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Cristallini C, Rossin D, Vanni R, Barbani N, Bulgheresi C, Labardi M, Perveen S, Burchielli S, Terlizzi D, Kusmic C, Del Ry S, Cabiati M, Trouki C, Rossino D, Sergi F, Villano A, Aquaro GD, Scarpellino G, Ruffinatti FA, Amorim S, Pires RA, Reis RL, Rastaldo R, Giachino C. A biodegradable, microstructured, electroconductive and nano-integrated drug eluting patch (MENDEP) for myocardial tissue engineering. Bioact Mater 2025; 50:246-272. [PMID: 40270551 PMCID: PMC12017858 DOI: 10.1016/j.bioactmat.2025.04.008] [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: 12/04/2024] [Revised: 03/24/2025] [Accepted: 04/05/2025] [Indexed: 04/25/2025] Open
Abstract
We produced a microstructured, electroconductive and nano-functionalized drug eluting cardiac patch (MENDEP) designed to attract endogenous precursor cells, favor their differentiation and counteract adverse ventricular remodeling in situ. MENDEP showed mechanical anisotropy and biaxial strength comparable to porcine myocardium, reduced impedance, controlled biodegradability, molecular recognition ability and controlled drug release activity. In vitro, cytocompatibility and cardioinductivity were demonstrated. Migration tests showed the chemoattractive capacity of the patches and conductivity assays showed unaltered cell-cell interactions and cell beating synchronicity. MENDEP was then epicardially implanted in a rat model of ischemia/reperfusion (I/R). Histological, immunofluorescence and biomarker analysis indicated that implantation did not cause damage to the healthy myocardium. After I/R, MENDEP recruited precursor cells into the damaged myocardium and triggered their differentiation towards the vascular lineage. Under the patch, the myocardial tissue appeared well preserved and cardiac gap junctions were correctly distributed at the level of the intercalated discs. The fibrotic area measured in the I/R group was partially reduced in the patch group. Overall, these results demonstrate that MENDEP was fully retained on the epicardial surface of the left ventricle over 4-week implantation period, underwent progressive vascularization, did not perturb the healthy myocardium and showed great potential in repairing the infarcted area.
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Affiliation(s)
- Caterina Cristallini
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
- Department of Civil and Industrial Engineering, DICI, University of Pisa, Largo Lucio Lazzarino, 56126, Pisa, Italy
| | - Daniela Rossin
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
| | - Roberto Vanni
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
| | - Niccoletta Barbani
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
- Department of Civil and Industrial Engineering, DICI, University of Pisa, Largo Lucio Lazzarino, 56126, Pisa, Italy
| | - Chiara Bulgheresi
- Department of Civil and Industrial Engineering, DICI, University of Pisa, Largo Lucio Lazzarino, 56126, Pisa, Italy
| | - Massimiliano Labardi
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
| | - Sadia Perveen
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
| | | | | | - Claudia Kusmic
- Clinical Physiology Institute, CNR-IFC, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
| | - Silvia Del Ry
- Clinical Physiology Institute, CNR-IFC, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
| | - Manuela Cabiati
- Clinical Physiology Institute, CNR-IFC, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
| | - Cheherazade Trouki
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
- Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126, Pisa, Italy
| | - Dawid Rossino
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
- Department of Civil and Industrial Engineering, DICI, University of Pisa, Largo Lucio Lazzarino, 56126, Pisa, Italy
| | - Francesca Sergi
- Department of Civil and Industrial Engineering, DICI, University of Pisa, Largo Lucio Lazzarino, 56126, Pisa, Italy
| | - Anthea Villano
- Institute for Chemical and Physical Processes, CNR-IPCF, Via Giuseppe Moruzzi 1, 56124, Pisa, Italy
| | - Giovanni D. Aquaro
- Academic Radiology Unit, Department of Surgical, Medical and Molecular Pathology and of the Critical Area, University of Pisa, Via Paradisa 2, 56124, Pisa, Italy
| | - Giorgia Scarpellino
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123, Torino, Italy
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Via Adolfo Ferrata 9, 27100, Pavia, Italy
| | - Federico A. Ruffinatti
- Department of Life Sciences and Systems Biology, University of Turin, Via Accademia Albertina 13, 10123, Torino, Italy
| | - Sara Amorim
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Ricardo A. Pires
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Rui L. Reis
- 3B's Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-017, Barco, Guimarães, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães, Portugal
| | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
| | - Claudia Giachino
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043, Orbassano, Italy
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Huang H, Huang G, Li R, Wei L, Yuan Z, Huang W. Exercise Training After Myocardial Infarction Enhances Endothelial Progenitor Cells Function via NRG-1 Signaling. Cardiovasc Toxicol 2025; 25:411-426. [PMID: 39893285 DOI: 10.1007/s12012-025-09967-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 01/24/2025] [Indexed: 02/04/2025]
Abstract
Vascular regeneration after myocardial infarction (MI) is essential to improve myocardial ischemia, delay post-infarction ventricular remodeling, and improve the long-term prognosis of MI. Endothelial progenitor cells (EPCs) play important roles in the functional repair and homeostatic maintenance of the vascular endothelium. Exercise training stimulates EPC mobilization and increases the number of circulating EPCs, which has beneficial effects on the restoration of vascular integrity and hemodynamic reconstitution. After post-MI exercise training, cardiac function, the myocardial infarct area, and capillary density in the peri-infarct zone were measured. Bone marrow-derived EPCs were isolated from mice to measure the proliferation, migration, and in vitro angiogenesis of EPCs after myocardial infarction exercise. The expression of NRG-1/ErbB4 signaling factor and related proteins in downstream PI3K/AKT signaling pathway were detected, and the level of autocrine NRG-1 in EPCs was detected. Post-MI resistance training, aerobic exercise training, and combined exercise training increased EPC mobilization and proliferation, migration, and tube-forming capacity, promoted myocardial vascular regeneration, improved cardiac function, and reduced infarct size. Exercise training upregulated NRG-1 expression in EPCs, and NRG-1/ErbB4 signaling activated the downstream PI3K/Akt signaling pathway. Moreover, EPCs may have a positive feedback autocrine loop with NRG-1 to improve the function of EPCs and promote vascular repair and regeneration in mice with MI. Exercise training after MI promotes the function of bone marrow-derived EPCs through NRG-1/ErbB4/PI3K/AKT signaling, thus exerting a role in angiogenesis.
