|
1
|
Zhang Y, Lu Y, Hu X, Jiang M, Chen Z, Jin L, Li M, Chen C, Wang J. Functional characterization and therapeutic potential of human umbilical cord blood mononuclear cells. Regen Ther 2025; 28:101-114. [PMID: 40166041 PMCID: PMC11955793 DOI: 10.1016/j.reth.2024.11.019] [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: 10/16/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 04/02/2025] Open
Abstract
Human umbilical cord blood mononuclear cells (hUCB-MNCs) are a population of cells derived from neonatal cord blood, encompassing various stem cells and immune cells. The unique characteristics of hUCB-MNCs endow them with distinctive multifunctionality, including the promotion of angiogenesis, acceleration of tissue repair, regulation of immune responses, neuroprotection, alleviation of inflammatory reactions, enhancement of antioxidant capacity, reduction of fibrosis processes, and inhibition of apoptosis. These diverse biological properties underscore the significant clinical therapeutic potential of hUCB-MNCs, which are widely applied in the treatment of various diseases. This review aims to summarize the underlying mechanisms responsible for the multifunctional attributes of hUCB-MNCs, elucidating their potential modes of action in disease management and providing novel theoretical insights and practical guidance for their expanded application across different disease domains. By synthesizing current research findings, this review may provide insights into the potential clinical applications of hUCB-MNCs in the fields of regenerative medicine and cell therapy.
Collapse
Affiliation(s)
- Yu Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Yueda Lu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Xinyue Hu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Mengxing Jiang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Zhixiu Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Lingkun Jin
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Min Li
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| | - Chen Chen
- Department of Surgical Oncology, Anhui Provincial Children's Hospital, No.39 East Wangjiang Road, Hefei 230022, Anhui, China
| | - Jianye Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No 218 Jixi Road, Hefei 230022, Anhui, China
- The First Clinical College of Anhui Medical University, No 81 Meishan Road, Hefei 230032, Anhui, China
- Engineering Research Center of Biopreservation and Artificial Organs, Ministry of Education, No 81 Meishan Road, Hefei 230032, Anhui, China
| |
Collapse
|
|
2
|
Park G, Hwang DY, Kim DY, Han JY, Lee E, Hwang H, Park JS, Kim DW, Hong S, Yim SV, Hong HS, Son Y. Identification of CD141 +vasculogenic precursor cells from human bone marrow and their endothelial engagement in the arteriogenesis by co-transplantation with mesenchymal stem cells. Stem Cell Res Ther 2024; 15:388. [PMID: 39482744 PMCID: PMC11526567 DOI: 10.1186/s13287-024-03994-9] [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: 07/09/2024] [Accepted: 10/10/2024] [Indexed: 11/03/2024] Open
Abstract
BACKGROUND Critical limb ischemia (CLI) is a condition characterized by insufficient blood flow to the lower limbs, resulting in severe ischemia and potentially leading to amputation. This study aims to identify novel vasculogenic precursor cells (VPCs) in human bone marrow and evaluate their efficacy in combination with bone marrow-derived mesenchymal stem cells (BM-MSCs) for the treatment of CLI. METHODS Ex vivo cultured VPCs and BM-MSCs from bone marrow were characterized and their effects on neovascularization and long-term tissue regeneration were tested in a mouse CLI model. RESULTS VPCs, expressing high levels of hepatocyte growth factor and c-MET, were identified from human bone marrow aspirates. These cells exhibited strong vasculogenic capacity in vitro but possessed a cellular phenotype distinct from those of previously reported endothelial precursor cells in circulation or cord blood. They also expressed most surface markers of BM-MSCs and demonstrated multipotent differentiation ability. Screening of 376 surface markers revealed that VPCs uniquely display CD141 (thrombomodulin). CD141+VPCs are present in BM aspirates as a rare population and can be expanded ex vivo with a population doubling time of approximately 20 h, generating an elaborate vascular network even under angiogenic factor-deficient conditions and recruiting BM-MSCs to the network as pericyte-like cells. Intramuscular transplantation of a combination of human CD141+VPCs and BM-MSCs at a ratio of 2:1 resulted in limb salvage, blood flow recovery, and regeneration of large vessels in the femoral artery-removed CLI model, with an efficacy superior to that of singular transplantation. Importantly, large arteries and arterioles in dual cell transplantation expressed human CD31 in the intima and human α-smooth muscle actin in media layer at 4 and 12 weeks, likely indicating their lineage commitment to endothelial cells and vascular smooth muscle, respectively, in vivo. CONCLUSION Dual-cell therapy using BM-derived CD141+ VPCs and BM-MSCs holds potential for further development in clinical trials to treat peripheral artery disease and diabetic ulcers.
Collapse
Affiliation(s)
- Gabee Park
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Dae Yeon Hwang
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Do Young Kim
- Department of Biomedical Science and Technology, Graduated School, Kyung Hee University, Seoul, Korea
| | - Ji Young Han
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Euiseon Lee
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Hwakyung Hwang
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Jeong Seop Park
- Department of Biomedical Science and Technology, Graduated School, Kyung Hee University, Seoul, Korea
| | - Dae Wook Kim
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yong In, Korea
| | - Seonmin Hong
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
| | - Sung Vin Yim
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Hyun Sook Hong
- Department of Biomedical Science and Technology, Graduated School, Kyung Hee University, Seoul, Korea.
- East-West Medical Research Institute, Kyung Hee University, Seoul, Korea.
| | - Youngsook Son
- R&D Center, Elphis Cell Therapeutics Inc, Yong In, 17095, Korea.
- Department of Genetic Engineering, Graduate School of Biotechnology, Kyung Hee University, Yong In, Korea.
| |
Collapse
|
|
3
|
Hassanpour M, Salybkov AA, Kobayashi S, Asahara T. Anti-inflammatory Prowess of endothelial progenitor cells in the realm of biology and medicine. NPJ Regen Med 2024; 9:27. [PMID: 39349482 PMCID: PMC11442670 DOI: 10.1038/s41536-024-00365-z] [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: 12/15/2023] [Accepted: 08/23/2024] [Indexed: 10/02/2024] Open
Abstract
Endothelial inflammation plays a crucial role in vascular-related diseases, a leading cause of global mortality. Among various cellular players, endothelial progenitor cells (EPCs) emerge as non-differentiated endothelial cells circulating in the bloodstream. Recent evidence highlights the transformative role of EPCs in shifting from an inflammatory/immunosuppressive crisis to an anti-inflammatory/immunomodulatory response. Despite the importance of these functions, the regulatory mechanisms governing EPC activities and their physiological significance in vascular regenerative medicine remain elusive. Surprisingly, the current literature lacks a comprehensive review of EPCs' effects on inflammatory processes. This narrative review aims to fill this gap by exploring the cutting-edge role of EPCs against inflammation, from molecular intricacies to broader medical perspectives. By examining how EPCs modulate inflammatory responses, we aim to unravel their anti-inflammatory significance in vascular regenerative medicine, deepening insights into EPCs' molecular mechanisms and guiding future therapeutic strategies targeting vascular-related diseases.
Collapse
Affiliation(s)
- Mehdi Hassanpour
- Shonan Research, Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Center for Cell therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Amankeldi A Salybkov
- Shonan Research, Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Center for Cell therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Shuzo Kobayashi
- Shonan Research, Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Takayuki Asahara
- Shonan Research, Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan.
- Center for Cell therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan.
| |
Collapse
|
|
4
|
Tan B, Lin L, Yuan Y, Long Y, Kang Y, Huang B, Huang LF, Li JH, Tong C, Qi HB. Endothelial progenitor cells control remodeling of uterine spiral arteries for the establishment of utero-placental circulation. Dev Cell 2024; 59:1842-1859.e12. [PMID: 38663400 DOI: 10.1016/j.devcel.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/08/2024] [Accepted: 04/04/2024] [Indexed: 07/25/2024]
Abstract
Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.
Collapse
Affiliation(s)
- Bin Tan
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
| | - Li Lin
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Yu Yuan
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Department of Prenatal Diagnosis Center, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China
| | - Yao Long
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Yi Kang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Biao Huang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Li-Fei Huang
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Jian-Hua Li
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China
| | - Chao Tong
- Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
| | - Hong-Bo Qi
- Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing 401147, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing 400016, China; Joint International Research Laboratory of Reproduction and Development of Chinese Ministry of Education, Chongqing Medical University, Chongqing 400016, China.
| |
Collapse
|
|
5
|
Tkacz M, Zgutka K, Tomasiak P, Tarnowski M. Responses of Endothelial Progenitor Cells to Chronic and Acute Physical Activity in Healthy Individuals. Int J Mol Sci 2024; 25:6085. [PMID: 38892272 PMCID: PMC11173310 DOI: 10.3390/ijms25116085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Endothelial progenitor cells (EPCs) are circulating cells of various origins that possess the capacity for renewing and regenerating the endothelial lining of blood vessels. During physical activity, in response to factors such as hypoxia, changes in osmotic pressure, and mechanical forces, endothelial cells undergo intense physiological stress that results in endothelial damage. Circulating EPCs participate in blood vessel repair and vascular healing mainly through paracrine signalling. Furthermore, physical activity may play an important role in mobilising this important cell population. In this narrative review, we summarise the current knowledge on the biology of EPCs, including their characteristics, assessment, and mobilisation in response to both chronic and acute physical activity in healthy individuals.
Collapse
Affiliation(s)
- Marta Tkacz
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
| | - Katarzyna Zgutka
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
| | - Patrycja Tomasiak
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
| | - Maciej Tarnowski
- Department of Physiology in Health Sciences, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, Zolnierska 48, 70-210 Szczecin, Poland
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland
| |
Collapse
|
|
6
|
Ya J, Pellumbaj J, Hashmat A, Bayraktutan U. The Role of Stem Cells as Therapeutics for Ischaemic Stroke. Cells 2024; 13:112. [PMID: 38247804 PMCID: PMC10814781 DOI: 10.3390/cells13020112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/01/2024] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Stroke remains one of the leading causes of death and disability worldwide. Current reperfusion treatments for ischaemic stroke are limited due to their narrow therapeutic window in rescuing ischaemic penumbra. Stem cell therapy offers a promising alternative. As a regenerative medicine, stem cells offer a wider range of treatment strategies, including long-term intervention for chronic patients, through the reparation and replacement of injured cells via mechanisms of differentiation and proliferation. The purpose of this review is to evaluate the therapeutic role of stem cells for ischaemic stroke. This paper discusses the pathology during acute, subacute, and chronic phases of cerebral ischaemic injury, highlights the mechanisms involved in mesenchymal, endothelial, haematopoietic, and neural stem cell-mediated cerebrovascular regeneration, and evaluates the pre-clinical and clinical data concerning the safety and efficacy of stem cell-based treatments. The treatment of stroke patients with different types of stem cells appears to be safe and efficacious even at relatively higher concentrations irrespective of the route and timing of administration. The priming or pre-conditioning of cells prior to administration appears to help augment their therapeutic impact. However, larger patient cohorts and later-phase trials are required to consolidate these findings.
Collapse
Affiliation(s)
| | | | | | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neurosciences, Queens Medical Centre, School of Medicine, University of Nottingham, Nottingham NG7 2UH, UK
| |
Collapse
|
|
7
|
Schwarz N, Yadegari H. Potentials of Endothelial Colony-Forming Cells: Applications in Hemostasis and Thrombosis Disorders, from Unveiling Disease Pathophysiology to Cell Therapy. Hamostaseologie 2023; 43:325-337. [PMID: 37857295 DOI: 10.1055/a-2101-5936] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023] Open
Abstract
Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells circulating in a limited number in peripheral blood. They can give rise to mature endothelial cells (ECs) and, with intrinsically high proliferative potency, contribute to forming new blood vessels and restoring the damaged endothelium in vivo. ECFCs can be isolated from peripheral blood or umbilical cord and cultured to generate large amounts of autologous ECs in vitro. Upon differentiation in culture, ECFCs are excellent surrogates for mature ECs showing the same phenotypic, genotypic, and functional features. In the last two decades, the ECFCs from various vascular disease patients have been widely used to study the diseases' pathophysiology ex vivo and develop cell-based therapeutic approaches, including vascular regenerative therapy, tissue engineering, and gene therapy. In the current review, we will provide an updated overview of past studies, which have used ECFCs to elucidate the molecular mechanisms underlying the pathogenesis of hemostatic disorders in basic research. Additionally, we summarize preceding studies demonstrating the utility of ECFCs as cellular tools for diagnostic or therapeutic clinical applications in thrombosis and hemostasis.
