7), beyond the current clinical recommendation of P3. METHODS Cultured autologous chondrocytes were passaged from P3 up to P7, and quantitative polymerase chain reaction (qPCR) was used to assess mRNA expression of chondrogenic markers, including collagen type I (COLI), collagen type II (COLII), aggrecan (AGG), bone morphogenetic protein 4 (BMP4), transcription factor SOX-9 (SOX9), proteoglycan 4 (PGR4), and transformation-related protein 53 (p53), between P3 and P7. RESULTS Except for AGG, no significant differences were found in the expression of markers between passages, suggesting the maintenance of chondrogenic potential in cultured chondrocytes. Differential expression identified between SOX9 and PGR4, as well as between COLI and SOX9, indicates that differences in chondrogenic markers are present between age groups and sexes, respectively. CONCLUSIONS Overall, expression profiles of younger and male chondrocytes exhibit conversion of mature cartilage characteristics compared to their counterparts, with signs of dedifferentiation and loss of phenotype within-group passaging. These results may have implications in guiding the use of higher passaged chondrocytes for engineering constructs and provide a foundation for clinical recommendations surrounding the repair and treatment of articular cartilage pathology in both sexes.
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Affiliation(s)
- John-Peter Bonello
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - M. Yat Tse
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - Trevor J. G. Robinson
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - Davide D. Bardana
- Division of Surgery, Kingston General Hospital, Kingston, ON, Canada
| | - Stephen D. Waldman
- Department of Chemical Engineering, Toronto Metropolitan University, Toronto, ON, Canada
| | - Stephen C. Pang
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
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Grant JK, Orringer CE. Coronary and Extra-coronary Subclinical Atherosclerosis to Guide Lipid-Lowering Therapy. Curr Atheroscler Rep 2023; 25:911-920. [PMID: 37971683 DOI: 10.1007/s11883-023-01161-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE OF REVIEW To discuss and review the technical considerations, fundamentals, and guideline-based indications for coronary artery calcium scoring, and the use of other non-invasive imaging modalities, such as extra-coronary calcification in cardiovascular risk prediction. RECENT FINDINGS The most robust evidence for the use of CAC scoring is in select individuals, 40-75 years of age, at borderline to intermediate 10-year ASCVD risk. Recent US recommendations support the use of CAC scoring in varying clinical scenarios. First, in adults with very high CAC scores (CAC ≥ 1000), the use of high-intensity statin therapy and, if necessary, guideline-based add-on LDL-C lowering therapies (ezetimibe, PCSK9-inhibitors) to achieve a ≥ 50% reduction in LDL-C and optimally an LDL-C < 70 mg/dL is recommended. In patients with a CAC score ≥ 100 at low risk of bleeding, the benefits of aspirin use may outweigh the risk of bleeding. Other applications of CAC scoring include risk estimation on non-contrast CT scans of the chest, risk prediction in younger patients (< 40 years of age), its value as a gatekeeper for the decision to perform nuclear stress testing, and to aid in risk stratification in patients presenting with low-risk chest pain. There is a correlation between extra-coronary calcification (e.g., breast arterial calcification, aortic calcification, and aortic valve calcification) and incident ASCVD events. However, its role in informing lipid management remains unclear. Identification of coronary calcium in selected patients is the single best non-invasive imaging modality to identify future ASCVD risk and inform lipid-lowering therapy decision-making.
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Affiliation(s)
- Jelani K Grant
- Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA
| | - Carl E Orringer
- NCH Rooney Heart Institute, 399 9th Street North, Suite 300, Naples, FL, 34102, USA.
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Qin Z, Yu L, Zhang Y, Xu Q, Li C, Zhao S, Xi X, Tian Y, Wang Z, Tian J, Yu B. Coronary artery calcification and plaque stability： an optical coherence tomography study. Heliyon 2023; 9:e23191. [PMID: 38149191 PMCID: PMC10750051 DOI: 10.1016/j.heliyon.2023.e23191] [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: 01/19/2023] [Revised: 10/12/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023] Open
Abstract
Background Coronary artery calcification (CAC), a surrogate of atherosclerosis, is related to stent underexpansion and adverse cardiac events. However, the effect of CAC on plaque stability is still controversial and the morphological significance of CAC has yet to be elucidated. Methods A retrospective series of 419 patients with acute coronary syndrome (ACS) who underwent optical coherence tomography (OCT) were enrolled. Patients were classified into three groups based on the calcification size in culprit plaques and the features of the culprit and non-culprit plaques among these groups were compared. Logistic regression was used to analyze independent risk factors for culprit plaque rupture and the nonlinear relationship between calcification parameters and culprit plaque rupture. Furthermore, we compared the detailed calcification parameters of different kinds of plaques. Results A total of 419 culprit plaques and 364 non-culprit plaques were identified. The incidence of calcification was 53.9 % in culprit plaques and 50.3 % in non-culprit plaques. Compared with culprit plaques without calcification, plaque rupture, macrophages and cholesterol crystals were more frequently observed in the spotty calcification group, and the lipid length was longer; the incidence of macrophages and cholesterol crystals was higher in the macrocalcification group. Calcification tended to be smaller in ruptured plaques than in non-ruptured plaques. Moreover, the arc and length of calcification were greater in culprit plaques than in non-culprit plaques. Conclusions Vulnerable features were more frequently observed in culprit plaques with spotty calcification, whereas the presence of macrocalcification calcifications did not significantly increase plaque vulnerability. Calcification tends to be larger in culprit plaques than in non-culprit plaques.
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Affiliation(s)
- Zhifeng Qin
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Li Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Yanwen Zhang
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Qinglu Xu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Chao Li
- School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Suhong Zhao
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Xiangwen Xi
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Yanan Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Zhao Wang
- School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China
| | - Jinwei Tian
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Bo Yu
- Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
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11
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Bernardini C, Mantia DL, Salaroli R, Ventrella D, Elmi A, Zannoni A, Forni M. Isolation of Vascular Wall Mesenchymal Stem Cells from the Thoracic Aorta of Adult Göttingen Minipigs: A New Protocol for the Simultaneous Endothelial Cell Collection. Animals (Basel) 2023; 13:2601. [PMID: 37627392 PMCID: PMC10451532 DOI: 10.3390/ani13162601] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/27/2023] Open
Abstract
Two main classes of perivascular multipotent populations have been described: the microvascular pericytes and the vascular wall mesenchymal stem cells (VW-MSCs). VW-MSCs are isolated from large vessels in many species and they participate in vascular remodeling together with other cellular components such as endothelial cells. Considering that the Göttingen Minipigs are widely used in Europe as a translational model in the field of cardiovascular diseases, the aim of the present research was to isolate VW-MSCs from the adult aorta of Göttingen Minipigs while preserving and also collecting endothelial cells. The results obtained in the present research demonstrated that this new protocol allows us to obtain a pure population of VW-MSCs and endothelial cells. VW-MSCs from Göttingen Minipigs responded fully to the MSC minima international criteria, being positive to CD105, CD90, and CD44 and negative to CD45 and CD34. Moreover, VW-MSCs presented a differentiative potential towards osteogenic, chondrogenic, and adipogenic lineages. Overall, the present protocol, preserving the viability and phenotypic features of the two isolated populations, opens future possibilities of using minipig VW-MSCs and endothelial cells in in vitro vascular remodeling studies.
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Affiliation(s)
- Chiara Bernardini
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
- Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy;
| | - Debora La Mantia
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
| | - Roberta Salaroli
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
| | - Domenico Ventrella
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
| | - Alberto Elmi
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
| | - Augusta Zannoni
- Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy; (C.B.); (R.S.); (D.V.); (A.E.); (A.Z.)
- Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy;
| | - Monica Forni
- Health Sciences and Technologies-Interdepartmental Center for Industrial Research (CIRI-SDV), Alma Mater Studiorum—University of Bologna, 40126 Bologna, Italy;
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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12
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Ouyang L, Yu C, Xie Z, Su X, Xu Z, Song P, Li J, Huang H, Ding Y, Zou MH. Indoleamine 2,3-Dioxygenase 1 Deletion-Mediated Kynurenine Insufficiency in Vascular Smooth Muscle Cells Exacerbates Arterial Calcification. Circulation 2022; 145:1784-1798. [PMID: 35582948 PMCID: PMC9197997 DOI: 10.1161/circulationaha.121.057868] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 04/20/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND IDO1 (indoleamine 2,3-dioxygenase 1) is the rate-limiting enzyme for tryptophan metabolism. IDO1 malfunction is involved in the pathogenesis of atherosclerosis. Vascular smooth muscle cells (VSMCs) with an osteogenic phenotype promote calcification and features of plaque instability. However, it remains unclear whether aberrant IDO1-regulated tryptophan metabolism causes VSMCs osteogenic reprogramming and calcification. METHODS We generated global Apoe (apolipoprotein E) and Ido1 double knockout mice, and Apoe knockout mice with specific deletion of IDO1 in VSMCs or macrophages. Arterial intimal calcification was evaluated by a Western diet-induced atherosclerotic calcification model. RESULTS Global deficiency of IDO1 boosted calcific lesion formation without sex bias in vivo. Conditional IDO1 loss of function in VSMCs rather than macrophages promoted calcific lesion development and the abundance of RUNX2 (runt-related transcription factor 2). In contrast, administration of kynurenine via intraperitoneal injection markedly delayed the progression of intimal calcification in parallel with decreased RUNX2 expression in both Apoe-/- and Apoe-/-Ido1-/- mice. We found that IDO1 deletion restrained RUNX2 from proteasomal degradation, which resulted in enhanced osteogenic reprogramming of VSMCs. Kynurenine administration downregulated RUNX2 in an aryl hydrocarbon receptor-dependent manner. Kynurenine acted as the endogenous ligand of aryl hydrocarbon receptor, controlled resultant interactions between cullin 4B and aryl hydrocarbon receptor to form an E3 ubiquitin ligase that bound with RUNX2, and subsequently promoted ubiquitin-mediated instability of RUNX2 in VSMCs. Serum samples from patients with coronary artery calcification had impaired IDO1 activity and decreased kynurenine catabolites compared with those without calcification. CONCLUSIONS Kynurenine, an IDO1-mediated tryptophan metabolism main product, promotes RUNX2 ubiquitination and subsequently leads to its proteasomal degradation via an aryl hydrocarbon receptor-dependent nongenomic pathway. Insufficient kynurenine exerts the deleterious role of IDO1 ablation in promoting RUNX2-mediated VSMCs osteogenic reprogramming and calcification in vivo.