Collapse
Affiliation(s)
- Nadine Schwarz
- Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany
| | - Hamideh Yadegari
- Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Bonn, Germany
| |
Collapse
|
|
8
|
An integrated single cell and spatial transcriptomic map of human white adipose tissue. Nat Commun 2023; 14:1438. [PMID: 36922516 PMCID: PMC10017705 DOI: 10.1038/s41467-023-36983-2] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 02/27/2023] [Indexed: 03/18/2023] Open
Abstract
To date, single-cell studies of human white adipose tissue (WAT) have been based on small cohort sizes and no cellular consensus nomenclature exists. Herein, we performed a comprehensive meta-analysis of publicly available and newly generated single-cell, single-nucleus, and spatial transcriptomic results from human subcutaneous, omental, and perivascular WAT. Our high-resolution map is built on data from ten studies and allowed us to robustly identify >60 subpopulations of adipocytes, fibroblast and adipogenic progenitors, vascular, and immune cells. Using these results, we deconvolved spatial and bulk transcriptomic data from nine additional cohorts to provide spatial and clinical dimensions to the map. This identified cell-cell interactions as well as relationships between specific cell subtypes and insulin resistance, dyslipidemia, adipocyte volume, and lipolysis upon long-term weight changes. Altogether, our meta-map provides a rich resource defining the cellular and microarchitectural landscape of human WAT and describes the associations between specific cell types and metabolic states.
Collapse
|
|
9
|
Bell A, Watt AP, Dudink I, Pham Y, Sutherland AE, Allison BJ, McDonald CA, Castillo-Melendez M, Jenkin G, Malhotra A, Miller SL, Yawno T. Endothelial colony forming cell administration promotes neurovascular unit development in growth restricted and appropriately grown fetal lambs. Stem Cell Res Ther 2023; 14:29. [PMID: 36788590 PMCID: PMC9930266 DOI: 10.1186/s13287-023-03249-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Fetal growth restriction (FGR) is associated with deficits in the developing brain, including neurovascular unit (NVU) dysfunction. Endothelial colony forming cells (ECFC) can mediate improved vascular stability, and have demonstrated potential to enhance vascular development and protection. This investigation examined whether ECFCs from human umbilical cord blood (UCB) enhanced NVU development in FGR and appropriate for gestational age (AGA) fetal sheep. METHODS Twin-bearing ewes had surgery performed at 88-90 days' gestation, inducing FGR in one fetus. At 113 days, ECFCs (1 × 107 cells) cultured from human UCB were administered intravenously to fetal sheep in utero. At 127 days, ewes and their fetuses were euthanised, fetal brains collected, and NVU components analysed by immunohistochemistry. RESULTS Twenty-four fetal lambs, arranged in four groups: AGA (n = 7), FGR (n = 5), AGA + ECFC (n = 6), and FGR + ECFC (n = 6), were included in analyses. FGR resulted in lower body weight than AGA (P = 0.002) with higher brain/body weight ratio (P = 0.003). ECFC treatment was associated with increased vascular density throughout the brain in both AGA + ECFC and FGR + ECFC groups, as well as increased vascular-astrocyte coverage and VEGF expression in the cortex (P = 0.003, P = 0.0006, respectively) and in the subcortical white matter (P = 0.01, P = 0.0002, respectively) when compared with the untreated groups. CONCLUSIONS ECFC administration enhanced development of NVU components in both the AGA and FGR fetal brain. Further investigation is required to assess how to optimise the enhanced angiogenic capabilities of ECFCs to provide a therapeutic strategy to protect the developing NVU against vulnerabilities associated with FGR.
Collapse
Affiliation(s)
- Alexander Bell
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Ashalyn P. Watt
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Ingrid Dudink
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Yen Pham
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Amy E. Sutherland
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia
| | - Beth J. Allison
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Courtney A. McDonald
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | | | - Graham Jenkin
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Atul Malhotra
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia. .,Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC, 3168, Australia. .,Monash Newborn, Monash Children's Hospital, Melbourne, Australia.
| | - Suzanne L. Miller
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
| | - Tamara Yawno
- grid.452824.dThe Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia ,grid.1002.30000 0004 1936 7857Department of Paediatrics, Monash University, 246 Clayton Road, Clayton, Melbourne, VIC 3168 Australia
| |
Collapse
|
|
10
|
Yoshida Y, Takeda Y, Yamahara K, Yamamoto H, Takagi T, Kuramoto Y, Nakano-Doi A, Nakagomi T, Soma T, Matsuyama T, Doe N, Yoshimura S. Enhanced angiogenic properties of umbilical cord blood primed by OP9 stromal cells ameliorates neurological deficits in cerebral infarction mouse model. Sci Rep 2023; 13:262. [PMID: 36609640 PMCID: PMC9822952 DOI: 10.1038/s41598-023-27424-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/29/2022] [Indexed: 01/09/2023] Open
Abstract
Umbilical cord blood (UCB) transplantation shows proangiogenic effects and contributes to symptom amelioration in animal models of cerebral infarction. However, the effect of specific cell types within a heterogeneous UCB population are still controversial. OP9 is a stromal cell line used as feeder cells to promote the hematoendothelial differentiation of embryonic stem cells. Hence, we investigated the changes in angiogenic properties, underlying mechanisms, and impact on behavioral deficiencies caused by cerebral infarction in UCB co-cultured with OP9 for up to 24 h. In the network formation assay, only OP9 pre-conditioned UCB formed network structures. Single-cell RNA sequencing and flow cytometry analysis showed a prominent phenotypic shift toward M2 in the monocytic fraction of OP9 pre-conditioned UCB. Further, OP9 pre-conditioned UCB transplantation in mice models of cerebral infarction facilitated angiogenesis in the peri-infarct lesions and ameliorated the associated symptoms. In this study, we developed a strong, fast, and feasible method to augment the M2, tissue-protecting, pro-angiogenic features of UCB using OP9. The ameliorative effect of OP9-pre-conditioned UCB in vivo could be partly due to promotion of innate angiogenesis in peri-infarct lesions.
Collapse
Affiliation(s)
- Yasunori Yoshida
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yuki Takeda
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Kenichi Yamahara
- Laboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Hanae Yamamoto
- grid.272264.70000 0000 9142 153XLaboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshinori Takagi
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yoji Kuramoto
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Akiko Nakano-Doi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Takayuki Nakagomi
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshihiro Soma
- grid.272264.70000 0000 9142 153XDepartment of Hematology, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Tomohiro Matsuyama
- grid.272264.70000 0000 9142 153XDepartment of Therapeutic Progress in Brain Diseases, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Nobutaka Doe
- Laboratory of Neurogenesis and CNS Repair, Institute for Advanced Medical Sciences, Hyogo Medial University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan ,grid.272264.70000 0000 9142 153XDepartment of Occupational Therapy, School of Rehabilitation, Hyogo Medical University, 1-3-6 Minatojima, Chuo-Ku, Kobe, Hyogo 650-8530 Japan
| | - Shinichi Yoshimura
- grid.272264.70000 0000 9142 153XDepartment of Neurosurgery, Hyogo Medical University, 1-1 Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| |
Collapse
|
|
11
|
Transplantation of Endothelial Progenitor Cells: Summary and prospect. Acta Histochem 2023; 125:151990. [PMID: 36587456 DOI: 10.1016/j.acthis.2022.151990] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 12/17/2022] [Accepted: 12/18/2022] [Indexed: 12/31/2022]
Abstract
Endothelial Progenitor Cells (EPCs) are precursor cells of endothelial cells (ECs), which can differentiate into vascular ECs, protect from endothelial dysfunction and tissue ischemia, and reduce vascular hyperplasia. Due to these functions, EPCs are used as a candidate cell source for transplantation strategies. In recent years, a great progress was achieved in EPCs biology research, and EPCs transplantation has become a research hotspot. At present, transplanted EPCs have been used to treat ischemic diseases due to their powerful vasculogenesis and beneficial paracrine effects. Although EPCs transplantation has been proved to play an important role, the clinical application of EPCs still faces many challenges. This review briefly summarized the basic characteristics of EPCs, the process of EPCs transplantation promoting the healing of ischemic tissue, and the ways to improve the efficiency of EPCs transplantation. In addition, the application of EPCs in neurological improvement, cardiovascular and respiratory diseases and the challenges and problems in clinical application of EPCs were also discussed. In the end, the application of EPCs transplantation in regenerative medicine and tissue engineering was discussed.
Collapse
|
|
12
|
Abstract
Endothelial colony-forming cells (ECFCs) are progenitor cells that can give rise to colonies of highly proliferative vascular endothelial cells (ECs) with clonal expansion and in vivo blood vessel-forming potential. More than two decades ago, the identification of ECFCs in human peripheral blood created tremendous opportunities as having a clinically accessible source of autologous ECs could facilitate meaningful therapies with the potential to impact multiple vascular diseases. Nevertheless, until recently, the field of endothelial progenitor cells has been plagued with ambiguities and controversies, and reaching a consensus on the definition of ECFCs has not been straightforward. Moreover, although the basic phenotypical and functional characteristics of cultured ECFCs are now well established, some fundamental questions such as the origin of ECFCs and their physiological roles in health and disease remain incompletely understood. Here, I highlight some critical studies that have shaped our current understanding of ECFCs in humans. Insights into the biological attributes of ECFCs are essential for facilitating the clinical translation of their therapeutic potential.
Collapse
Affiliation(s)
- Juan M Melero-Martin
- Department of Cardiac Surgery, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
| |
Collapse
|
|
13
|
Zhang Q, Duncan S, Szulc DA, Kutryk MJB. Antibody functionalized intravascular devices combined with genetically engineered endothelial colony-forming cells for targeted drug delivery: a proof-of-concept study. Eur J Pharm Biopharm 2022; 181:218-226. [DOI: 10.1016/j.ejpb.2022.11.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 11/06/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022]
|
|
14
|
Potential contribution of early endothelial progenitor cell (eEPC)-to-macrophage switching in the development of pulmonary plexogenic lesion. Respir Res 2022; 23:290. [PMID: 36274148 PMCID: PMC9590182 DOI: 10.1186/s12931-022-02210-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 10/04/2022] [Indexed: 11/12/2022] Open
Abstract
Background Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. Methods The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Results Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. Conclusions This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-022-02210-7.
Collapse
|
|
15
|
Rudnicka-Drożak E, Drożak P, Mizerski G, Drożak M. Endothelial Progenitor Cells in Neurovascular Disorders—A Comprehensive Overview of the Current State of Knowledge. Biomedicines 2022; 10:biomedicines10102616. [PMID: 36289878 PMCID: PMC9599182 DOI: 10.3390/biomedicines10102616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 10/11/2022] [Accepted: 10/15/2022] [Indexed: 11/16/2022] Open
Abstract
Endothelial progenitor cells (EPCs) are a population of cells that circulate in the blood looking for areas of endothelial or vascular injury in order to repair them. Endothelial dysfunction is an important component of disorders with neurovascular involvement. Thus, the subject of involvement of EPCs in such conditions has been gaining increasing scientific interest in recent years. Overall, decreased levels of EPCs are associated with worse disease outcome. Moreover, their functionalities appear to decline with severity of disease. These findings inspired the application of EPCs as therapeutic targets and agents. So far, EPCs appear safe and promising based on the results of pre-clinical studies conducted on their use in the treatment of Alzheimer’s disease and ischemic stroke. In the case of the latter, human clinical trials have recently started to be performed in this subject and provided optimistic results thus far. Whereas in the case of migraine, existing findings pave the way for testing EPCs in in vitro studies. This review aims to thoroughly summarize current knowledge on the role EPCs in four disorders with neurovascular involvement, which are Alzheimer’s disease, cerebral small vessel disease, ischemic stroke and migraine, with a particular focus on the potential practical use of these cells as a treatment remedy.