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Affiliation(s)
- Liu Ouyang
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Changjiang Yu
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Zhiyong Xie
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Xiaoyan Su
- Department of Nephropathy, Tungwah Hospital of Sun Yat-sen University, Sun Yat-sen University, Dongguan, China
| | - Zengmei Xu
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Guangzhou, China
| | - Ping Song
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Jian Li
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China
| | - Ye Ding
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
| | - Ming-Hui Zou
- Center for Molecular and Translational Medicine, Georgia State University, Atlanta, USA
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13
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Chowdhury A, Balogh E, Ababneh H, Tóth A, Jeney V. Activation of Nrf2/HO-1 Antioxidant Pathway by Heme Attenuates Calcification of Human Lens Epithelial Cells. Pharmaceuticals (Basel) 2022; 15:ph15050493. [PMID: 35631320 PMCID: PMC9145770 DOI: 10.3390/ph15050493] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/07/2022] [Accepted: 04/16/2022] [Indexed: 02/04/2023] Open
Abstract
Cataract, an opacification in the crystalline lens, is a leading cause of blindness. Deposition of hydroxyapatite occurs in a cataractous lens that could be the consequence of osteogenic differentiation of lens epithelial cells (LECs). Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the transcription of a wide range of cytoprotective genes. Nrf2 upregulation attenuates cataract formation. Here we aimed to investigate the effect of Nrf2 system upregulation in LECs calcification. We induced osteogenic differentiation of human LECs (HuLECs) with increased phosphate and calcium-containing osteogenic medium (OM). OM-induced calcium and osteocalcin deposition in HuLECs. We used heme to activate Nrf2, which strongly upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1). Heme-mediated Nrf2 activation was dependent on the production of reactive oxygens species. Heme inhibited Ca deposition, and the OM-induced increase of osteogenic markers, RUNX2, alkaline phosphatase, and OCN. Anti-calcification effect of heme was lost when the transcriptional activity of Nrf2 or the enzyme activity of HO-1 was blocked with pharmacological inhibitors. Among products of HO-1 catalyzed heme degradation iron mimicked the anti-calcification effect of heme. We concluded that heme-induced upregulation of the Nrf2/HO-1 system inhibits HuLECs calcification through the liberation of heme iron.
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Affiliation(s)
- Arpan Chowdhury
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Enikő Balogh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
| | - Haneen Ababneh
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Andrea Tóth
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Doctoral School of Molecular Cell and Immune Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
| | - Viktória Jeney
- MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (A.C.); (E.B.); (H.A.); (A.T.)
- Correspondence:
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14
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Huang X, D'Addabbo J, Nguyen PK. Coronary artery calcification: More than meets the eye. J Nucl Cardiol 2021; 28:2215-2219. [PMID: 32170644 PMCID: PMC9060393 DOI: 10.1007/s12350-020-02058-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Accepted: 01/27/2020] [Indexed: 02/05/2023]
Affiliation(s)
- Xianxi Huang
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA
- Stanford Cardiovascular Institute, Stanford, CA, 94305, USA
- The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, China
| | - Jessica D'Addabbo
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA
- Stanford Cardiovascular Institute, Stanford, CA, 94305, USA
| | - Patricia K Nguyen
- Division of Cardiovascular Medicine, Stanford University, Stanford, CA, 94305, USA.
- Stanford Cardiovascular Institute, Stanford, CA, 94305, USA.
- Department of Veteran Affairs, Palo Alto, CA, 94304, USA.
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15
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Jiang L, Chen T, Sun S, Wang R, Deng J, Lyu L, Wu H, Yang M, Pu X, Du L, Chen Q, Hu Y, Hu X, Zhou Y, Xu Q, Zhang L. Nonbone Marrow CD34 + Cells Are Crucial for Endothelial Repair of Injured Artery. Circ Res 2021; 129:e146-e165. [PMID: 34474592 DOI: 10.1161/circresaha.121.319494] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
[Figure: see text].
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Affiliation(s)
- Liujun Jiang
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Ting Chen
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu).,Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Hangzhou, Zhejiang Province, China (T. Chen)
| | - Shasha Sun
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu).,Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. (S. Sun, M. Yang, Q. Chen, L. Zhang)
| | - Ruilin Wang
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Jiacheng Deng
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Lingxia Lyu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Hong Wu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Mei Yang
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. (S. Sun, M. Yang, Q. Chen, L. Zhang)
| | - Xiangyuan Pu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Luping Du
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Qishan Chen
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. (S. Sun, M. Yang, Q. Chen, L. Zhang)
| | - Yanhua Hu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Xiaosheng Hu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Yijiang Zhou
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu)
| | - Qingbo Xu
- Department of Cardiology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China (L. Jiang, T. Chen, S. Sun, R. Wang, J. Deng, L. Lyu, H. Wu, X. Pu, L. Du, Y. Hu, X. Hu, Y. Zhou, Q. Xu).,Centre for Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom (Q. Xu)
| | - Li Zhang
- Department of Cardiology and Institute for Developmental and Regenerative Cardiovascular Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China. (S. Sun, M. Yang, Q. Chen, L. Zhang)
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16
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Roth SP, Brehm W, Troillet A. [Cell-based therapeutic strategies for osteoarthritis in equine patients - Basic knowledge for clinical practitioners]. Tierarztl Prax Ausg G Grosstiere Nutztiere 2021; 49:189-202. [PMID: 34157748 DOI: 10.1055/a-1482-7752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Cell-based therapies for the treatment of osteoarthritis in equine patients experienced a real boom within the last few years. In every day medical practice, attending veterinary surgeons extract patient's blood or other autologous tissue samples and process the material for the purpose of administering the resulting product to the same patient under their own responsibility. Although being consistently classified as treatment option within the framework of regenerative medicine, the manufacturing processes, ingredients, and mechanisms of action remain highly diverse among cell-based therapies. Thus, sound knowledge about the latter ones forms the basis for therapeutic decision-making and best possible treatment regimes.
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Affiliation(s)
- Susanne P Roth
- Klinik für Pferde, Veterinärmedizinische Fakultät, Universität Leipzig.,Sächsischer Inkubator für Klinische Translation, Universität Leipzig
| | - Walter Brehm
- Klinik für Pferde, Veterinärmedizinische Fakultät, Universität Leipzig.,Sächsischer Inkubator für Klinische Translation, Universität Leipzig
| | - Antonia Troillet
- Klinik für Pferde, Veterinärmedizinische Fakultät, Universität Leipzig.,Sächsischer Inkubator für Klinische Translation, Universität Leipzig
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17
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Chinetti G, Neels JG. Roles of Nuclear Receptors in Vascular Calcification. Int J Mol Sci 2021; 22:6491. [PMID: 34204304 PMCID: PMC8235358 DOI: 10.3390/ijms22126491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/10/2021] [Accepted: 06/14/2021] [Indexed: 12/17/2022] Open
Abstract
Vascular calcification is defined as an inappropriate accumulation of calcium depots occurring in soft tissues, including the vascular wall. Growing evidence suggests that vascular calcification is an actively regulated process, sharing similar mechanisms with bone formation, implicating both inhibitory and inducible factors, mediated by osteoclast-like and osteoblast-like cells, respectively. This process, which occurs in nearly all the arterial beds and in both the medial and intimal layers, mainly involves vascular smooth muscle cells. In the vascular wall, calcification can have different clinical consequences, depending on the pattern, localization and nature of calcium deposition. Nuclear receptors are transcription factors widely expressed, activated by specific ligands that control the expression of target genes involved in a multitude of pathophysiological processes, including metabolism, cancer, inflammation and cell differentiation. Some of them act as drug targets. In this review we describe and discuss the role of different nuclear receptors in the control of vascular calcification.
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Affiliation(s)
- Giulia Chinetti
- Université Côte d’Azur, CHU, INSERM, C3M, 06204 Nice, France;
| | - Jaap G. Neels
- Université Côte d’Azur, INSERM, C3M, 06204 Nice, France
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18
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Li C, Mills Z, Zheng Z. Novel cell sources for bone regeneration. MedComm (Beijing) 2021; 2:145-174. [PMID: 34766140 PMCID: PMC8491221 DOI: 10.1002/mco2.51] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/03/2020] [Accepted: 12/09/2020] [Indexed: 01/09/2023] Open
Abstract
A plethora of both acute and chronic conditions, including traumatic, degenerative, malignant, or congenital disorders, commonly induce bone disorders often associated with severe persisting pain and limited mobility. Over 1 million surgical procedures involving bone excision, bone grafting, and fracture repair are performed each year in the U.S. alone, resulting in immense levels of public health challenges and corresponding financial burdens. Unfortunately, the innate self-healing capacity of bone is often inadequate for larger defects over a critical size. Moreover, as direct transplantation of committed osteoblasts is hindered by deficient cell availability, limited cell spreading, and poor survivability, an urgent need for novel cell sources for bone regeneration is concurrent. Thanks to the development in stem cell biology and cell reprogramming technology, many multipotent and pluripotent cells that manifest promising osteogenic potential are considered the regenerative remedy for bone defects. Considering these cells' investigation is still in its relative infancy, each of them offers their own particular challenges that must be conquered before the large-scale clinical application.
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Affiliation(s)
- Chenshuang Li
- Department of Orthodontics, School of Dental MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Zane Mills
- College of DentistryUniversity of OklahomaOklahoma CityOklahomaUSA
| | - Zhong Zheng
- Division of Growth and Development, School of DentistryUniversity of CaliforniaLos AngelesCaliforniaUSA
- Department of Surgery, David Geffen School of MedicineUniversity of CaliforniaLos AngelesCaliforniaUSA
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19
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Vazquez-Padron RI, Martinez L, Duque JC, Salman LH, Tabbara M. The anatomical sources of neointimal cells in the arteriovenous fistula. J Vasc Access 2021; 24:99-106. [PMID: 33960241 PMCID: PMC8958841 DOI: 10.1177/11297298211011875] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Neointimal cells are an elusive population with ambiguous origins, functions, and states of differentiation. Expansion of the venous intima in arteriovenous fistula (AVF) is one of the most prominent remodeling processes in the wall after access creation. However, most of the current knowledge about neointimal cells in AVFs comes from extrapolations from the arterial neointima in non-AVF systems. Understanding the origin of neointimal cells in fistulas may have important implications for the design and effective delivery of therapies aimed to decrease intimal hyperplasia (IH). In addition, a broader knowledge of cellular dynamics during postoperative remodeling of the AVF may help clarify other transformation processes in the wall that combined with IH determine the successful remodeling or failure of the access. In this review, we discuss the possible anatomical sources of neointimal cells in AVFs and their relative contribution to intimal expansion.
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Affiliation(s)
- Roberto I Vazquez-Padron
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Laisel Martinez
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Juan C Duque
- Katz Family Division of Nephrology, Department of Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Loay H Salman
- Division of Nephrology, Albany Medical College, Albany, NY, USA
| | - Marwan Tabbara
- DeWitt Daughtry Family Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL, USA
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20
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Induced Pluripotent Stem Cells (iPSCs) in Vascular Research: from Two- to Three-Dimensional Organoids. Stem Cell Rev Rep 2021; 17:1741-1753. [PMID: 33738695 PMCID: PMC7972819 DOI: 10.1007/s12015-021-10149-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/04/2021] [Indexed: 01/19/2023]
Abstract
Stem cell technology has been around for almost 30 years and in that time has grown into an enormous field. The stem cell technique progressed from the first successful isolation of mammalian embryonic stem cells (ESCs) in the 1990s, to the production of human induced-pluripotent stem cells (iPSCs) in the early 2000s, to finally culminate in the differentiation of pluripotent cells into highly specialized cell types, such as neurons, endothelial cells (ECs), cardiomyocytes, fibroblasts, and lung and intestinal cells, in the last decades. In recent times, we have attained a new height in stem cell research whereby we can produce 3D organoids derived from stem cells that more accurately mimic the in vivo environment. This review summarizes the development of stem cell research in the context of vascular research ranging from differentiation techniques of ECs and smooth muscle cells (SMCs) to the generation of vascularized 3D organoids. Furthermore, the different techniques are critically reviewed, and future applications of current 3D models are reported.
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21
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Trillhaase A, Schmidt B, Märtens M, Haferkamp U, Erdmann J, Aherrahrou Z. The CAD risk locus 9p21 increases the risk of vascular calcification in an iPSC-derived VSMC model. Stem Cell Res Ther 2021; 12:166. [PMID: 33676559 PMCID: PMC7936418 DOI: 10.1186/s13287-021-02229-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 02/14/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Coronary artery disease (CAD) is the leading cause of death worldwide. Chromosome locus 9p21 was the first to be associated with increased risk of CAD and coronary artery calcification (CAC). Vascular calcification increases the risk for CAD. Vascular smooth muscle cells (VSMCs) are one of the major cell types involved in the development of vascular calcification. METHODS So far, mainly animal models or primary SMCs have been used to model human vascular calcification. In this study, a human in vitro assay using iPSC-derived VSMCs was developed to examine vascular calcification. Human iPSCs were derived from a healthy non-risk (NR) and risk (R) donor carrying SNPs in the 9p21 locus. Additionally, 9p21 locus knockouts of each donor iPSC line (NR and R) were used. Following differentiation, the iPSC-derived VSMCs were characterized based on cell type, proliferation, and migration rate, along with calcium phosphate (CaP) deposits. CaP deposits were confirmed using Calcein and Alizarin Red S staining and then quantified. RESULTS The data demonstrated significantly more proliferation, migration, and CaP deposition in VSMCs derived from the R and both KO iPSC lines than in those derived from the NR line. Molecular analyses confirmed upregulation of calcification markers. These results are consistent with recent data demonstrating increased calcification when the 9p21 murine ortholog is knocked-out. CONCLUSION Therefore, in conclusion, genetic variation or deletion of the CAD risk locus leads to an increased risk of vascular calcification. This in vitro human iPSC model of calcification could be used to develop new drug screening strategies to combat CAC.
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Affiliation(s)
- Anja Trillhaase
- Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Luebeck, Germany.,University Heart Centre Luebeck, 23562, Luebeck, Germany
| | - Beatrice Schmidt
- Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Luebeck, Germany.,University Heart Centre Luebeck, 23562, Luebeck, Germany
| | - Marlon Märtens
- Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Luebeck, Germany.,University Heart Centre Luebeck, 23562, Luebeck, Germany
| | - Undine Haferkamp
- Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), 22525, Hamburg, Germany
| | - Jeanette Erdmann
- Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany.,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Luebeck, Germany.,University Heart Centre Luebeck, 23562, Luebeck, Germany
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, University of Luebeck, Ratzeburger Allee 160, 23562, Luebeck, Germany. .,DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Luebeck, Germany. .,University Heart Centre Luebeck, 23562, Luebeck, Germany.
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22
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I T, Ueda Y, Wörsdörfer P, Sumita Y, Asahina I, Ergün S. Resident CD34-positive cells contribute to peri-endothelial cells and vascular morphogenesis in salivary gland after irradiation. J Neural Transm (Vienna) 2020; 127:1467-1479. [PMID: 33025085 PMCID: PMC7578140 DOI: 10.1007/s00702-020-02256-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 09/22/2020] [Indexed: 02/08/2023]
Abstract
Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.
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Affiliation(s)
- Takashi I
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany. .,Unit of Translational Medicine, Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Yuichiro Ueda
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
| | - Philipp Wörsdörfer
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
| | - Yoshinori Sumita
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Izumi Asahina
- Unit of Translational Medicine, Department of Regenerative Oral Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany
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23
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Dayekh K, Mequanint K. The effects of progenitor and differentiated cells on ectopic calcification of engineered vascular tissues. Acta Biomater 2020; 115:288-298. [PMID: 32853805 DOI: 10.1016/j.actbio.2020.08.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Revised: 08/15/2020] [Accepted: 08/18/2020] [Indexed: 12/17/2022]
Abstract
Ectopic vascular calcification associated with aging, diabetes mellitus, atherosclerosis, and chronic kidney disease is a considerable risk factor for cardiovascular events and death. Although vascular smooth muscle cells are primarily implicated in calcification, the role of progenitor cells is less known. In this study, we engineered tubular vascular tissues from embryonic multipotent mesenchymal progenitor cells either without differentiating or after differentiating them into smooth muscle cells and studied ectopic calcification through targeted gene analysis. Tissues derived from both differentiated and undifferentiated cells calcified in response to hyperphosphatemic inorganic phosphate (Pi) treatment suggesting that a single cell-type (progenitor cells or differentiated cells) may not be the sole cause of the process. We also demonstrated that Vitamin K, which is the matrix gla protein activator, had a protective role against calcification in engineered vascular tissues. Addition of partially-soluble elastin upregulated osteogenic marker genes suggesting a calcification process. Furthermore, partially-soluble elastin downregulated smooth muscle myosin heavy chain (Myh11) gene which is a late-stage differentiation marker. This latter point, in turn, suggests that SMC may be switching into a synthetic phenotype which is one feature of vascular calcification. Taken together, our approach presents a valuable tool to study ectopic calcification and associated gene expressions relevant to clinical therapeutic targets.