Collapse
Affiliation(s)
- Ewa Rudnicka-Drożak
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Paulina Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
- Correspondence: ; Tel.: +48-669-084-455
| | - Grzegorz Mizerski
- Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| | - Martyna Drożak
- Student Scientific Society, Department of Family Medicine, Medical University of Lublin, Langiewicza 6a, 20-035 Lublin, Poland
| |
Collapse
|
|
16
|
Marei I, Ahmetaj-Shala B, Triggle CR. Biofunctionalization of cardiovascular stents to induce endothelialization: Implications for in- stent thrombosis in diabetes. Front Pharmacol 2022; 13:982185. [PMID: 36299902 PMCID: PMC9589287 DOI: 10.3389/fphar.2022.982185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/31/2022] [Indexed: 11/13/2022] Open
Abstract
Stent thrombosis remains one of the main causes that lead to vascular stent failure in patients undergoing percutaneous coronary intervention (PCI). Type 2 diabetes mellitus is accompanied by endothelial dysfunction and platelet hyperactivity and is associated with suboptimal outcomes following PCI, and an increase in the incidence of late stent thrombosis. Evidence suggests that late stent thrombosis is caused by the delayed and impaired endothelialization of the lumen of the stent. The endothelium has a key role in modulating inflammation and thrombosis and maintaining homeostasis, thus restoring a functional endothelial cell layer is an important target for the prevention of stent thrombosis. Modifications using specific molecules to induce endothelial cell adhesion, proliferation and function can improve stents endothelialization and prevent thrombosis. Blood endothelial progenitor cells (EPCs) represent a potential cell source for the in situ-endothelialization of vascular conduits and stents. We aim in this review to summarize the main biofunctionalization strategies to induce the in-situ endothelialization of coronary artery stents using circulating endothelial stem cells.
Collapse
Affiliation(s)
- Isra Marei
- Department of Pharmacology, Weill Cornell Medicine- Qatar, Doha, Qatar
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- *Correspondence: Isra Marei, ; Chris R. Triggle,
| | | | - Chris R. Triggle
- Department of Pharmacology, Weill Cornell Medicine- Qatar, Doha, Qatar
- *Correspondence: Isra Marei, ; Chris R. Triggle,
| |
Collapse
|
|
17
|
Steens J, Klein D. HOX genes in stem cells: Maintaining cellular identity and regulation of differentiation. Front Cell Dev Biol 2022; 10:1002909. [PMID: 36176275 PMCID: PMC9514042 DOI: 10.3389/fcell.2022.1002909] [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: 07/25/2022] [Accepted: 08/25/2022] [Indexed: 11/13/2022] Open
Abstract
Stem cells display a unique cell type within the body that has the capacity to self-renew and differentiate into specialized cell types. Compared to pluripotent stem cells, adult stem cells (ASC) such as mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) exhibit restricted differentiation capabilities that are limited to cell types typically found in the tissue of origin, which implicates that there must be a certain code or priming determined by the tissue of origin. HOX genes, a subset of homeobox genes encoding transcription factors that are generally repressed in undifferentiated pluripotent stem cells, emerged here as master regulators of cell identity and cell fate during embryogenesis, and in maintaining this positional identity throughout life as well as specifying various regional properties of respective tissues. Concurrently, intricate molecular circuits regulated by diverse stem cell-typical signaling pathways, balance stem cell maintenance, proliferation and differentiation. However, it still needs to be unraveled how stem cell-related signaling pathways establish and regulate ASC-specific HOX expression pattern with different temporal-spatial topography, known as the HOX code. This comprehensive review therefore summarizes the current knowledge of specific ASC-related HOX expression patterns and how these were integrated into stem cell-related signaling pathways. Understanding the mechanism of HOX gene regulation in stem cells may provide new ways to manipulate stem cell fate and function leading to improved and new approaches in the field of regenerative medicine.
Collapse
|
|
18
|
Kourek C, Briasoulis A, Zouganeli V, Karatzanos E, Nanas S, Dimopoulos S. Exercise Training Effects on Circulating Endothelial and Progenitor Cells in Heart Failure. J Cardiovasc Dev Dis 2022; 9:222. [PMID: 35877584 PMCID: PMC9322098 DOI: 10.3390/jcdd9070222] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a major public health issue worldwide with increased prevalence and a high number of hospitalizations. Patients with chronic HF and either reduced ejection fraction (HFrEF) or mildly reduced ejection fraction (HFmrEF) present vascular endothelial dysfunction and significantly decreased circulating levels of endothelial progenitor cells (EPCs). EPCs are bone marrow-derived cells involved in endothelium regeneration, homeostasis, and neovascularization. One of the unsolved issues in the field of EPCs is the lack of an established method of identification. The most widely approved method is the use of monoclonal antibodies and fluorescence-activated cell sorting (FACS) analysis via flow cytometry. The most frequently used markers are CD34, VEGFR-2, CD45, CD31, CD144, and CD146. Exercise training has demonstrated beneficial effects on EPCs by increasing their number in peripheral circulation and improving their functional capacities in patients with HFrEF or HFmrEF. There are two potential mechanisms of EPCs mobilization: shear stress and the hypoxic/ischemic stimulus. The combination of both leads to the release of EPCs in circulation promoting their repairment properties on the vascular endothelium barrier. EPCs are important therapeutic targets and one of the most promising fields in heart failure and, therefore, individualized exercise training programs should be developed in rehabilitation centers.
Collapse
Affiliation(s)
- Christos Kourek
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
- Department of Cardiology, 417 Army Share Fund Hospital of Athens (NIMTS), 11521 Athens, Greece
| | - Alexandros Briasoulis
- Department of Clinical Therapeutics, Alexandra Hospital, Faculty of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece;
- Division of Cardiovascular Medicine, Section of Heart Failure and Transplantation, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
| | - Virginia Zouganeli
- Second Cardiology Department, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Eleftherios Karatzanos
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
| | - Serafim Nanas
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
| | - Stavros Dimopoulos
- Clinical Ergospirometry, Exercise & Rehabilitation Laboratory, 1st Critical Care Medicine Department, Evangelismos Hospital, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (E.K.); (S.N.)
- Cardiac Surgery Intensive Care Unit, Onassis Cardiac Surgery Center, 17674 Athens, Greece
| |
Collapse
|
|
19
|
Exploring Endothelial Colony-Forming Cells to Better Understand the Pathophysiology of Disease: An Updated Review. Stem Cells Int 2022; 2022:4460041. [PMID: 35615696 PMCID: PMC9126670 DOI: 10.1155/2022/4460041] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/20/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022] Open
Abstract
Endothelial cell (EC) dysfunction has been implicated in a variety of pathological conditions. The collection of ECs from patients is typically conducted postmortem or through invasive procedures, such as surgery and interventional procedures, hampering efforts to clarify the role of ECs in disease onset and progression. In contrast, endothelial colony-forming cells (ECFCs), also termed late endothelial progenitor cells, late outgrowth endothelial cells, blood outgrowth endothelial cells, or endothelial outgrowth cells, are obtained in a minimally invasive manner, namely, by the culture of human peripheral blood mononuclear cells in endothelial growth medium. ECFCs resemble mature ECs phenotypically, genetically, and functionally, making them excellent surrogates for ECs. Numerous studies have been performed that examined ECFC function in conditions such as coronary artery disease, diabetes mellitus, hereditary hemorrhagic telangiectasia, congenital bicuspid aortic valve disease, pulmonary arterial hypertension, venous thromboembolic disease, and von Willebrand disease. Here, we provide an updated review of studies using ECFCs that were performed to better understand the pathophysiology of disease. We also discuss the potential of ECFCs as disease biomarkers and the standardized methods to culture, quantify, and evaluate ECFCs and suggest the future direction of research in this field.
Collapse
|
|
20
|
Phillippi JA. On vasa vasorum: A history of advances in understanding the vessels of vessels. SCIENCE ADVANCES 2022; 8:eabl6364. [PMID: 35442731 PMCID: PMC9020663 DOI: 10.1126/sciadv.abl6364] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 03/01/2022] [Indexed: 05/09/2023]
Abstract
The vasa vasorum are a vital microvascular network supporting the outer wall of larger blood vessels. Although these dynamic microvessels have been studied for centuries, the importance and impact of their functions in vascular health and disease are not yet fully realized. There is now rich knowledge regarding what local progenitor cell populations comprise and cohabitate with the vasa vasorum and how they might contribute to physiological and pathological changes in the network or its expansion via angiogenesis or vasculogenesis. Evidence of whether vasa vasorum remodeling incites or governs disease progression or is a consequence of cardiovascular pathologies remains limited. Recent advances in vasa vasorum imaging for understanding cardiovascular disease severity and pathophysiology open the door for theranostic opportunities. Approaches that strive to control angiogenesis and vasculogenesis potentiate mitigation of vasa vasorum-mediated contributions to cardiovascular diseases and emerging diseases involving the microcirculation.
Collapse
Affiliation(s)
- Julie A. Phillippi
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| |
Collapse
|
|
21
|
Duranova H, Valkova V, Olexikova L, Radochova B, Balazi A, Chrenek P, Vasicek J. Rabbit Endothelial Progenitor Cells Derived From Peripheral Blood and Bone Marrow: An Ultrastructural Comparative Study. MICROSCOPY AND MICROANALYSIS : THE OFFICIAL JOURNAL OF MICROSCOPY SOCIETY OF AMERICA, MICROBEAM ANALYSIS SOCIETY, MICROSCOPICAL SOCIETY OF CANADA 2022; 28:1-11. [PMID: 35297367 DOI: 10.1017/s143192762200037x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The present study was designed to compare the ultrastructure of early endothelial progenitor cells (EPCs) derived from rabbit peripheral blood (PB-EPCs) and bone marrow (BM-EPCs). After the cells had been isolated and cultivated up to passage 3, microphotographs obtained from transmission electron microscope were evaluated from qualitative and quantitative (unbiased stereological approaches) points of view. Our results revealed that both cell populations displayed almost identical ultrastructural characteristics represented by abundant cellular organelles dispersed in the cytoplasm. Moreover, the presence of very occasionally occurring mature endothelial-specific Weibel–Palade bodies (WPBs) confirmed their endothelial lineage origin. The more advanced stage of their differentiation was also demonstrated by the relatively low nucleus/cytoplasm (N/C) ratios (0.41 ± 0.19 in PB-EPCs; 0.37 ± 0.25 in BM-EPCs). Between PB-EPCs and BM-EPCs, no differences in proportions of cells occupied by nucleus (28.13 ± 8.97 versus 25.10 ± 11.48%), mitochondria (3.71 ± 1.33 versus 4.23 ± 1.00%), and lipid droplets (0.65 ± 1.01 versus 0.36 ± 0.40%), as well as in estimations of the organelles surface densities were found. The data provide the first quantitative evaluation of the organelles of interest in PB-EPCs and BM-EPCs, and they can serve as a research framework for understanding cellular function.
Collapse
Affiliation(s)
- Hana Duranova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, Nitra94976, Slovak Republic
| | - Veronika Valkova
- AgroBioTech Research Centre, Slovak University of Agriculture, Tr. A. Hlinku 2, Nitra94976, Slovak Republic
| | - Lucia Olexikova
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, Lužianky951 41, Slovak Republic
| | - Barbora Radochova
- Laboratory of Biomathematics, Institute of Physiology, The Czech Academy of Sciences, Vídeňská 1083, Prague 4CZ-14220, Czech Republic
| | - Andrej Balazi
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, Lužianky951 41, Slovak Republic
| | - Peter Chrenek
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, Lužianky951 41, Slovak Republic
- Faculty of Biotechnology and Food Science, Institute of Biotechnology, Slovak University of Agriculture, Tr. A. Hlinku 2, Nitra94976, Slovak Republic
| | - Jaromir Vasicek
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, Lužianky951 41, Slovak Republic
- Faculty of Biotechnology and Food Science, Institute of Biotechnology, Slovak University of Agriculture, Tr. A. Hlinku 2, Nitra94976, Slovak Republic
| |
Collapse
|
|
22
|
Marei I, Abu Samaan T, Al-Quradaghi MA, Farah AA, Mahmud SH, Ding H, Triggle CR. 3D Tissue-Engineered Vascular Drug Screening Platforms: Promise and Considerations. Front Cardiovasc Med 2022; 9:847554. [PMID: 35310996 PMCID: PMC8931492 DOI: 10.3389/fcvm.2022.847554] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Despite the efforts devoted to drug discovery and development, the number of new drug approvals have been decreasing. Specifically, cardiovascular developments have been showing amongst the lowest levels of approvals. In addition, concerns over the adverse effects of drugs to the cardiovascular system have been increasing and resulting in failure at the preclinical level as well as withdrawal of drugs post-marketing. Besides factors such as the increased cost of clinical trials and increases in the requirements and the complexity of the regulatory processes, there is also a gap between the currently existing pre-clinical screening methods and the clinical studies in humans. This gap is mainly caused by the lack of complexity in the currently used 2D cell culture-based screening systems, which do not accurately reflect human physiological conditions. Cell-based drug screening is widely accepted and extensively used and can provide an initial indication of the drugs' therapeutic efficacy and potential cytotoxicity. However, in vitro cell-based evaluation could in many instances provide contradictory findings to the in vivo testing in animal models and clinical trials. This drawback is related to the failure of these 2D cell culture systems to recapitulate the human physiological microenvironment in which the cells reside. In the body, cells reside within a complex physiological setting, where they interact with and respond to neighboring cells, extracellular matrix, mechanical stress, blood shear stress, and many other factors. These factors in sum affect the cellular response and the specific pathways that regulate variable vital functions such as proliferation, apoptosis, and differentiation. Although pre-clinical in vivo animal models provide this level of complexity, cross species differences can also cause contradictory results from that seen when the drug enters clinical trials. Thus, there is a need to better mimic human physiological conditions in pre-clinical studies to improve the efficiency of drug screening. A novel approach is to develop 3D tissue engineered miniaturized constructs in vitro that are based on human cells. In this review, we discuss the factors that should be considered to produce a successful vascular construct that is derived from human cells and is both reliable and reproducible.
Collapse
Affiliation(s)
- Isra Marei
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
- *Correspondence: Isra Marei
| | - Tala Abu Samaan
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Asmaa A. Farah
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Hong Ding
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Chris R. Triggle
- Department of Pharmacology, Weill Cornell Medicine-Qatar, Doha, Qatar
- Chris R. Triggle
| |
Collapse
|
|
23
|
Alwjwaj M, Kadir RRA, Bayraktutan U. Outgrowth endothelial progenitor cells restore cerebral barrier function following ischaemic damage: the impact of NOX2 inhibition. Eur J Neurosci 2022; 55:1658-1670. [PMID: 35179812 DOI: 10.1111/ejn.15627] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/08/2022] [Accepted: 02/15/2022] [Indexed: 11/29/2022]
Abstract
Disruption of blood-brain barrier (BBB), formed mainly by human brain microvascular endothelial cells (HBMECs), constitutes the major cause of mortality following ischaemic stroke. This study investigates whether OECs (outgrowth endothelial cells) can restore BBB integrity and function following ischaemic damage, and how inhibition of NOX2, a main source of vascular oxidative stress, affects the characteristics of BBB established with OECs and HBMECs in ischaemic settings. In vitro models of human BBB were constructed by co-culture of pericytes and astrocytes with either OECs or HBMECs before exposure to oxygen-glucose deprivation (OGD) alone or followed by reperfusion (OGD+R) in the absence or presence of NOX2 inhibitor, gp91ds-tat. The function and integrity of BBB were assessed by measurements of paracellular flux of sodium fluorescein (NaF) and transendothelial electrical resistance (TEER), respectively. Treatment with OECs during OGD+R effectively restored BBB integrity and function. Compared to HBMECs, OECs possessed lower NADPH oxidase activity, superoxide anion levels, and had greater total antioxidant capacity during OGD and OGD+R. Inhibition of NADPH oxidase during OGD and OGD+R restored the integrity and function of BBB established by HBMECs. This was evidenced by reductions in NADPH oxidase activity and superoxide anion levels. In contrast, treatment with gp91ds-tat aggravated ischaemic injury-induced BBB damage constructed by OECs. In conclusion, OECs are more resistant to ischaemic conditions and can effectively repair cerebral barrier following ischaemic damage. Suppression of oxidative stress through specific targeting of NOX2 requires close attention while using OECs as therapeutics.
Collapse
Affiliation(s)
- Mansour Alwjwaj
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
| | - Rais Reskiawan A Kadir
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
| | - Ulvi Bayraktutan
- Academic Unit of Mental Health and Clinical Neuroscience, School of Medicine, Nottingham, UK
| |
Collapse
|
|
24
|
Wu KX, Yeo NJY, Ng CY, Chioh FWJ, Fan Q, Tian X, Yang B, Narayanan G, Tay HM, Hou HW, Dunn NR, Su X, Cheung CMG, Cheung C. Hyaluronidase-1-mediated glycocalyx impairment underlies endothelial abnormalities in polypoidal choroidal vasculopathy. BMC Biol 2022; 20:47. [PMID: 35164755 PMCID: PMC8845246 DOI: 10.1186/s12915-022-01244-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 02/01/2022] [Indexed: 11/11/2022] Open
Abstract
Background Polypoidal choroidal vasculopathy (PCV), a subtype of age-related macular degeneration (AMD), is a global leading cause of vision loss in older populations. Distinct from typical AMD, PCV is characterized by polyp-like dilatation of blood vessels and turbulent blood flow in the choroid of the eye. Gold standard anti-vascular endothelial growth factor (anti-VEGF) therapy often fails to regress polypoidal lesions in patients. Current animal models have also been hampered by their inability to recapitulate such vascular lesions. These underscore the need to identify VEGF-independent pathways in PCV pathogenesis. Results We cultivated blood outgrowth endothelial cells (BOECs) from PCV patients and normal controls to serve as our experimental disease models. When BOECs were exposed to heterogeneous flow, single-cell transcriptomic analysis revealed that PCV BOECs preferentially adopted migratory-angiogenic cell state, while normal BOECs undertook proinflammatory cell state. PCV BOECs also had a repressed protective response to flow stress by demonstrating lower mitochondrial functions. We uncovered that elevated hyaluronidase-1 in PCV BOECs led to increased degradation of hyaluronan, a major component of glycocalyx that interfaces between flow stress and vascular endothelium. Notably, knockdown of hyaluronidase-1 in PCV BOEC improved mechanosensitivity, as demonstrated by a significant 1.5-fold upregulation of Krüppel-like factor 2 (KLF2) expression, a flow-responsive transcription factor. Activation of KLF2 might in turn modulate PCV BOEC migration. Barrier permeability due to glycocalyx impairment in PCV BOECs was also reversed by hyaluronidase-1 knockdown. Correspondingly, hyaluronidase-1 was detected in PCV patient vitreous humor and plasma samples. Conclusions Hyaluronidase-1 inhibition could be a potential therapeutic modality in preserving glycocalyx integrity and endothelial stability in ocular diseases with vascular origin. Supplementary Information The online version contains supplementary material available at 10.1186/s12915-022-01244-z.
Collapse
Affiliation(s)
- Kan Xing Wu
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Natalie Jia Ying Yeo
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Chun Yi Ng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | | | - Qiao Fan
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.,Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), Duke-NUS Medical School, Singapore, Singapore
| | - Xianfeng Tian
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore, Singapore
| | - Binxia Yang
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Gunaseelan Narayanan
- Institute of Medical Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Hui Min Tay
- School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore
| | - Han Wei Hou
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,School of Mechanical and Aerospace Engineering, Nanyang Technological University, Singapore, Singapore
| | - N Ray Dunn
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.,School of Biological Sciences Nanyang Technological University, Singapore, Singapore.,Institute of Medical Biology, Agency for Science Technology and Research, Singapore, Singapore
| | - Xinyi Su
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.,Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Singapore Eye Research Institute, Singapore, Singapore.,Department of Ophthalmology, National University Hospital, Singapore, Singapore
| | - Chui Ming Gemmy Cheung
- Duke-NUS Medical School, National University of Singapore, Singapore, Singapore.,Singapore Eye Research Institute, Singapore, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore. .,Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore.
| |
Collapse
|
|
25
|
Shradhanjali A, Uthamaraj S, Dragomir-Daescu D, Gulati R, Sandhu GS, Tefft BJ. Characterization of Blood Outgrowth Endothelial Cells (BOEC) from Porcine Peripheral Blood. JOURNAL OF VISUALIZED EXPERIMENTS : JOVE 2022:10.3791/63285. [PMID: 35068481 PMCID: PMC9645770 DOI: 10.3791/63285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The endothelium is a dynamic integrated structure that plays an important role in many physiological functions such as angiogenesis, hemostasis, inflammation, and homeostasis. The endothelium also plays an important role in pathophysiologies such as atherosclerosis, hypertension, and diabetes. Endothelial cells form the inner lining of blood and lymphatic vessels and display heterogeneity in structure and function. Various groups have evaluated the functionality of endothelial cells derived from human peripheral blood with a focus on endothelial progenitor cells derived from hematopoietic stem cells or mature blood outgrowth endothelial cells (or endothelial colony-forming cells). These cells provide an autologous resource for therapeutics and disease modeling. Xenogeneic cells may provide an alternative source of therapeutics due to their availability and homogeneity achieved by using genetically similar animals raised in similar conditions. Hence, a robust protocol for the isolation and expansion of highly proliferative blood outgrowth endothelial cells from porcine peripheral blood has been presented. These cells can be used for numerous applications such as cardiovascular tissue engineering, cell therapy, disease modeling, drug screening, studying endothelial cell biology, and in vitro co-cultures to investigate inflammatory and coagulation responses in xenotransplantation.
Collapse
Affiliation(s)
- Akankshya Shradhanjali
- Department of Biomedical Engineering, Medical College of Wisconsin & Marquette University
| | | | | | - Rajiv Gulati
- Department of Cardiovascular Medicine, Mayo Clinic
| | | | - Brandon J. Tefft
- Department of Biomedical Engineering, Medical College of Wisconsin & Marquette University
| |
Collapse
|
|
26
|
Moraes de Lima Perini M, Valuch CR, Dadwal UC, Awosanya OD, Mostardo SL, Blosser RJ, Knox AM, McGuire AC, Battina HL, Nazzal M, Kacena MA, Li J. Characterization and assessment of lung and bone marrow derived endothelial cells and their bone regenerative potential. Front Endocrinol (Lausanne) 2022; 13:935391. [PMID: 36120459 PMCID: PMC9470942 DOI: 10.3389/fendo.2022.935391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
Angiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites.
Collapse
Affiliation(s)
| | - Conner R. Valuch
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States
| | - Ushashi C. Dadwal
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Olatundun D. Awosanya
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Sarah L. Mostardo
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Rachel J. Blosser
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Adam M. Knox
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Anthony C. McGuire
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Hanisha L. Battina
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Murad Nazzal
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Melissa A. Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Richard L. Roudebush Veterans Affairs (VA) Medical Center, Indianapolis, IN, United States
| | - Jiliang Li
- Department of Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN, United States
- *Correspondence: Jiliang Li,
| |
Collapse
|
|
27
|
Yan F, Liu X, Ding H, Zhang W. Paracrine mechanisms of endothelial progenitor cells in vascular repair. Acta Histochem 2022; 124:151833. [PMID: 34929523 DOI: 10.1016/j.acthis.2021.151833] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 12/01/2021] [Accepted: 12/09/2021] [Indexed: 12/20/2022]
Abstract
Endothelial progenitor cells (EPCs) play an important role in repairing damaged blood vessels and promoting neovascularization. However, the specific mechanism of EPCs promoting vascular repair is still unclear. Currently, there are two different views on the repair of damaged vessels by EPCs, one is that EPCs can directly differentiate into endothelial cells (ECs) and integrate into injured vessels, the other is that EPCs act on cells and blood vessels by releasing paracrine substances. But more evidence now supports the latter. Therefore, the paracrine mechanisms of EPCs are worth further study. This review describes the substances secreted by EPCs, some applications based on paracrine effects of EPCs, and the studies of paracrine mechanisms in cardiovascular diseases--all of these are to support the view that EPCs repair blood vessels through paracrine effects rather than integrating directly into damaged vessels.