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24
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Rajamannan NM, Moura LM, Best P. Bench to bedside defining calcific aortic valve disease: osteocardiology. Expert Rev Cardiovasc Ther 2020; 18:239-247. [PMID: 32319841 DOI: 10.1080/14779072.2020.1757431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
INTRODUCTION For years, calcific aortic valve disease (CAVD) was thought to be due to a degenerative process, but recent scientific discoveries have proven it to be an active process. Understanding the cellular mechanisms for the development of disease and translating the cellular changes critical in the development of calcific phenotypes. The use of multimodality imaging has been the gold standard to define the development of calcification to determine the timing of therapy. AREAS COVERED This review will discuss the scientific literature in a new and evolving field known as osteocardiology, which specifically defines the cellular mechanisms involved in the development of the osteogenic phenotype in the heart and vasculature. The work in this field has been highlighted by the calcific aortic valve disease working group at the NIH. This review will discuss the appropriate use criteria for multimodality imaging techniques to identify early cellular and hemodynamic disease progression in the aortic valve to help determine the timing of therapy, the osteocardiology theory. EXPERT OPINION The authors will provide their background in basic science and clinical medicine to support the opinions in this paper.
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Affiliation(s)
- Nalini M Rajamannan
- Division of Biochemistry and Molecular Biology, Visiting Scientist Mayo Clinic , Rochester, MN, USA.,Most Sacred Heart of Jesus Cardiology and Valvular Institute , Sheboygan, MN, USA
| | - Luis M Moura
- Faculty of Medicine and 3s Institute of Research and the Innovation in Health, University of Porto Hospital Lusiadas, Porto, Portugal
| | - Patricia Best
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN
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25
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Nwadozi E, Rudnicki M, Haas TL. Metabolic Coordination of Pericyte Phenotypes: Therapeutic Implications. Front Cell Dev Biol 2020; 8:77. [PMID: 32117997 PMCID: PMC7033550 DOI: 10.3389/fcell.2020.00077] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 01/29/2020] [Indexed: 12/15/2022] Open
Abstract
Pericytes are mural vascular cells found predominantly on the abluminal wall of capillaries, where they contribute to the maintenance of capillary structural integrity and vascular permeability. Generally quiescent cells in the adult, pericyte activation and proliferation occur during both physiological and pathological vascular and tissue remodeling. A considerable body of research indicates that pericytes possess attributes of a multipotent adult stem cell, as they are capable of self-renewal as well as commitment and differentiation into multiple lineages. However, pericytes also display phenotypic heterogeneity and recent studies indicate that lineage potential differs between pericyte subpopulations. While numerous microenvironmental cues and cell signaling pathways are known to regulate pericyte functions, the roles that metabolic pathways play in pericyte quiescence, self-renewal or differentiation have been given limited consideration to date. This review will summarize existing data regarding pericyte metabolism and will discuss the coupling of signal pathways to shifts in metabolic pathway preferences that ultimately regulate pericyte quiescence, self-renewal and trans-differentiation. The association between dysregulated metabolic processes and development of pericyte pathologies will be highlighted. Despite ongoing debate regarding pericyte classification and their functional capacity for trans-differentiation in vivo, pericytes are increasingly exploited as a cell therapy tool to promote tissue healing and regeneration. Ultimately, the efficacy of therapeutic approaches hinges on the capacity to effectively control/optimize the fate of the implanted pericytes. Thus, we will identify knowledge gaps that need to be addressed to more effectively harness the opportunity for therapeutic manipulation of pericytes to control pathological outcomes in tissue remodeling.
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Affiliation(s)
| | | | - Tara L. Haas
- School of Kinesiology and Health Science, Angiogenesis Research Group and Muscle Health Research Centre, York University, Toronto, ON, Canada
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26
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Deutsch O, Bruehl F, Cleuziou J, Prinzing A, Schlitter AM, Krane M, Lange R. Histological examination of explanted tissue-engineered bovine pericardium following heart valve repair. Interact Cardiovasc Thorac Surg 2020; 30:64-73. [PMID: 31605480 DOI: 10.1093/icvts/ivz234] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 07/30/2019] [Accepted: 08/16/2019] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Our goal was to present histopathological findings of human explants of a tissue-engineered bovine pericardium CardioCel (Admedus Regen Pty Ltd, Malaga, WA, Australia) used for heart valve repair in patients with congenital and acquired heart valve disease. METHODS Sixty patients underwent heart valve repair from May 2014 to November 2018 using CardioCel as a substitute for valve tissue. We identified 9 cases in which the CardioCel patch was explanted following valve repair and available for histomorphological analyses. CardioCel explants were evaluated histologically using haematoxylin and oeosin, Elastica van Gieson and immunohistochemical stains. RESULTS The indications for explantation were related to the CardioCel patch in 6 patients. Median time between the implantation and explantation was 242 (range 3-1247) days. We demonstrated a characteristic remodelling pattern with superficial coating of the tissue-engineered bovine pericardium by granulation tissue composed of histiocytes, few lymphocytes and fibrin. We had 2 cases with a multifocal nodular disruption, fragmentation and sclerosis of the decellularized collagen matrix with focal calcification after 795 and 1247 days in situ. CONCLUSIONS Our data suggest that the tissue-engineered CardioCel patch is initially tolerated in the valvular position in the majority of patients. However, we also experienced graft failures that showed degeneration with fragmentation of the collagen matrix and even 2 cases with focal calcification evident from the histopathological analysis. Further analyses of mid- and long-term performance are mandatory.
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Affiliation(s)
- Oliver Deutsch
- Department of Cardiovascular Surgery, German Heart Centre Munich, Munich, Germany.,INSURE-Institute for Translational Cardiac Surgery, German Heart Centre Munich, Munich, Germany
| | - Frido Bruehl
- Institute for Pathology, Technical University Munich, Munich, Germany
| | - Julie Cleuziou
- INSURE-Institute for Translational Cardiac Surgery, German Heart Centre Munich, Munich, Germany.,Department of Congenital and Pediatric Heart Surgery, German Heart Centre Munich, Munich, Germany
| | - Anatol Prinzing
- Department of Cardiovascular Surgery, German Heart Centre Munich, Munich, Germany.,INSURE-Institute for Translational Cardiac Surgery, German Heart Centre Munich, Munich, Germany
| | | | - Markus Krane
- Department of Cardiovascular Surgery, German Heart Centre Munich, Munich, Germany.,INSURE-Institute for Translational Cardiac Surgery, German Heart Centre Munich, Munich, Germany
| | - Rüdiger Lange
- Department of Cardiovascular Surgery, German Heart Centre Munich, Munich, Germany.,INSURE-Institute for Translational Cardiac Surgery, German Heart Centre Munich, Munich, Germany
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27
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Matsuo K, Chavez RD, Barruet E, Hsiao EC. Inflammation in Fibrodysplasia Ossificans Progressiva and Other Forms of Heterotopic Ossification. Curr Osteoporos Rep 2019; 17:387-394. [PMID: 31721068 PMCID: PMC7271746 DOI: 10.1007/s11914-019-00541-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Heterotopic ossification (HO) is associated with inflammation. The goal of this review is to examine recent findings on the roles of inflammation and the immune system in HO. We examine how inflammation changes in fibrodysplasia ossificans progressiva, in traumatic HO, and in other clinical conditions of HO. We also discuss how inflammation may be a target for treating HO. RECENT FINDINGS Both genetic and acquired forms of HO show similarities in their inflammatory cell types and signaling pathways. These include macrophages, mast cells, and adaptive immune cells, along with hypoxia signaling pathways, mesenchymal stem cell differentiation signaling pathways, vascular signaling pathways, and inflammatory cytokines. Because there are common inflammatory mediators across various types of HO, these mediators may serve as common targets for blocking HO. Future research may focus on identifying new inflammatory targets and testing combinatorial therapies based on these results.
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Affiliation(s)
- Koji Matsuo
- Division of Endocrinology and Metabolism, University of California, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA
- Department of Medicine, The Institute for Human Genetics, University of California, CA, San Francisco, USA
- The Program in Craniofacial Biology, University of California, CA, San Francisco, USA
| | - Robert Dalton Chavez
- Division of Endocrinology and Metabolism, University of California, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA
- Department of Medicine, The Institute for Human Genetics, University of California, CA, San Francisco, USA
- The Program in Craniofacial Biology, University of California, CA, San Francisco, USA
| | - Emilie Barruet
- Division of Endocrinology and Metabolism, University of California, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA
- Department of Medicine, The Institute for Human Genetics, University of California, CA, San Francisco, USA
- The Program in Craniofacial Biology, University of California, CA, San Francisco, USA
| | - Edward C Hsiao
- Division of Endocrinology and Metabolism, University of California, 513 Parnassus Ave., HSE901, San Francisco, CA, 94143-0794, USA.
- Department of Medicine, The Institute for Human Genetics, University of California, CA, San Francisco, USA.
- The Program in Craniofacial Biology, University of California, CA, San Francisco, USA.