Collapse
Affiliation(s)
- Fanchen Yan
- The Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Xiaodan Liu
- The Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Huang Ding
- The Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China
| | - Wei Zhang
- The Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Diseases, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
| |
Collapse
|
|
28
|
Sen A, Vincent V, Thakkar H, Abraham R, Ramakrishnan L. Beneficial Role of Vitamin D on Endothelial Progenitor Cells (EPCs) in Cardiovascular Diseases. J Lipid Atheroscler 2022; 11:229-249. [PMID: 36212746 PMCID: PMC9515729 DOI: 10.12997/jla.2022.11.3.229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 11/23/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death in the world. Endothelial progenitor cells (EPCs) are currently being explored in the context of CVD risk. EPCs are bone marrow derived progenitor cells involved in postnatal endothelial repair and neovascularization. A large body of evidence from clinical, animal, and in vitro studies have shown that EPC numbers in circulation and their functionality reflect endogenous vascular regenerative capacity. Traditionally vitamin D is known to be beneficial for bone health and calcium metabolism and in the last two decades, its role in influencing CVD and cancer risk has generated significant interest. Observational studies have shown that low vitamin D levels are associated with an adverse cardiovascular risk profile. Still, Mendelian randomization studies and randomized control trials (RCTs) have not shown significant effects of vitamin D on cardiovascular events. The criticism regarding the RCTs on vitamin D and CVD is that they were not designed to investigate cardiovascular outcomes in vitamin D-deficient individuals. Overall, the association between vitamin D and CVD remains inconclusive. Recent clinical and experimental studies have demonstrated the beneficial role of vitamin D in increasing the circulatory level of EPC as well as their functionality. In this review we present evidence supporting the beneficial role of vitamin D in CVD through its modulation of EPC homeostasis.
Collapse
Affiliation(s)
- Atanu Sen
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Vinnyfred Vincent
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Himani Thakkar
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Ransi Abraham
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Lakshmy Ramakrishnan
- Department of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
29
|
Qin K, Lei J, Yang J. The Differentiation of Pluripotent Stem Cells towards Endothelial Progenitor Cells - Potential Application in Pulmonary Arterial Hypertension. Int J Stem Cells 2021; 15:122-135. [PMID: 34711697 PMCID: PMC9148829 DOI: 10.15283/ijsc21044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 08/26/2021] [Accepted: 09/02/2021] [Indexed: 11/22/2022] Open
Abstract
Background and Objectives Endothelial progenitor cells (EPCs) and endothelial cells (ECs) have been applied in the clinic to treat pulmonary arterial hypertension (PAH), a disease characterized by disordered pulmonary vasculature. However, the lack of sufficient transplantable cells before the deterioration of disease condition is a current limitation to apply cell therapy in patients. It is necessary to differentiate pluripotent stem cells (PSCs) into EPCs and identify their characteristics. Methods and Results Comparing previously reported methods of human PSCs-derived ECs, we optimized a highly efficient differentiation protocol to obtain cells that match the phenotype of isolated EPCs from healthy donors. The protocol is compatible with chemically defined medium (CDM), it could produce a large number of clinically applicable cells with low cost. Moreover, we also found PSCs-derived EPCs express CD133, have some characteristics of mesenchymal stem cells and are capable of homing to repair blood vessels in zebrafish xenograft assays. In addition, we further revealed that IPAH PSCs-derived EPCs have higher expression of proliferation-related genes and lower expression of immune-related genes than normal EPCs and PSCs-derived EPCs through microarray analysis. Conclusions In conclusion, we optimized a highly efficient differentiation protocol to obtain PSCs-derived EPCs with the phenotypic and molecular characteristics of EPCs from healthy donors which distinguished them from EPCs from PAH.
Collapse
Affiliation(s)
- Kezhou Qin
- Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia Lei
- Department of Physiology, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Yang
- Department of Cell Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.,Department of Physiology, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| |
Collapse
|
|
30
|
Salybekov AA, Kunikeyev AD, Kobayashi S, Asahara T. Latest Advances in Endothelial Progenitor Cell-Derived Extracellular Vesicles Translation to the Clinic. Front Cardiovasc Med 2021; 8:734562. [PMID: 34671654 PMCID: PMC8520929 DOI: 10.3389/fcvm.2021.734562] [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: 07/01/2021] [Accepted: 08/30/2021] [Indexed: 12/16/2022] Open
Abstract
Almost all nucleated cells secrete extracellular vesicles (EVs) that are heterogeneous spheroid patterned or round shape particles ranging from 30 to 200 nm in size. Recent preclinical and clinical studies have shown that endothelial progenitor cell-derived EVs (EPC-EVs) have a beneficial therapeutic effect in various diseases, including cardiovascular diseases and kidney, and lung disorders. Moreover, some animal studies have shown that EPC-EVs selectively accumulate at the injury site with a specific mechanism of binding along with angiogenic and restorative effects that are superior to those of their ancestors. This review article highlights current advances in the biogenesis, delivery route, and long-term storage methods of EPC-EVs and their favorable effects such as anti-inflammatory, angiogenic, and tissue protection in various diseases. Finally, we review the possibility of therapeutic application of EPC-EVs in the clinic.
Collapse
Affiliation(s)
- Amankeldi A Salybekov
- Division of Regenerative Medicine, Department of Center for Clinical and Translational Science, Shonan Kamakura General Hospital, Kamakura, Japan.,Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan.,Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Aidyn D Kunikeyev
- Department of Software Engineering, Kazakh National Technical University After K.I. Satpayev, Almaty, Kazakhstan
| | - Shuzo Kobayashi
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan.,Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
| | - Takayuki Asahara
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura, Japan
| |
Collapse
|
|
31
|
Dight J, Zhao J, Styke C, Khosrotehrani K, Patel J. Resident vascular endothelial progenitor definition and function: the age of reckoning. Angiogenesis 2021; 25:15-33. [PMID: 34499264 PMCID: PMC8813834 DOI: 10.1007/s10456-021-09817-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Abstract
The cardiovascular system is composed around the central function of the endothelium that lines the inner surfaces of its vessels. In recent years, the existence of a progenitor population within the endothelium has been validated through the study of endothelial colony-forming cells (ECFCs) in human peripheral blood and certain vascular beds. However, our knowledge on endothelial populations in vivo that can give rise to ECFCs in culture has been limited. In this review we report and analyse recent attempts at describing progenitor populations in vivo from murine studies that reflect the self-renewal and stemness capacity observed in ECFCs. We pinpoint seminal discoveries within the field, which have phenotypically defined, and functionally scrutinised these endothelial progenitors. Furthermore, we review recent publications utilising single-cell sequencing technologies to better understand the endothelium in homeostasis and pathology.
Collapse
Affiliation(s)
- James Dight
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Jilai Zhao
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Cassandra Styke
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
| | - Jatin Patel
- The University of Queensland Diamantina Institute, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia. .,Cancer and Ageing Research Program, School of Biomedical Sciences, Queensland University of Technology, 37 Kent Street, Woolloongabba, Brisbane, 4102, Australia.
| |
Collapse
|
|
32
|
Cell-based therapies for vascular regeneration: Past, present and future. Pharmacol Ther 2021; 231:107976. [PMID: 34480961 DOI: 10.1016/j.pharmthera.2021.107976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/01/2021] [Accepted: 08/05/2021] [Indexed: 12/27/2022]
Abstract
Tissue vascularization remains one of the outstanding challenges in regenerative medicine. Beyond its role in circulating oxygen and nutrients, the vasculature is critical for organ development, function and homeostasis. Importantly, effective vascular regeneration is key in generating large 3D tissues for regenerative medicine applications to enable the survival of cells post-transplantation, organ growth, and integration into the host system. Therefore, the absence of clinically applicable means of (re)generating vessels is one of the main obstacles in cell replacement therapy. In this review, we highlight cell-based vascularization strategies which demonstrate clinical potential, discuss their strengths and limitations and highlight the main obstacles hindering cell-based therapeutic vascularization.
Collapse
|
|
33
|
Tan CMJ, Lewandowski AJ, Williamson W, Huckstep OJ, Yu GZ, Fischer R, Simon JN, Alsharqi M, Mohamed A, Leeson P, Bertagnolli M. Proteomic Signature of Dysfunctional Circulating Endothelial Colony-Forming Cells of Young Adults. J Am Heart Assoc 2021; 10:e021119. [PMID: 34275329 PMCID: PMC8475699 DOI: 10.1161/jaha.121.021119] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
Background A subpopulation of endothelial progenitor cells called endothelial colony-forming cells (ECFCs) may offer a platform for cellular assessment in clinical studies because of their remarkable angiogenic and expansion potentials in vitro. Despite endothelial cell function being influenced by cardiovascular risk factors, no studies have yet provided a comprehensive proteomic profile to distinguish functional (ie, more angiogenic and expansive cells) versus dysfunctional circulating ECFCs of young adults. The aim of this study was to provide a detailed proteomic comparison between functional and dysfunctional ECFCs. Methods and Results Peripheral blood ECFCs were isolated from 11 subjects (45% men, aged 27±5 years) using Ficoll density gradient centrifugation. ECFCs expressed endothelial and progenitor surface markers and displayed cobblestone-patterned morphology with clonal and angiogenic capacities in vitro. ECFCs were deemed dysfunctional if <1 closed tube formed during the in vitro tube formation assay and proliferation rate was <20%. Hierarchical functional clustering revealed distinct ECFC proteomic signatures between functional and dysfunctional ECFCs with changes in cellular mechanisms involved in exocytosis, vesicle transport, extracellular matrix organization, cell metabolism, and apoptosis. Targeted antiangiogenic proteins in dysfunctional ECFCs included SPARC (secreted protein acidic and rich in cysteine), CD36 (cluster of differentiation 36), LUM (lumican), and PTX3 (pentraxin-related protein PYX3). Conclusions Circulating ECFCs with impaired angiogenesis and expansion capacities have a distinct proteomic profile and significant phenotype changes compared with highly angiogenic endothelial cells. Impaired angiogenesis in dysfunctional ECFCs may underlie the link between endothelial dysfunction and cardiovascular disease risks in young adults.
Collapse
Affiliation(s)
- Cheryl M. J. Tan
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
| | - Adam J. Lewandowski
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
| | - Wilby Williamson
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
| | - Odaro J. Huckstep
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
- Department of BiologyUnited States Air Force AcademyColorado SpringsCOUSA
| | - Grace Z. Yu
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
- Wellcome Centre for Human GeneticsUniversity of OxfordOxfordUK
| | - Roman Fischer
- Target Discovery Institute (TDI) Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Jillian N. Simon
- Division of Cardiovascular Medicine, Radcliffe Department of MedicineUniversity of OxfordOxfordUnited Kingdom
| | - Maryam Alsharqi
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
- Department of Cardiac TechnologyImam Abdulrahman Bin Faisal UniversityDammamSaudi Arabia
| | - Afifah Mohamed
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
- Department of Diagnostic Imaging & Applied Health Sciences, Faculty of Health SciencesUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Paul Leeson
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
| | - Mariane Bertagnolli
- Oxford Cardiovascular Clinical Research Facility, Radcliffe Department of Medicine, Division of Cardiovascular MedicineUniversity of OxfordOxfordUK
- Montreal Hospital Sacré‐Cœur Research CentreCentre Intégré Universitaire de Santé et de Services Sociaux du Nord‐de‐l'Île‐de‐MontréalMontréalQCCanada
- School of Physical and Occupational Therapy, Faculty of MedicineMcGill UniversityMontréalQCCanada
| |
Collapse
|
|
34
|
Clinically compatible advances in blood-derived endothelial progenitor cell isolation and reprogramming for translational applications. N Biotechnol 2021; 63:1-9. [PMID: 33588094 DOI: 10.1016/j.nbt.2021.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 01/27/2021] [Accepted: 02/07/2021] [Indexed: 11/21/2022]
Abstract
The promise of using induced pluripotent stem cells (iPSCs) for cellular therapies has been hampered by the lack of easily isolatable and well characterized source cells whose genomes have undergone minimal changes during their processing. Blood-derived late-outgrowth endothelial progenitor cells (EPCs) are used for disease modeling and have potential therapeutic uses including cell transplantation and the translation of induced pluripotent stem cell (iPSC) derivatives. However, the current isolation of EPCs has been inconsistent and requires at least 40-80 mL of blood, limiting their wider use. In addition, previous EPC reprogramming methods precluded the translation of EPC-derived iPSCs to the clinic. Here a series of clinically-compatible advances in the isolation and reprogramming of EPCs is presented, including a reduction of blood sampling volumes to 10 mL and use of highly efficient RNA-based reprogramming methods together with autologous human serum, resulting in clinically relevant iPSCs carrying minimal copy number variations (CNVs) compared to their parent line.
Collapse
|
|
35
|
Aquino JB, Sierra R, Montaldo LA. Diverse cellular origins of adult blood vascular endothelial cells. Dev Biol 2021; 477:117-132. [PMID: 34048734 DOI: 10.1016/j.ydbio.2021.05.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/26/2021] [Accepted: 05/14/2021] [Indexed: 12/11/2022]
Abstract
During embryonic stages, vascular endothelial cells (ECs) originate from the mesoderm, at specific extraembryonic and embryonic regions, through a process called vasculogenesis. In the adult, EC renewal/replacement mostly depend on local resident ECs or endothelial progenitor cells (EPCs). Nevertheless, contribution from circulating ECs/EPCs was also reported. In addition, cells lacking from EC/EPC markers with in vitro extended plasticity were shown to originate endothelial-like cells (ELCs). Most of these cells consist of mesenchymal stromal progenitors, which would eventually get mobilized from the bone marrow after injury. Based on that, current knowledge on different mouse and human bone marrow stromal cell (BM-SC) subpopulations, able to contribute with mesenchymal stromal/stem cells (MSCs), is herein reviewed. Such analyses underline an unexpected heterogeneity among sinusoidal LepR+ stromal/CAR cells. For instance, in a recent report a subgroup of LepR+ stromal/CAR progenitors, which express GLAST and is traced in Wnt1Cre;R26RTom mice, was found to contribute with ELCs in vivo. These GLAST + Wnt1+ BM-SCs were shown to get mobilized to the peripheral blood and to contribute with liver regeneration. Other sources of ELCs, such as adipose, neural and dental pulp tissues, were also published. Finally, mechanisms likely involved in the enhanced cellular plasticity properties of bone marrow/adipose tissue stromal cells, able to originate ELCs, are assessed. In the future, strategies to analyze the in vivo expression profile of stromal cells, with MSC properties, in combination with screening of active genomic regions at the single cell-level, during early postnatal development and/or after injury, will likely help understanding properties of these ELC sources.
Collapse
Affiliation(s)
- Jorge B Aquino
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina.
| | - Romina Sierra
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina
| | - Laura A Montaldo
- CONICET-Universidad Austral, Instituto de Investigaciones en Medicina Traslacional (IIMT), Developmental Biology & Regenerative Medicine Laboratory, Argentina
| |
Collapse
|
|
36
|
Guduric-Fuchs J, Pedrini E, Lechner J, Chambers SE, O’Neill CL, Mendes Lopes de Melo J, Pathak V, Church RH, McKeown S, Bojdo J, Mcloughlin KJ, Stitt AW, Medina RJ. miR-130a activates the VEGFR2/STAT3/HIF1α axis to potentiate the vasoregenerative capacity of endothelial colony-forming cells in hypoxia. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 23:968-981. [PMID: 33614244 PMCID: PMC7869000 DOI: 10.1016/j.omtn.2021.01.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 01/14/2021] [Indexed: 01/01/2023]
Abstract
Hypoxia modulates reparative angiogenesis, which is a tightly regulated pathophysiological process. MicroRNAs (miRNAs) are important regulators of gene expression in hypoxia and angiogenesis. However, we do not yet have a clear understanding of how hypoxia-induced miRNAs fine-tune vasoreparative processes. Here, we identify miR-130a as a mediator of the hypoxic response in human primary endothelial colony-forming cells (ECFCs), a well-characterized subtype of endothelial progenitors. Under hypoxic conditions of 1% O2, miR-130a gain-of-function enhances ECFC pro-angiogenic capacity in vitro and potentiates their vasoreparative properties in vivo. Mechanistically, miR-130a orchestrates upregulation of VEGFR2, activation of STAT3, and accumulation of HIF1α via translational inhibition of Ddx6. These findings unveil a new role for miR-130a in hypoxia, whereby it activates the VEGFR2/STAT3/HIF1α axis to enhance the vasoregenerative capacity of ECFCs.
Collapse
Affiliation(s)
- Jasenka Guduric-Fuchs
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Edoardo Pedrini
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Judith Lechner
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Sarah E.J. Chambers
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Christina L. O’Neill
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Joana Mendes Lopes de Melo
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Varun Pathak
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Rachel H. Church
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Stuart McKeown
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - James Bojdo
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Kiran J. Mcloughlin
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Alan W. Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| | - Reinhold J. Medina
- Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Sciences, Queen’s University Belfast, Belfast BT9 7BL, UK
| |
Collapse
|
|
37
|
Vašíček J, Baláži A, Bauer M, Svoradová A, Tirpáková M, Tomka M, Chrenek P. Molecular Profiling and Gene Banking of Rabbit EPCs Derived from Two Biological Sources. Genes (Basel) 2021; 12:genes12030366. [PMID: 33806502 PMCID: PMC7998175 DOI: 10.3390/genes12030366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 02/27/2021] [Accepted: 03/03/2021] [Indexed: 12/20/2022] Open
Abstract
Endothelial progenitor cells (EPCs) have been broadly studied for several years due to their outstanding regenerative potential. Moreover, these cells might be a valuable source of genetic information for the preservation of endangered animal species. However, a controversy regarding their characterization still exists. The aim of this study was to isolate and compare the rabbit peripheral blood- and bone marrow-derived EPCs with human umbilical vein endothelial cells (HUVECs) in terms of their phenotype and morphology that could be affected by the passage number or cryopreservation as well as to assess their possible neuro-differentiation potential. Briefly, cells were isolated and cultured under standard endothelial conditions until passage 3. The morphological changes during the culture were monitored and each passage was analyzed for the typical phenotype using flow cytometry, quantitative real–time polymerase chain reaction (qPCR) and novel digital droplet PCR (ddPCR), and compared to HUVECs. The neurogenic differentiation was induced using a commercial kit. Rabbit cells were also cryopreserved for at least 3 months and then analyzed after thawing. According to the obtained results, both rabbit EPCs exhibit a spindle-shaped morphology and high proliferation rate. The both cell lines possess same stable phenotype: CD14−CD29+CD31−CD34−CD44+CD45−CD49f+CD73+CD90+CD105+CD133−CD146−CD166+VE-cadherin+VEGFR-2+SSEA-4+MSCA-1−vWF+eNOS+AcLDL+ALDH+vimentin+desmin+α-SMA+, slightly different from HUVECs. Moreover, both induced rabbit EPCs exhibit neuron-like morphological changes and expression of neuronal markers ENO2 and MAP2. In addition, cryopreserved rabbit cells maintained high viability (>85%) and endothelial phenotype after thawing. In conclusion, our findings suggest that cells expanded from the rabbit peripheral blood and bone marrow are of the endothelial origin with a stable marker expression and interesting proliferation and differentiation capacity.
Collapse
Affiliation(s)
- Jaromír Vašíček
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
- Department of Biochemistry and Biotechnology, Faculty of Biotechnology and Food Science, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia;
- Correspondence: (J.V.); (P.C.); Tel.: +421-37-654-6600 (J.V.); +421-37-641-4274 (P.C.)
| | - Andrej Baláži
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
| | - Miroslav Bauer
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
- Department of Botany and Genetics, Faculty of Natural Sciences, Constantine the Philosopher University in Nitra, Nábrežie mládeže 91, 949 74 Nitra, Slovakia
| | - Andrea Svoradová
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
| | - Mária Tirpáková
- Department of Biochemistry and Biotechnology, Faculty of Biotechnology and Food Science, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia;
- AgroBioTech Research Center, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia
| | - Marián Tomka
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
| | - Peter Chrenek
- NPPC, Research Institute for Animal Production Nitra, Institute of Farm Animal Genetics and Reproduction, Hlohovecká 2, 951 41 Lužianky, Slovakia; (A.B.); (M.B.); (A.S.); (M.T.)
- Department of Biochemistry and Biotechnology, Faculty of Biotechnology and Food Science, Slovak University of Agriculture in Nitra, Tr. A. Hlinku 2, 949 76 Nitra, Slovakia;
- Correspondence: (J.V.); (P.C.); Tel.: +421-37-654-6600 (J.V.); +421-37-641-4274 (P.C.)
| |
Collapse
|
|
38
|
Atkinson SP. A preview of selected articles. Stem Cells Transl Med 2021; 10:160-163. [PMID: 33522152 PMCID: PMC7848349 DOI: 10.1002/sctm.20-0565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 11/29/2022] Open
|
|
39
|
Zhang J, Chan HF, Wang H, Shao D, Tao Y, Li M. Stem cell therapy and tissue engineering strategies using cell aggregates and decellularized scaffolds for the rescue of liver failure. J Tissue Eng 2021; 12:2041731420986711. [PMID: 35003615 PMCID: PMC8733710 DOI: 10.1177/2041731420986711] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022] Open
Abstract
Liver failure is a lethal condition with hepatocellular dysfunction, and liver transplantation is presently the only effective treatment. However, due to the limited availability of donors and the potential immune rejection, novel therapeutic strategies are actively sought to restore the normal hepatic architectures and functions, especially for livers with inherited metabolic dysfunctions or chronic diseases. Although the conventional cell therapy has shown promising results, the direct infusion of hepatocytes is hampered by limited hepatocyte sources, poor cell viability, and engraftment. Hence, this review mainly highlights the role of stem cells and progenitors as the alternative cell source and summarizes the potential approaches based on tissue engineering to improve the delivery efficiency of cells. Particularly, the underlying mechanisms for cell therapy using stem cells and progenitors are discussed in two main aspects: paracrine effect and cell differentiation. Moreover, tissue-engineering approaches using cell aggregates and decellularized liver scaffolds for bioengineering of functional hepatic constructs are discussed and compared in terms of the potential to replicate liver physiological structures. In the end, a potentially effective strategy combining the premium advantages of stem cell aggregates and decellularized liver scaffolds is proposed as the future direction of liver tissue engineering and regeneration.
Collapse
Affiliation(s)
- Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease, Guangzhou, China
| | - Hon Fai Chan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Hong Kong, China
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dan Shao
- Institutes of Life Sciences, School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease, Guangzhou, China
| |
Collapse
|
|
40
|
Alwjwaj M, Kadir RRA, Bayraktutan U. The secretome of endothelial progenitor cells: a potential therapeutic strategy for ischemic stroke. Neural Regen Res 2021; 16:1483-1489. [PMID: 33433461 PMCID: PMC8323700 DOI: 10.4103/1673-5374.303012] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Ischemic stroke continues to be a leading cause of mortality and morbidity in the world. Despite recent advances in the field of stroke medicine, thrombolysis with recombinant tissue plasminogen activator remains as the only pharmacological therapy for stroke patients. However, due to short therapeutic window (4.5 hours of stroke onset) and increased risk of hemorrhage beyond this point, each year globally less than 1% of stroke patients receive this therapy which necessitate the discovery of safe and efficacious therapeutics that can be used beyond the acute phase of stroke. Accumulating evidence indicates that endothelial progenitor cells (EPCs), equipped with an inherent capacity to migrate, proliferate and differentiate, may be one such therapeutics. However, the limited availability of EPCs in peripheral blood and early senescence of few isolated cells in culture conditions adversely affect their application as effective therapeutics. Given that much of the EPC-mediated reparative effects on neurovasculature is realized by a wide range of biologically active substances released by these cells, it is possible that EPC-secretome may serve as an important therapeutic after an ischemic stroke. In light of this assumption, this review paper firstly discusses the main constituents of EPC-secretome that may exert the beneficial effects of EPCs on neurovasculature, and then reviews the currently scant literature that focuses on its therapeutic capacity.