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28
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Piccirillo F, Carpenito M, Verolino G, Chello C, Nusca A, Lusini M, Spadaccio C, Nappi F, Di Sciascio G, Nenna A. Changes of the coronary arteries and cardiac microvasculature with aging: Implications for translational research and clinical practice. Mech Ageing Dev 2019; 184:111161. [PMID: 31647940 DOI: 10.1016/j.mad.2019.111161] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022]
Abstract
Aging results in functional and structural changes in the cardiovascular system, translating into a progressive increase of mechanical vessel stiffness, due to a combination of changes in micro-RNA expression patterns, autophagy, arterial calcification, smooth muscle cell migration and proliferation. The two pivotal mechanisms of aging-related endothelial dysfunction are oxidative stress and inflammation, even in the absence of clinical disease. A comprehensive understanding of the aging process is emerging as a primary concern in literature, as vascular aging has recently become a target for prevention and treatment of cardiovascular disease. Change of life-style, diet, antioxidant regimens, anti-inflammatory treatments, senolytic drugs counteract the pro-aging pathways or target senescent cells modulating their detrimental effects. Such therapies aim to reduce the ineluctable burden of age and contrast aging-associated cardiovascular dysfunction. This narrative review intends to summarize the macrovascular and microvascular changes related with aging, as a better understanding of the pathways leading to arterial aging may contribute to design new mechanism-based therapeutic approaches to attenuate the features of vascular senescence and its clinical impact on the cardiovascular system.
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Affiliation(s)
| | | | | | - Camilla Chello
- Dermatology, Università "La Sapienza" di Roma, Rome, Italy
| | | | - Mario Lusini
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | | | - Francesco Nappi
- Cardiac surgery, Centre Cardiologique du Nord de Saint Denis, Paris, France
| | | | - Antonio Nenna
- Cardiovascular surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
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29
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Vasuri F, Ciavarella C, Fittipaldi S, Pini R, Vacirca A, Gargiulo M, Faggioli G, Pasquinelli G. Different histological types of active intraplaque calcification underlie alternative miRNA-mRNA axes in carotid atherosclerotic disease. Virchows Arch 2019; 476:307-316. [PMID: 31506771 DOI: 10.1007/s00428-019-02659-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 08/14/2019] [Accepted: 08/26/2019] [Indexed: 12/11/2022]
Abstract
Arterial calcification is an actively regulated process, with different morphological manifestations. Micro-RNAs emerged as potential regulators of vascular calcification; they may become novel diagnostic tools and be used for a finest staging of the carotid plaque progression. The present study aimed at characterizing the different miRNA-mRNA axes in carotid plaques according to their histological patterns of calcification. Histopathological analysis was performed on 124 retrospective carotid plaques, with clinical data and preoperatory angio-CT. miRNA analysis was carried out with microfluidic cards. Real-time PCR was performed for selected miRNAs validation and for RUNX-2 and SOX-9 mRNA levels. CD31, CD68, SMA, and SOX-9 were analyzed by immunohistochemistry. miRNA levels on HUVEC cells were analyzed for confirming results under in vitro osteogenic conditions. Histopathological analysis revealed two main calcification subtypes of plaques: calcific cores (CC) and protruding nodules (PN). miRNA array and PCR validation of miR-1275, miR-30a-5p, and miR-30d indicated a significant upregulation of miR-30a-5p and miR-30d in the PN plaques. Likewise, the miRNA targets RUNX-2 and SOX-9 resulted poorly expressed in PN plaques. The inverse correlation between miRNA and RUNX-2 levels was confirmed on osteogenic-differentiated HUVEC. miR-30a-5p and miR-30d directly correlated with calcification extension and thickness at angio-CT imaging. Our study demonstrated the presence of two distinct morphological subtypes of calcification in carotid atheromatous plaques, supported by different miRNA signatures, and by different angio-CT features. These results shed the light on the use of miRNA as novel diagnostic markers, suggestive of plaque evolution.
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Affiliation(s)
- Francesco Vasuri
- Clinical and Surgical Pathology, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Carmen Ciavarella
- Clinical and Surgical Pathology, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Silvia Fittipaldi
- Clinical and Surgical Pathology, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Rodolfo Pini
- Vascular Surgery, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, Bologna, 40138, Italy
| | - Andrea Vacirca
- Vascular Surgery, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, Bologna, 40138, Italy
| | - Mauro Gargiulo
- Vascular Surgery, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, Bologna, 40138, Italy
| | - Gianluca Faggioli
- Vascular Surgery, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, Bologna, 40138, Italy
| | - Gianandrea Pasquinelli
- Clinical and Surgical Pathology, Department of Specialty, Diagnostic and Experimental Medicine, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy.
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Lin H, Sohn J, Shen H, Langhans MT, Tuan RS. Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. Biomaterials 2019; 203:96-110. [PMID: 29980291 PMCID: PMC6733253 DOI: 10.1016/j.biomaterials.2018.06.026] [Citation(s) in RCA: 258] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 12/11/2022]
Abstract
Bone has well documented natural healing capacity that normally is sufficient to repair fractures and other common injuries. However, the properties of bone change throughout life, and aging is accompanied by increased incidence of bone diseases and compromised fracture healing capacity, which necessitate effective therapies capable of enhancing bone regeneration. The therapeutic potential of adult mesenchymal stem cells (MSCs) for bone repair has been long proposed and examined. Actions of MSCs may include direct differentiation to become bone cells, attraction and recruitment of other cells, or creation of a regenerative environment via production of trophic growth factors. With systemic aging, MSCs also undergo functional decline, which has been well investigated in a number of recent studies. In this review, we first describe the changes in MSCs during aging and discuss how these alterations can affect bone regeneration. We next review current research findings on bone tissue engineering, which is considered a promising and viable therapeutic solution for structural and functional restoration of bone. In particular, the importance of MSCs and bioscaffolds is highlighted. Finally, potential approaches for the prevention of MSC aging and the rejuvenation of aged MSC are discussed.
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Affiliation(s)
- Hang Lin
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jihee Sohn
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - He Shen
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Nanobiomedicine, Suzhou Institute of Nano-tech and Nano-bionics, Chinese Academy of Sciences, China
| | - Mark T Langhans
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Rocky S Tuan
- Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; The Chinese University of Hong Kong, Hong Kong SAR, China.
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31
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Summerhill V, Orekhov A. Pericytes in Atherosclerosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1147:279-297. [DOI: 10.1007/978-3-030-16908-4_13] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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32
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Lee LL, Chintalgattu V. Pericytes in the Heart. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:187-210. [PMID: 30937870 DOI: 10.1007/978-3-030-11093-2_11] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Mural cells known as pericytes envelop the endothelial layer of microvessels throughout the body and have been described to have tissue-specific functions. Cardiac pericytes are abundantly found in the heart, but they are relatively understudied. Currently, their importance is emerging in cardiovascular homeostasis and dysfunction due to their pleiotropism. They are known to play key roles in vascular tone and vascular integrity as well as angiogenesis. However, their dysfunctional presence and/or absence is critical in the mechanisms that lead to cardiac pathologies such as myocardial infarction, fibrosis, and thrombosis. Moreover, they are targeted as a therapeutic potential due to their mesenchymal properties that could allow them to repair and regenerate a damaged heart. They are also sought after as a cell-based therapy based on their healing potential in preclinical studies of animal models of myocardial infarction. Therefore, recognizing the importance of cardiac pericytes and understanding their biology will lead to new therapeutic concepts.
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Affiliation(s)
- Linda L Lee
- Department of CardioMetabolic Disorders, Amgen Research and Discovery, Amgen Inc., South San Francisco, CA, USA
| | - Vishnu Chintalgattu
- Department of CardioMetabolic Disorders, Amgen Research and Discovery, Amgen Inc., South San Francisco, CA, USA.
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33
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Bartoli-Leonard F, Wilkinson FL, Langford-Smith AWW, Alexander MY, Weston R. The Interplay of SIRT1 and Wnt Signaling in Vascular Calcification. Front Cardiovasc Med 2018; 5:183. [PMID: 30619890 PMCID: PMC6305318 DOI: 10.3389/fcvm.2018.00183] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 12/04/2018] [Indexed: 12/24/2022] Open
Abstract
Vascular calcification is a major health risk and is highly correlated with atherosclerosis, diabetes, and chronic kidney disease. The development of vascular calcification is an active and complex process linked with a multitude of signaling pathways, which regulate promoters and inhibitors of osteogenesis, the balance of which become deregulated in disease conditions. SIRT1, a protein deacetylase, known to be protective in inhibiting oxidative stress and inflammation within the vessel wall, has been shown as a possible key player in modulating the cell-fate determining canonical Wnt signaling pathways. Suppression of SIRT1 has been reported in patients suffering with cardiovascular pathologies, suggesting that the sustained acetylation of osteogenic factors could contribute to their activation and in turn, lead to the progression of calcification. There is clear evidence of the synergy between β-Catenin and elevated Runx2, and with Wnt signaling being β-Catenin dependent, further understanding is needed as to how these molecular pathways converge and interact, in order to provide novel insight into the mechanism by which smooth muscle cells switch to an osteogenic differentiation programme. Therefore, this review will describe the current concepts of pathological soft tissue mineralization, with a focus on the contribution of SIRT1 as a regulator of Wnt signaling and its targets, discussing SIRT1 as a potential target for manipulation and therapy.
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Affiliation(s)
- Francesca Bartoli-Leonard
- Translational Cardiovascular Science, Centre for Bioscience, Manchester Metropolitan University, Manchester, United Kingdom
| | - Fiona L Wilkinson
- Translational Cardiovascular Science, Centre for Bioscience, Manchester Metropolitan University, Manchester, United Kingdom
| | - Alex W W Langford-Smith
- Translational Cardiovascular Science, Centre for Bioscience, Manchester Metropolitan University, Manchester, United Kingdom
| | - M Y Alexander
- Translational Cardiovascular Science, Centre for Bioscience, Manchester Metropolitan University, Manchester, United Kingdom
| | - Ria Weston
- Translational Cardiovascular Science, Centre for Bioscience, Manchester Metropolitan University, Manchester, United Kingdom
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Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary Calcium Score and Cardiovascular Risk. J Am Coll Cardiol 2018; 72:434-447. [PMID: 30025580 PMCID: PMC6056023 DOI: 10.1016/j.jacc.2018.05.027] [Citation(s) in RCA: 619] [Impact Index Per Article: 88.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 05/03/2018] [Accepted: 05/16/2018] [Indexed: 01/01/2023]
Abstract
Coronary artery calcium (CAC) is a highly specific feature of coronary atherosclerosis. On the basis of single-center and multicenter clinical and population-based studies with short-term and long-term outcomes data (up to 15-year follow-up), CAC scoring has emerged as a widely available, consistent, and reproducible means of assessing risk for major cardiovascular outcomes, especially useful in asymptomatic people for planning primary prevention interventions such as statins and aspirin. CAC testing in asymptomatic populations is cost effective across a broad range of baseline risk. This review summarizes evidence concerning CAC, including its pathobiology, modalities for detection, predictive role, use in prediction scoring algorithms, CAC progression, evidence that CAC changes the clinical approach to the patient and patient behavior, novel applications of CAC, future directions in scoring CAC scans, and new CAC guidelines.
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Affiliation(s)
- Philip Greenland
- Departments of Preventive Medicine and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
| | - Michael J Blaha
- Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins School of Medicine, Baltimore, Maryland. https://twitter.com/MichaelJBlaha
| | | | - Raimund Erbel
- Institute of Medical Informatics, Biometry and Epidemiology, University Clinic, Essen, Germany
| | - Karol E Watson
- Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. https://twitter.com/kewatson
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Trillhaase A, Haferkamp U, Rangnau A, Märtens M, Schmidt B, Trilck M, Seibler P, Aherrahrou R, Erdmann J, Aherrahrou Z. Differentiation of human iPSCs into VSMCs and generation of VSMC-derived calcifying vascular cells. Stem Cell Res 2018; 31:62-70. [PMID: 30029055 DOI: 10.1016/j.scr.2018.07.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 07/03/2018] [Accepted: 07/11/2018] [Indexed: 02/06/2023] Open
Abstract
Vascular calcification displays a major cause of death worldwide, which involve mainly vascular smooth muscle cells (VSMCs). Since 2007, there are increasing numbers of protocols to obtain different cell types from human induced-pluripotent stem cells (iPSCs), however a protocol for calcification is missing. Few protocols exist today for the differentiation of iPSCs towards VSMCs and none are known for their calcification. Here we present a protocol for the calcification of iPSC-derived VSMCs. We successfully differentiated iPSCs into VSMCs based on a modified protocol. Calcification in VSMCs is induced by a commercial StemXVivo™ osteogenic medium. Calcification was verified using Calcein and Alizarin Red S staining or Calcium assays, and molecular analyses showed enhanced expression of calcification-associated genes. The presented method could help to study genetic risk variants, using the CRISPR/Cas technology through the introduction of Knockouts or Knockins of risk variants. Finally, this method can be applied for drug screening.
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Affiliation(s)
- Anja Trillhaase
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Undine Haferkamp
- Institute for Cardiogenetics, University of Luebeck, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), 22525Hamburg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Alexandra Rangnau
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Marlon Märtens
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Beatrice Schmidt
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Michaela Trilck
- Institute for Neurogenetics, University of Luebeck, 23562 Luebeck, Germany
| | - Philip Seibler
- Institute for Neurogenetics, University of Luebeck, 23562 Luebeck, Germany
| | - Redouane Aherrahrou
- Institute for Cardiogenetics, University of Luebeck, Germany; Center for Public Health Genomics, Department of Biomedical Engineering, University of Virginia, Charlottesville, VA22908, USA; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Jeanette Erdmann
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany
| | - Zouhair Aherrahrou
- Institute for Cardiogenetics, University of Luebeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Luebeck, Germany; University Heart Centre Luebeck, 23562 Luebeck, Germany.
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Rajamannan NM, Moura L. The Lipid Hypothesis in Calcific Aortic Valve Disease: The Role of the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol 2018; 36:774-6. [PMID: 27122627 DOI: 10.1161/atvbaha.116.307435] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Nalini M Rajamannan
- From the Division of Cardiology, Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, WI (N.M.R.); Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN (N.M.R.); Department of Medicine, Division of Cardiology, Hospital Pedro Hispano, Matosinhos, Oporto, Portugal (L.M.); and Department of Cardiology, University Medical School, Oporto, Portugal (L.M.).
| | - Luis Moura
- From the Division of Cardiology, Most Sacred Heart of Jesus Cardiology and Valvular Institute, Sheboygan, WI (N.M.R.); Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN (N.M.R.); Department of Medicine, Division of Cardiology, Hospital Pedro Hispano, Matosinhos, Oporto, Portugal (L.M.); and Department of Cardiology, University Medical School, Oporto, Portugal (L.M.)
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Abstract
Vascular, resident stem cells are present in all 3 layers of the vessel wall; they play a role in vascular formation under physiological conditions and in remodeling in pathological situations. Throughout development and adult early life, resident stem cells participate in vessel formation through vasculogenesis and angiogenesis. In adults, the vascular stem cells are mostly quiescent in their niches but can be activated in response to injury and participate in endothelial repair and smooth muscle cell accumulation to form neointima. However, delineation of the characteristics and of the migration and differentiation behaviors of these stem cells is an area of ongoing investigation. A set of genetic mouse models for cell lineage tracing has been developed to specifically address the nature of these cells and both migration and differentiation processes during physiological angiogenesis and in vascular diseases. This review summarizes the current knowledge on resident stem cells, which has become more defined and refined in vascular biology research, thus contributing to the development of new potential therapeutic strategies to promote endothelial regeneration and ameliorate vascular disease development.
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Affiliation(s)
- Li Zhang
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
| | - Shirin Issa Bhaloo
- School of Cardiovascular Medicine and Sciences, King’s College London, BHF Centre, United Kingdom (S.I.B., Q.X.)
| | - Ting Chen
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
| | - Bin Zhou
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academic of Sciences (B.Z.)
| | - Qingbo Xu
- From the Department of Cardiology, the First Affiliated Hospital, School of Medicine, Zhejiang University, China (L.Z., T.C., Q.X.)
- School of Cardiovascular Medicine and Sciences, King’s College London, BHF Centre, United Kingdom (S.I.B., Q.X.)
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Özkalaycı F, Gülmez Ö, Uğur-Altun B, Pandi-Perumal SR, Altun A. The Role of Osteoprotegerin as a Cardioprotective Versus Reactive Inflammatory Marker: the Chicken or the Egg Paradox. Balkan Med J 2018; 35:225-232. [PMID: 29687784 PMCID: PMC5981118 DOI: 10.4274/balkanmedj.2018.0579] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Cardiovascular disease is one of the most frequent causes of mortality and morbidity worldwide. Several variables have been identified as risk factors for cardiovascular disease. Recently, the role of receptor activator of nuclear factor kappa B, receptor activator of nuclear factor kappa B ligand, and the osteoprotegerin system has been recognized as more important in the pathogenesis of cardiovascular disease. Besides their roles in the regulation of bone resorption, these molecules have been reported to be associated with the pathophysiology of cardiovascular disease. There are conflicting data regarding the impact of osteoprotegerin, a glycoprotein with a regulatory role in the cardiovascular system. The aim of this review is to discuss the current knowledge and the role of osteoprotegerin in cardiovascular disease.
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Affiliation(s)
- Flora Özkalaycı
- Department of Cardiology, Başkent University İstanbul Hospital, İstanbul, Turkey
| | - Öykü Gülmez
- Department of Cardiology, Başkent University İstanbul Hospital, İstanbul, Turkey
| | - Betül Uğur-Altun
- Department of Endocrinology and Metabolism, Başkent University İstanbul Hospital, İstanbul, Turkey
| | | | - Armağan Altun
- Department of Cardiology, Başkent University İstanbul Hospital, İstanbul, Turkey
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Fuery MA, Liang L, Kaplan FS, Mohler ER. Vascular ossification: Pathology, mechanisms, and clinical implications. Bone 2018; 109:28-34. [PMID: 28688892 DOI: 10.1016/j.bone.2017.07.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/04/2017] [Accepted: 07/04/2017] [Indexed: 12/28/2022]
Abstract
In recent years, the mechanisms and clinical significance of vascular calcification have been increasingly investigated. For over a century, however, pathologists have recognized that vascular calcification is a form of heterotopic ossification. In this review, we aim to describe the pathology and molecular processes of vascular ossification, to characterize its clinical significance and treatment options, and to elucidate areas that require further investigation. The molecular mechanisms of vascular ossification involve the activation of regulators including bone morphogenic proteins and chondrogenic transcription factors and the loss of mineralization inhibitors like fetuin-A and pyrophosphate. Although few studies have examined the gross pathology of vascular ossification, the presence of these molecular regulators and evidence of microfractures and cartilage have been demonstrated on heart valves and atherosclerotic plaques. These changes are often triggered by common inflammatory and metabolic disorders like diabetes, hyperlipidemia, and chronic kidney disease. The increasing prevalence of these diseases warrants further research into the clinical significance of vascular ossification and future treatment options.