Collapse
Affiliation(s)
- Mansour Alwjwaj
- Stroke, Division of Clinical Neuroscience, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Rais Reskiawan A Kadir
- Stroke, Division of Clinical Neuroscience, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Ulvi Bayraktutan
- Stroke, Division of Clinical Neuroscience, University of Nottingham, Clinical Sciences Building, City Hospital, Hucknall Road, Nottingham, NG5 1PB, UK
| |
Collapse
|
|
41
|
Anti-endothelial cell antibodies are associated with apoptotic endothelial microparticles, endothelial sloughing and decrease in angiogenic progenitors in systemic sclerosis. Postepy Dermatol Alergol 2020; 37:725-735. [PMID: 33240013 PMCID: PMC7675085 DOI: 10.5114/ada.2019.84230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 03/11/2019] [Indexed: 11/18/2022] Open
Abstract
Introduction Evidence has accumulated for the role of endothelial damage in systemic sclerosis (SSc) and the anti-endothelial cell antibodies (AECAs) might underlie vascular injury. Aim Since endothelial microparticles (EMPs) and circulating endothelial cells (CECs) reflect endothelial damage, we aimed to investigate their possible relationship with AECAs in SSc. We examined whether AECAs could affect endothelial repair based on the number of endothelial progenitor cells (EPCs). Material and methods Forty-seven SSc patients were screened. The AECAs were identified in serum by indirect immunofluorescence. EPCs and CECs were isolated from the peripheral blood using anti-CD34-based immunomagnetic separation, whereas EMPs were analyzed in plasma. Flow cytometry was used to quantify EMPs, CECs and EPCs. Results AECAs were found in 21 (44.7%) SSc patients and were significantly associated with higher levels of total as well as apoptotic (AnnV+ and CD51+) EMPs, whereas activated (CD62E+/AnnV–) EMPs did not differ between groups. Patients with AECAs had significantly elevated total CECs as well as activated CD105+ CECs. Total endothelial progenitors did not differ between patients with or without AECAs; however AECAs was negatively associated with the population of EPCs that express VEGFR2 or Tie2 receptors. Conclusions We found an association between AECAs and the severity of endothelial damage in SSc based on higher levels of total EMPs and CECs. In our study, AECAs were associated with apoptosis of ECs rather than their activation. We also identified a possible role of AECAs in the impairment of vascular repair in SSc as evidenced by significantly fewer angiogenic EPCs.
Collapse
|
|
42
|
Evans WS, Sapp RM, Kim KI, Heilman JM, Hagberg J, Prior SJ. Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells. Int J Sports Med 2020; 42:1047-1057. [PMID: 33124014 DOI: 10.1055/a-1273-8390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Exercise training has various benefits on cardiovascular health, and circulating angiogenic cells have been proposed as executing these changes. Work from the late 1990s supported an important role of these circulating post-natal cells in contributing to the maintenance and repair of the endothelium and vasculature. It was later found that circulating angiogenic cells were a heterogenous population of cells and primarily functioned in a paracrine manner by adhering to damaged endothelium and releasing growth factors. Many studies have discovered novel circulating angiogenic cell secreted proteins, microRNA and extracellular vesicles that mediate their angiogenic potential, and some studies have shown that both acute and chronic aerobic exercise training have distinct benefits. This review highlights work establishing an essential role of secreted factors from circulating angiogenic cells and summarizes studies regarding the effects of exercise training on these factors. Finally, we highlight the various gaps in the literature in hopes of guiding future work.
Collapse
Affiliation(s)
- William S Evans
- Department of Kinesiology, University of Maryland School of Public Health, College Park
| | - Ryan M Sapp
- Department of Kinesiology, University of Maryland School of Public Health, College Park
| | - Katherine I Kim
- Department of Kinesiology, University of Maryland School of Public Health, College Park
| | - James M Heilman
- Department of Kinesiology, University of Maryland School of Public Health, College Park
| | - James Hagberg
- Department of Kinesiology, University of Maryland School of Public Health, College Park
| | - Steven J Prior
- Department of Kinesiology, University of Maryland School of Public Health, College Park.,Baltimore Veterans Affairs Geriatric Research, Education and Clinical Center, Department of Veterans Affairs, Baltimore
| |
Collapse
|
|
43
|
Perrotta F, Perna A, Komici K, Nigro E, Mollica M, D’Agnano V, De Luca A, Guerra G. The State of Art of Regenerative Therapy in Cardiovascular Ischemic Disease: Biology, Signaling Pathways, and Epigenetics of Endothelial Progenitor Cells. Cells 2020; 9:E1886. [PMID: 32796767 PMCID: PMC7465688 DOI: 10.3390/cells9081886] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 07/19/2020] [Accepted: 08/07/2020] [Indexed: 12/18/2022] Open
Abstract
Ischemic heart disease is currently a major cause of mortality and morbidity worldwide. Nevertheless, the actual therapeutic scenario does not target myocardial cell regeneration and consequently, the progression toward the late stage of chronic heart failure is common. Endothelial progenitor cells (EPCs) are bone marrow-derived stem cells that contribute to the homeostasis of the endothelial wall in acute and chronic ischemic disease. Calcium modulation and other molecular pathways (NOTCH, VEGFR, and CXCR4) contribute to EPC proliferation and differentiation. The present review provides a summary of EPC biology with a particular focus on the regulatory pathways of EPCs and describes promising applications for cardiovascular cell therapy.
Collapse
Affiliation(s)
- Fabio Perrotta
- Dipartimento di Medicina e Scienze della Salute “V.Tiberio”, Università del Molise, 86100 Campobasso, Italy; (A.P.); (K.K.); (G.G.)
| | - Angelica Perna
- Dipartimento di Medicina e Scienze della Salute “V.Tiberio”, Università del Molise, 86100 Campobasso, Italy; (A.P.); (K.K.); (G.G.)
| | - Klara Komici
- Dipartimento di Medicina e Scienze della Salute “V.Tiberio”, Università del Molise, 86100 Campobasso, Italy; (A.P.); (K.K.); (G.G.)
| | - Ersilia Nigro
- Dipartimento di Scienze e Tecnologie Ambientali, Biologiche, Farmaceutiche, Università della Campania “Luigi Vanvitelli”, 81100 Caserta, Italy;
- CEINGE-Biotecnologie avanzate, 80145 Naples, Italy
| | - Mariano Mollica
- Dipartimento di Scienze Mediche Traslazionali, Università della Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.M.); (V.D.)
| | - Vito D’Agnano
- Dipartimento di Scienze Mediche Traslazionali, Università della Campania “Luigi Vanvitelli”, 80131 Naples, Italy; (M.M.); (V.D.)
| | - Antonio De Luca
- Department of Mental and Physical Health and Preventive Medicine, Section of Human Anatomy, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Germano Guerra
- Dipartimento di Medicina e Scienze della Salute “V.Tiberio”, Università del Molise, 86100 Campobasso, Italy; (A.P.); (K.K.); (G.G.)
| |
Collapse
|
|
44
|
Chillà A, Margheri F, Biagioni A, Del Rosso T, Fibbi G, Del Rosso M, Laurenzana A. Cell-Mediated Release of Nanoparticles as a Preferential Option for Future Treatment of Melanoma. Cancers (Basel) 2020; 12:cancers12071771. [PMID: 32630815 PMCID: PMC7408438 DOI: 10.3390/cancers12071771] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2020] [Revised: 06/22/2020] [Accepted: 06/30/2020] [Indexed: 01/15/2023] Open
Abstract
Targeted and immune therapies have unquestionably improved the prognosis of melanoma patients. However the treatment of this neoplasm still requires approaches with a higher therapeutic index, in order to reduce shortcomings related to toxic effects and aspecific targeting. This means developing therapeutic tools derived with high affinity molecules for tumor components differentially expressed in melanoma cells with respect to their normal counterpart. Nanomedicine has sought to address this problem owing to the high modulability of nanoparticles. This approach exploits not only the enhanced permeability and retention effect typical of the tumor microenvironment (passive targeting), but also the use of specific "molecular antennas" that recognize some tumor-overexpressed molecules (active targeting). This line of research has given rise to the so-called "smart nanoparticles," some of which have already passed the preclinical phase and are under clinical trials in melanoma patients. To further improve nanoparticles partition within tumors, for some years now a line of thought is exploiting the molecular systems that regulate the innate tumor-homing activity of platelets, granulocytes, monocytes/macrophages, stem cells, endothelial-colony-forming cells, and red blood cells loaded with nanoparticles. This new vision springs from the results obtained with some of these cells in regenerative medicine, an approach called "cell therapy." This review takes into consideration the advantages of cell therapy as the only one capable of overcoming the limits of targeting imposed by the increased interstitial pressure of tumors.
Collapse
Affiliation(s)
- Anastasia Chillà
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
| | - Francesca Margheri
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
| | - Alessio Biagioni
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
| | - Tommaso Del Rosso
- Department of Physics, Pontifical Catholic University of Rio de Janeiro, 22451-900 Rio de Janeiro-RJ, Brazil;
| | - Gabriella Fibbi
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
| | - Mario Del Rosso
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
- Correspondence: (M.D.R.); (A.L.)
| | - Anna Laurenzana
- Department of Experimental and Clinical Biomedical Sciences School of Health Sciences, University of Florence-Viale G.B. Morgagni, 50–50134 Florence, Italy; (A.C.); (F.M.); (A.B.); (G.F.)
- Correspondence: (M.D.R.); (A.L.)
| |
Collapse
|
|
45
|
Endothelial progenitor cell transplantation restores vascular injury in mice after whole-brain irradiation. Brain Res 2020; 1746:147005. [PMID: 32622827 DOI: 10.1016/j.brainres.2020.147005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/23/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023]
Abstract
Vascular damage plays an important role in the pathogenesis of radiation-induced brain injury (RBI). Endothelial progenitor cells (EPCs) are responsible for maintaining and repairing endothelial function, and have become a promising method for the treatment of cerebrovascular diseases. However, whether EPC transplantation plays a protective role in RBI has not been fully elucidated. Therefore, the present study investigated the effects of bone marrow-derived EPC transplantation in a whole-brain irradiation (WBI) mouse model. Mice were divided into the three groups: control group, irradiation group and EPCs group. Phosphate buffered saline or EPCs were intravenously injected into mice one week after irradiation, and brains were analyzed eight weeks after injection. Flow cytometry demonstrated that irradiation led to a significant reduction in the peripheral blood EPC count; however, EPC transplantation led to a significant increase in the circulating EPCs. Intravital two-photon imaging and western blotting demonstrated that EPC transplantation reversed the effects of irradiation by decreasing blood-brain barrier permeability and increasing the expression of tight junction proteins in the brain. Additionally, immunofluorescence staining revealed that the brain microvascular density was higher in the EPCs group than the irradiation group. Therefore, EPC transplantation may restore damage caused by WBI to the blood-brain barrier, tight junctions, and cerebral capillary density. These results highlight the potential beneficial effects of EPC transplantation on vascular damage induced by RBI.