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Affiliation(s)
- Michael A Fuery
- Department of Medicine, Cardiovascular Division, Section of Vascular Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
| | - Lusha Liang
- Department of Medicine, Cardiovascular Division, Section of Vascular Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
| | - Frederick S Kaplan
- Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
| | - Emile R Mohler
- Department of Medicine, Cardiovascular Division, Section of Vascular Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States.
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40
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Hortells L, Sur S, St Hilaire C. Cell Phenotype Transitions in Cardiovascular Calcification. Front Cardiovasc Med 2018; 5:27. [PMID: 29632866 PMCID: PMC5879740 DOI: 10.3389/fcvm.2018.00027] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 03/14/2018] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular calcification was originally considered a passive, degenerative process, however with the advance of cellular and molecular biology techniques it is now appreciated that ectopic calcification is an active biological process. Vascular calcification is the most common form of ectopic calcification, and aging as well as specific disease states such as atherosclerosis, diabetes, and genetic mutations, exhibit this pathology. In the vessels and valves, endothelial cells, smooth muscle cells, and fibroblast-like cells contribute to the formation of extracellular calcified nodules. Research suggests that these vascular cells undergo a phenotypic switch whereby they acquire osteoblast-like characteristics, however the mechanisms driving the early aspects of these cell transitions are not fully understood. Osteoblasts are true bone-forming cells and differentiate from their pluripotent precursor, the mesenchymal stem cell (MSC); vascular cells that acquire the ability to calcify share aspects of the transcriptional programs exhibited by MSCs differentiating into osteoblasts. What is unknown is whether a fully-differentiated vascular cell directly acquires the ability to calcify by the upregulation of osteogenic genes or, whether these vascular cells first de-differentiate into an MSC-like state before obtaining a “second hit” that induces them to re-differentiate down an osteogenic lineage. Addressing these questions will enable progress in preventative and regenerative medicine strategies to combat vascular calcification pathologies. In this review, we will summarize what is known about the phenotypic switching of vascular endothelial, smooth muscle, and valvular cells.
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Affiliation(s)
- Luis Hortells
- Division of Cardiology, Department of Medicine, and the Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States
| | - Swastika Sur
- Division of Cardiology, Department of Medicine, and the Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States
| | - Cynthia St Hilaire
- Division of Cardiology, Department of Medicine, and the Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, United States
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41
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Cho HJ, Lee JW, Cho HJ, Lee CS, Kim HS. Identification of Adult Mesodermal Progenitor Cells and Hierarchy in Atherosclerotic Vascular Calcification. Stem Cells 2018; 36:1075-1096. [PMID: 29484798 DOI: 10.1002/stem.2814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 01/26/2018] [Accepted: 02/05/2018] [Indexed: 01/01/2023]
Abstract
The nature of calcifying progenitor cells remains elusive. In this study, we investigated the developmental hierarchy and dynamics of progenitor cells. In vitro and in vivo reconstitution assays demonstrated that Sca-1+/PDGFRα- cells in the bone marrow (BM) are the ancestors of Sca-1+/PDGFRα+ cells. Cells of CD29 + Sca-1+/PDGFRα- lineage in the BM showed both hematopoietic potential with osteoclastic differentiation ability as well as mesenchymal stem cell-like properties with osteoblastic differentiation potential. Clonally-isolated BM-derived artery-infiltrated Sca-1+/PDGFRα- cells maintained osteoblastic/osteoclastic bipotency but lost hematopoietic activity. In hypercholesterolemic apolipoprotein-E-deficient (Apoe-/-) mice, the mobilization from BM to peripheral circulation, followed by migration into atherosclerotic plaques of Sca-1+/PDGFRα- cells, but not Sca-1+/PDGFRα+ cells, were significantly decreased, and Interleukin-1β (IL-1β) and Interleukin-5 (IL-5) mediated this response. Here, we demonstrated that Sca-1+/PDGFRα- cells are mesodermal progenitor cells in adults, and the dynamics of progenitor cells were regulated by atherosclerosis-related humoral factors. These results may contribute to better understanding of vascular homeostasis and assist in the development of novel therapies for atherosclerosis. Stem Cells 2018;36:1075-1096.
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Affiliation(s)
- Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jin-Woo Lee
- Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, Seoul, Korea.,National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun-Ju Cho
- Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, Seoul, Korea.,National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea
| | - Choon-Soo Lee
- Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, Seoul, Korea.,National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea.,World Class University Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Hyo-Soo Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.,Strategic Center of Cell & Bio Therapy, Seoul National University Hospital, Seoul, Korea.,National Research Laboratory for Stem Cell Niche, Seoul National University College of Medicine, Seoul, Korea.,World Class University Program, Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul, Korea
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42
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Leszczynska A, Murphy JM. Vascular Calcification: Is it rather a Stem/Progenitor Cells Driven Phenomenon? Front Bioeng Biotechnol 2018; 6:10. [PMID: 29479528 PMCID: PMC5811524 DOI: 10.3389/fbioe.2018.00010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/22/2018] [Indexed: 12/21/2022] Open
Abstract
Vascular calcification (VC) has witnessed a surge of interest. Vasculature is virtually an omnipresent organ and has a notably high capacity for repair throughout embryonic and adult life. Of the vascular diseases, atherosclerosis is a leading cause of morbidity and mortality on account of ectopic cartilage and bone formation. Despite the identification of a number of risk factors, all the current theories explaining pathogenesis of VC in atherosclerosis are far from complete. The most widely accepted response to injury theory and smooth muscle transdifferentiation to explain the VC observed in atherosclerosis is being challenged. Recent focus on circulating and resident progenitor cells in the vasculature and their role in atherogenesis and VC has been the driving force behind this review. This review discusses intrinsic cellular players contributing to fate determination of cells and tissues to form ectopic cartilage and bone formation.
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Affiliation(s)
- Aleksandra Leszczynska
- Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - J Mary Murphy
- Regenerative Medicine Institute, National University of Ireland Galway, Galway, Ireland
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Affiliation(s)
- Isabella Albanese
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Kashif Khan
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Bianca Barratt
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Hamood Al-Kindi
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Adel Schwertani
- Division of Cardiology and Division of Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
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Espitia O, Chatelais M, Steenman M, Charrier C, Maurel B, Georges S, Houlgatte R, Verrecchia F, Ory B, Lamoureux F, Heymann D, Gouëffic Y, Quillard T. Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification. PLoS One 2018; 13:e0191976. [PMID: 29373585 PMCID: PMC5786328 DOI: 10.1371/journal.pone.0191976] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/15/2018] [Indexed: 11/29/2022] Open
Abstract
Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcification among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ signaling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.
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Affiliation(s)
- Olivier Espitia
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
- CHU Hôtel Dieu, Nantes, France
| | - Mathias Chatelais
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - Marja Steenman
- Institut du Thorax, Inserm UMR1087, Faculté de Médecine, Université de Nantes, Nantes Atlantique Universités, Nantes, France
| | - Céline Charrier
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - Blandine Maurel
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
- CHU Hôtel Dieu, Nantes, France
| | - Steven Georges
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - Rémi Houlgatte
- Inserm U954, Faculty of Medicine, Nancy, France, DRCI, University Hospital of Nancy, Nancy, France
| | - Franck Verrecchia
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - Benjamin Ory
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - François Lamoureux
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
| | - Dominique Heymann
- Institut de Cancérologie de l'Ouest, site René Gauducheau, Boulevard Professeur Jacques Monod, Saint-Herblain, France
- University of Sheffield, Department of Oncology and Metabolism, INSERM, European Associated Laboratory “Sarcoma Research Unit”, Medical School, Sheffield, United Kingdom
- University of Nantes, Faculty of Medicine, Nantes, France
| | - Yann Gouëffic
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
- CHU Hôtel Dieu, Nantes, France
| | - Thibaut Quillard
- INSERM, UMR 1238, Nantes, France; Université de Nantes, Nantes Atlantique Universités, Laboratoire « Sarcome osseux et remodelage des tissus osseux calcifiés », Faculté de Médecine, Nantes, France
- CHU Hôtel Dieu, Nantes, France
- * E-mail:
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Wang D, Li LK, Dai T, Wang A, Li S. Adult Stem Cells in Vascular Remodeling. Am J Cancer Res 2018; 8:815-829. [PMID: 29344309 PMCID: PMC5771096 DOI: 10.7150/thno.19577] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 10/01/2017] [Indexed: 01/03/2023] Open
Abstract
Understanding the contribution of vascular cells to blood vessel remodeling is critical for the development of new therapeutic approaches to cure cardiovascular diseases (CVDs) and regenerate blood vessels. Recent findings suggest that neointimal formation and atherosclerotic lesions involve not only inflammatory cells, endothelial cells, and smooth muscle cells, but also several types of stem cells or progenitors in arterial walls and the circulation. Some of these stem cells also participate in the remodeling of vascular grafts, microvessel regeneration, and formation of fibrotic tissue around biomaterial implants. Here we review the recent findings on how adult stem cells participate in CVD development and regeneration as well as the current state of clinical trials in the field, which may lead to new approaches for cardiovascular therapies and tissue engineering.
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Esteves CL, Donadeu FX. Pericytes and their potential in regenerative medicine across species. Cytometry A 2017; 93:50-59. [PMID: 28941046 DOI: 10.1002/cyto.a.23243] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 08/15/2017] [Accepted: 08/25/2017] [Indexed: 12/17/2022]
Abstract
The discovery that pericytes are in vivo counterparts of Mesenchymal Stem/Stromal Cells (MSCs) has placed these perivascular cells in the research spotlight, bringing up hope for a well-characterized cell source for clinical applications, alternative to poorly defined, heterogeneous MSCs preparations currently in use. Native pericytes express typical MSC markers and, after isolation by fluorescence-activated cell sorting, display an MSC phenotype in culture. These features have been demonstrated in different species, including humans and horses, the main targets of regenerative treatments. Significant clinical potential of pericytes has been shown by transplantation of human cells into rodent models of tissue injury, and it is hoped that future studies will demonstrate clinical potential in veterinary species. Here, we provide an overview of the current knowledge on pericytes across different species including humans, companion and large animal models, in relation to their identification in different body tissues, methodology for prospective isolation, characterization, and potential for tissue regeneration. © 2017 International Society for Advancement of Cytometry.
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Affiliation(s)
- C L Esteves
- Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, United Kingdom
| | - F X Donadeu
- Division of Developmental Biology, The Roslin Institute, University of Edinburgh, Edinburgh EH25 9RG, United Kingdom
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Abstract
PURPOSE OF REVIEW We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
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MESH Headings
- Abnormalities, Multiple/drug therapy
- Abnormalities, Multiple/genetics
- Abnormalities, Multiple/metabolism
- Aortic Diseases/drug therapy
- Aortic Diseases/genetics
- Aortic Diseases/metabolism
- Basal Ganglia Diseases/drug therapy
- Basal Ganglia Diseases/genetics
- Basal Ganglia Diseases/metabolism
- Calcinosis/drug therapy
- Calcinosis/genetics
- Calcinosis/metabolism
- Cartilage Diseases/drug therapy
- Cartilage Diseases/genetics
- Cartilage Diseases/metabolism
- Dental Enamel Hypoplasia/drug therapy
- Dental Enamel Hypoplasia/genetics
- Dental Enamel Hypoplasia/metabolism
- Diphosphates/metabolism
- Enzyme Replacement Therapy
- Gaucher Disease/drug therapy
- Gaucher Disease/genetics
- Gaucher Disease/metabolism
- Hand Deformities, Congenital/drug therapy
- Hand Deformities, Congenital/genetics
- Hand Deformities, Congenital/metabolism
- Humans
- Hyperostosis, Cortical, Congenital/drug therapy
- Hyperostosis, Cortical, Congenital/genetics
- Hyperostosis, Cortical, Congenital/metabolism
- Hyperphosphatemia/drug therapy
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Interferons/metabolism
- Metacarpus/abnormalities
- Metacarpus/metabolism
- Muscular Diseases/drug therapy
- Muscular Diseases/genetics
- Muscular Diseases/metabolism
- Odontodysplasia/drug therapy
- Odontodysplasia/genetics
- Odontodysplasia/metabolism
- Osteoporosis/drug therapy
- Osteoporosis/genetics
- Osteoporosis/metabolism
- Phosphates/metabolism
- Progeria/drug therapy
- Progeria/genetics
- Progeria/metabolism
- Pseudoxanthoma Elasticum/drug therapy
- Pseudoxanthoma Elasticum/genetics
- Pseudoxanthoma Elasticum/metabolism
- Pulmonary Valve Stenosis/drug therapy
- Pulmonary Valve Stenosis/genetics
- Pulmonary Valve Stenosis/metabolism
- Vascular Calcification/drug therapy
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
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Affiliation(s)
- Yvonne Nitschke
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany
| | - Frank Rutsch
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.
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Mao F, Tu Q, Wang L, Chu F, Li X, Li HS, Xu W. Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease. Oncotarget 2017; 8:38008-38021. [PMID: 28402942 PMCID: PMC5514968 DOI: 10.18632/oncotarget.16682] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/06/2017] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem or stromal cells (MSCs) are non-hematopoietic stem cells that facilitate tissue regeneration through mechanisms involving self-renewal and differentiation, supporting angiogenesis and tissue cell survival, and limiting inflammation. MSCs were originally identified and expanded in long-term cultures of cells from bone marrow and other organs; and their native identity was recently confined into pericytes and adventitial cells in vascularized tissue. The multipotency, as well as the trophic and immunosuppressive effects, of MSCs have prompted the rapid development of clinical applications for many diseases involving tissue inflammation and immune disorders, including inflammatory bowel disease. Although standard criteria have been established to define MSCs, their therapeutic efficacy has varied significantly among studies due to their natural heterogenicity. Thus, understanding the biological and immunological features of MSCs is critical to standardize and optimize MSCs-based therapy. In this review, we highlight the cellular and molecular mechanisms involved in MSCs-mediated tissue repair and immunosuppression. We also provide an update on the current development of MSCs-based clinical trials, with a detailed discussion of MSC-based cell therapy in inflammatory bowel disease.
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Affiliation(s)
- Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Qiang Tu
- Jiangning Hospital of Nanjing, Nanjing, Jiangsu, P.R. China
| | - Li Wang
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Fuliang Chu
- Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xia Li
- Department of Gastroenterology, Binzhou Medical University Yantai Affiliated Hospital, Yantai, Shandong, P.R. China
| | - Haiyan S. Li
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
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Trohatou O, Roubelakis MG. Mesenchymal Stem/Stromal Cells in Regenerative Medicine: Past, Present, and Future. Cell Reprogram 2017; 19:217-224. [PMID: 28520465 DOI: 10.1089/cell.2016.0062] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The concept of Regenerative Medicine combined with Cell based Therapy and Tissue Engineering represents the fourth pillar of healthcare and provides a promising approach for the treatment of serious diseases. Recently, cell based therapies are focused on the use of mesenchymal stem/stromal cells (MSCs). Human MSCs, that represent a mesoderm derived population of progenitors, are easily expanded in culture. They are capable to differentiate into osteoblasts, chondrocytes, and adipocytes and exhibit the potential to repair or regenerate damaged tissues. The best characterized source of human MSCs to date is the bone marrow; recently, fetal sources, such as amniotic fluid, umbilical cord, amniotic membranes, or placenta, have also attracted increased attention. Thus, MSCs may represent a valuable tool for tissue repair and cell therapeutic applications. To this end, the main focus of this review is to summarize and evaluate the key characteristics, the sources, and the potential use of MSCs in therapeutic approaches and modalities.
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Affiliation(s)
- Ourania Trohatou
- 1 Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens , Athens, Greece .,2 Cell and Gene Therapy Laboratory, Centre of Basic Research II , Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
| | - Maria G Roubelakis
- 1 Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens , Athens, Greece .,2 Cell and Gene Therapy Laboratory, Centre of Basic Research II , Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece
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Davies JE, Walker JT, Keating A. Concise Review: Wharton's Jelly: The Rich, but Enigmatic, Source of Mesenchymal Stromal Cells. Stem Cells Transl Med 2017; 6:1620-1630. [PMID: 28488282 PMCID: PMC5689772 DOI: 10.1002/sctm.16-0492] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/03/2017] [Accepted: 02/24/2017] [Indexed: 12/21/2022] Open
Abstract
The umbilical cord has become an increasingly used source of mesenchymal stromal cells for preclinical and, more recently, clinical studies. Despite the increased activity, several aspects of this cell population have been under‐appreciated. Key issues are that consensus on the anatomical structures within the cord is lacking, and potentially different populations are identified as arising from a single source. To help address these points, we propose a histologically based nomenclature for cord structures and provide an analysis of their developmental origins and composition. Methods of cell isolation from Wharton's jelly are discussed and the immunophenotypic and clonal characteristics of the cells are evaluated. The perivascular origin of the cells is also addressed. Finally, clinical trials with umbilical cord cells are briefly reviewed. Interpreting the outcomes of the many clinical studies that have been undertaken with mesenchymal stromal cells from different tissue sources has been challenging, for many reasons. It is, therefore, particularly important that as umbilical cord cells are increasingly deployed therapeutically, we strive to better understand the derivation and functional characteristics of the cells from this important tissue source. Stem Cells Translational Medicine2017;6:1620–1630
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Affiliation(s)
- John E Davies
- Institute of Biomaterials and Biomedical Engineering, Toronto, Ontario, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - John T Walker
- Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Armand Keating
- Institute of Biomaterials and Biomedical Engineering, Toronto, Ontario, Canada.,Cell Therapy Program, Arthritis Program, Krembil Research Institute, and Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
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