Collapse
|
|
46
|
Yuan Y, Khan S, Stewart DJ, Courtman DW. Engineering blood outgrowth endothelial cells to optimize endothelial nitric oxide synthase and extracellular matrix production for coating of blood contacting surfaces. Acta Biomater 2020; 109:109-120. [PMID: 32302726 DOI: 10.1016/j.actbio.2020.04.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/26/2022]
Abstract
Coverage of blood contacting surfaces by a functional endothelial layer is likely required to induce and maintain homeostasis. Blood outgrowth endothelial cells (BOECs), cultured from human peripheral blood monocytes, are readily available and functional autologous endothelial source that may represent a reasonable alternative to vascular derived cells. Endothelial nitric oxide synthase (eNOS) produces NO, an important factor that regulates homeostasis at the blood-contacting surface. We found that BOECs express markedly lower levels of eNOS protein (34% ± 13%, Western blot) and mRNA (29% ± 17%, qRT-PCR), as well as exhibiting reduced activity (49% ± 18%, Nitrite analysis) when compared to human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells. HUVECs grown on fibronectin, type I collagen, or laminin -coated surfaces exhibited significant reduction of eNOS mRNA and protein expression. However, no decrease in eNOS levels was observed in BOECs. Interestingly BOECs expressed significantly higher Collagen (Col) I compared to HUVECs, and blocking Col I synthesis significantly enhanced eNOS expression in BOECs. Inhibition of β1 integrin, focal adhesion kinase (FAK), or actin polymerization increased eNOS in both BOECs and HUVECs suggesting involvement of a signaling pathway culminating in stabilization of the cytoskeleton. Finally, we demonstrated that a Rho-associated protein kinases (ROCK) inhibitor, as a disruptor of actin stabilization, enhanced both eNOS expression and bioactivity. Taken together, our findings demonstrate that cell-ECM interactions are fundamental to the regulation of eNOS in BOECs and suggest that disruption of key intracellular pathways (such as ROCK) may be necessary to enhance functional activity of an endothelialized surface. STATEMENT OF SIGNIFICANCE: Development of biocompatible blood-contacting biomaterial surfaces has not been possible to date, leading many investigators to believe that a complete autologous endothelial layer will be necessary. Blood outgrowth endothelial cells (BOECs), cultured from human peripheral blood monocytes, are readily available and functional autologous endothelial source. Endothelial nitric oxide synthase (eNOS) produces NO, an important factor that regulates homeostasis at the blood-contacting surface. In this study, we show that eNOS displays limited expression in cultured BOECs. We further demonstrate that a strong negative regulation of eNOS is mediated by collagen substrates and that treatment with ROCK inhibitor could enhance both eNOS expression and activity in BOECs and help to rapidly establish a functional autologous endothelial layer on cardiovascular biomaterials.
Collapse
Affiliation(s)
- Yifan Yuan
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Department of Anaesthesiology, Yale University, 10 Amistad Rd, New Haven, CT 06519, United States
| | - Saad Khan
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada
| | - Duncan J Stewart
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada; Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - David W Courtman
- Ottawa Hospital Research Institute, General Campus, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada; Department of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada.
| |
Collapse
|
|
47
|
Abdulkadir RR, Alwjwaj M, Othman OA, Rakkar K, Bayraktutan U. Outgrowth endothelial cells form a functional cerebral barrier and restore its integrity after damage. Neural Regen Res 2020; 15:1071-1078. [PMID: 31823887 PMCID: PMC7034270 DOI: 10.4103/1673-5374.269029] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Breakdown of blood-brain barrier, formed mainly by brain microvascular endothelial cells (BMECs), represents the major cause of mortality during early phases of ischemic strokes. Hence, discovery of novel agents that can effectively replace dead or dying endothelial cells to restore blood-brain barrier integrity is of paramount importance in stroke medicine. Although endothelial progenitor cells (EPCs) represent one such agents, their rarity in peripheral blood severely limits their adequate isolation and therapeutic use for acute ischemic stroke which necessitate their ex vivo expansion and generate early EPCs and outgrowth endothelial cells (OECs) as a result. Functional analyses of these cells, in the present study, demonstrated that only OECs endocytosed DiI-labelled acetylated low-density lipoprotein and formed tubules on matrigel, prominent endothelial cell and angiogenesis markers, respectively. Further analyses by flow cytometry demonstrated that OECs expressed specific markers for stemness (CD34), immaturity (CD133) and endothelial cells (CD31) but not for hematopoietic cells (CD45). Like BMECs, OECs established an equally tight in vitro model of human BBB with astrocytes and pericytes, suggesting their capacity to form tight junctions. Ischemic injury mimicked by concurrent deprivation of oxygen and glucose (4 hours) or deprivation of oxygen and glucose followed by reperfusion (20 hours) affected both barrier integrity and function in a similar fashion as evidenced by decreases in transendothelial electrical resistance and increases in paracellular flux, respectively. Wound scratch assays comparing the vasculoreparative capacity of cells revealed that, compared to BMECs, OECs possessed a greater proliferative and directional migratory capacity. In a triple culture model of BBB established with astrocytes, pericytes and BMEC, exogenous addition of OECs effectively repaired the damage induced on endothelial layer in serum-free conditions. Taken together, these data demonstrate that OECs may effectively home to the site of vascular injury and repair the damage to maintain (neuro)vascular homeostasis during or after a cerebral ischemic injury.
Collapse
Affiliation(s)
- Rais Reskiawan Abdulkadir
- Stroke, Division of Clinical Neuroscience, Clinical Sciences Building, School of Medicine, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Mansour Alwjwaj
- Stroke, Division of Clinical Neuroscience, Clinical Sciences Building, School of Medicine, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Othman Ahmad Othman
- Stroke, Division of Clinical Neuroscience, Clinical Sciences Building, School of Medicine, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Kamini Rakkar
- Stroke, Division of Clinical Neuroscience, Clinical Sciences Building, School of Medicine, Hucknall Road, Nottingham, NG5 1PB, UK
| | - Ulvi Bayraktutan
- Stroke, Division of Clinical Neuroscience, Clinical Sciences Building, School of Medicine, Hucknall Road, Nottingham, NG5 1PB, UK
- Correspondence to: Ulvi Bayraktutan, .
| |
Collapse
|
|
48
|
Vinci MC, Gambini E, Bassetti B, Genovese S, Pompilio G. When Good Guys Turn Bad: Bone Marrow's and Hematopoietic Stem Cells' Role in the Pathobiology of Diabetic Complications. Int J Mol Sci 2020; 21:ijms21113864. [PMID: 32485847 PMCID: PMC7312629 DOI: 10.3390/ijms21113864] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/15/2022] Open
Abstract
Diabetes strongly contributes to the development of cardiovascular disease, the leading cause of mortality and morbidity in these patients. It is widely accepted that hyperglycemia impairs hematopoietic stem/progenitor cell (HSPC) mobilization from the bone marrow (BM) by inducing stem cell niche dysfunction. Moreover, a recent study demonstrated that type 2 diabetic patients are characterized by significant depletion of circulating provascular progenitor cells and increased frequency of inflammatory cells. This unbalance, potentially responsible for the reduction of intrinsic vascular homeostatic capacity and for the establishment of a low-grade inflammatory status, suggests that bone BM-derived HSPCs are not only victims but also active perpetrators in diabetic complications. In this review, we will discuss the most recent literature on the molecular mechanisms underpinning hyperglycemia-mediated BM dysfunction and differentiation abnormality of HSPCs. Moreover, a section will be dedicated to the new glucose-lowering therapies that by specifically targeting the culprits may prevent or treat diabetic complications.
Collapse
Affiliation(s)
- Maria Cristina Vinci
- Unit of Vascular Biology and Regenerative Medicine, IRCCS Centro Cardiologico Monzino, I-20138- Milan, Italy; (E.G.); (B.B.); (G.P.)
- Correspondence: ; Tel.: +39-02-5800-2028
| | - Elisa Gambini
- Unit of Vascular Biology and Regenerative Medicine, IRCCS Centro Cardiologico Monzino, I-20138- Milan, Italy; (E.G.); (B.B.); (G.P.)
| | - Beatrice Bassetti
- Unit of Vascular Biology and Regenerative Medicine, IRCCS Centro Cardiologico Monzino, I-20138- Milan, Italy; (E.G.); (B.B.); (G.P.)
| | - Stefano Genovese
- Unit of Diabetes, Endocrine and Metabolic Diseases, IRCCS Centro Cardiologico Monzino, I-20138- Milan, Italy;
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, IRCCS Centro Cardiologico Monzino, I-20138- Milan, Italy; (E.G.); (B.B.); (G.P.)
| |
Collapse
|
|
49
|
Tamari T, Kawar-Jaraisy R, Doppelt O, Giladi B, Sabbah N, Zigdon-Giladi H. The Paracrine Role of Endothelial Cells in Bone Formation via CXCR4/SDF-1 Pathway. Cells 2020; 9:cells9061325. [PMID: 32466427 PMCID: PMC7349013 DOI: 10.3390/cells9061325] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 12/15/2022] Open
Abstract
Vascularization is a prerequisite for bone formation. Endothelial progenitor cells (EPCs) stimulate bone formation by creating a vascular network. Moreover, EPCs secrete various bioactive molecules that may regulate bone formation. The aim of this research was to shed light on the pathways of EPCs in bone formation. In a subcutaneous nude mouse ectopic bone model, the transplantation of human EPCs onto β-TCP scaffold increased angiogenesis (p < 0.001) and mineralization (p < 0.01), compared to human neonatal dermal fibroblasts (HNDF group) and a-cellular scaffold transplantation (β-TCP group). Human EPCs were lining blood vessels lumen; however, the majority of the vessels originated from endogenous mouse endothelial cells at a higher level in the EPC group (p < 01). Ectopic mineralization was mostly found in the EPCs group, and can be attributed to the recruitment of endogenous mesenchymal cells ten days after transplantation (p < 0.0001). Stromal derived factor-1 gene was expressed at high levels in EPCs and controlled the migration of mesenchymal and endothelial cells towards EPC conditioned medium in vitro. Blocking SDF-1 receptors on both cells abolished cell migration. In conclusion, EPCs contribute to osteogenesis mainly by the secretion of SDF-1, that stimulates homing of endothelial and mesenchymal cells. This data may be used to accelerate bone formation in the future.
Collapse
Affiliation(s)
- Tal Tamari
- Laboratory for Bone Repair, Rambam Health Care Campus, Haifa 3109601, Israel; (T.T.); (O.D.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (B.G.); (N.S.)
| | - Rawan Kawar-Jaraisy
- The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv 69978, Israel;
| | - Ofri Doppelt
- Laboratory for Bone Repair, Rambam Health Care Campus, Haifa 3109601, Israel; (T.T.); (O.D.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (B.G.); (N.S.)
| | - Ben Giladi
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (B.G.); (N.S.)
| | - Nadin Sabbah
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (B.G.); (N.S.)
| | - Hadar Zigdon-Giladi
- Laboratory for Bone Repair, Rambam Health Care Campus, Haifa 3109601, Israel; (T.T.); (O.D.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3200003, Israel; (B.G.); (N.S.)
- Correspondence: ; Tel.: +972-4-8543606
| |
Collapse
|
|
50
|
Bertelli PM, Pedrini E, Guduric-Fuchs J, Peixoto E, Pathak V, Stitt AW, Medina RJ. Vascular Regeneration for Ischemic Retinopathies: Hope from Cell Therapies. Curr Eye Res 2020; 45:372-384. [PMID: 31609636 DOI: 10.1080/02713683.2019.1681004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 10/11/2019] [Indexed: 12/18/2022]
Abstract
Retinal vascular diseases, such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, ocular ischemic syndrome and ischemic optic neuropathy, are leading causes of vision impairment and blindness. Whilst drug, laser or surgery-based treatments for the late stage complications of many of these diseases are available, interventions that target the early vasodegenerative stages are lacking. Progressive vasculopathy and ensuing ischemia is an underpinning pathology in many of these diseases, leading to hypoperfusion, hypoxia, and ultimately pathological neovascularization and/or edema in the retina and other ocular tissues, such as the optic nerve and iris. Therefore, repairing the retinal vasculature may prevent progression of ischemic retinopathies into late stage vascular complications. Various cell types have been explored for their vascular repair potential. Endothelial progenitor cells, mesenchymal stem cells and induced pluripotent stem cells are studied for their potential to integrate with the damaged retinal vasculature and limit ischemic injury. Clinical trials for some of these cell types have confirmed safety and feasibility in the treatment of ischemic diseases, including some retinopathies. Another promising avenue is mobilization of endogenous endothelial progenitors, whereby reparative cells are moved from their niche to circulating blood to target and home into ischemic tissues. Several aspects and properties of these cell types have yet to be elucidated. Nevertheless, we foresee that cell therapy, whether through delivery of exogenous or enhancement of endogenous reparative cells, will become a valuable and beneficial treatment for ischemic retinopathies.
Collapse
Affiliation(s)
- Pietro Maria Bertelli
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Edoardo Pedrini
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Jasenka Guduric-Fuchs
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Elisa Peixoto
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Varun Pathak
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Alan W Stitt
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Reinhold J Medina
- Centre for Experimental Medicine, School of Medicine, Dentistry, and Biomedical Science, Queen's University Belfast, Belfast, UK
| |
Collapse
|