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Affiliation(s)
- Huai Huang
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Guoqiang Huang
- Department of Cardiology, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, 528400, China
| | - Ruojun Li
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Liqin Wei
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Zhu Yuan
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Weiqiang Huang
- Department of Cardiology & Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention & Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi, China.
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Ferrari F, Tamburro R, Longo M, Brioschi FA, Auletta L, Stefanello D. Effect of cranial tibial artery laceration on radiographic bone healing and perioperative complications in dogs undergoing tibial plateau leveling osteotomy. Res Vet Sci 2024; 175:105322. [PMID: 38851052 DOI: 10.1016/j.rvsc.2024.105322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/30/2024] [Accepted: 06/01/2024] [Indexed: 06/10/2024]
Abstract
During tibial plateau leveling osteotomy (TPLO), the laceration of the cranial tibial artery (LCTA) may occur, and the ligation of the cranial tibial artery might lead to impaired blood supply to the osteotomy site. The present case-control study aimed to evaluate the effect of LCTA on TPLO healing and the occurrence of perioperative complications. The incidence and predisposing factors to LCTA were also investigated. Fourteen cases experiencing LCTA were retrospectively enrolled from medical records of two veterinary teaching hospitals (LCTA group), whereas 28 randomly selected TPLOs that did not experience LCTA were included in the control group. Signalment data, proximal tibial epiphysis conformation, osteotomy features, perioperative complications, and bone healing were compared between the two groups. Bone healing was evaluated using the modified radiographic union scale for tibial fracture and the visual analog scale. The mean incidence was 9.6%. Bodyweight was significantly higher in the LCTA group compared to the control group (P = 0.009). Dogs belonging to the LCTA groups were significantly younger (P = 0.01). Intraoperative hypotension was significantly overreported in the LCTA group (P = 0.0001). None of the other variables differed significantly between the two groups. Dogs' size seems to be a predisposing factor, with dogs weighing >15 kg having 22 times more chance of experiencing LCTA. Due to the well-developed collateral blood supply of the canine hindlimb, LCTA and the closure of the cranial tibial artery did not appear to delay the radiographic bone healing or affect the incidence of perioperative complications.
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Affiliation(s)
- Francesco Ferrari
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milano, via dell'Università 6, 29600 Lodi, Italy.
| | - Roberto Tamburro
- Department of Veterinary Medicine, University of Teramo, Località Piano d'Accio, 64100 Teramo, Italy.
| | - Maurizio Longo
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milano, via dell'Università 6, 29600 Lodi, Italy.
| | - Federica Alessandra Brioschi
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milano, via dell'Università 6, 29600 Lodi, Italy.
| | - Luigi Auletta
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milano, via dell'Università 6, 29600 Lodi, Italy.
| | - Damiano Stefanello
- Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milano, via dell'Università 6, 29600 Lodi, Italy.
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Gold DA, Sandesara PB, Kindya B, Gold ME, Jain V, Vatsa N, Desai SR, Yadalam A, Razavi A, Elhage Hassan M, Ko YA, Liu C, Alkhoder A, Rahbar A, Hossain MS, Waller EK, Jaber WA, Nicholson WJ, Quyyumi AA. Circulating Progenitor Cells and Coronary Collaterals in Chronic Total Occlusion. Int J Cardiol 2024; 407:132104. [PMID: 38677332 PMCID: PMC11559591 DOI: 10.1016/j.ijcard.2024.132104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND The role of circulating progenitor cells (CPC) in collateral formation that occurs in the presence of chronic total occlusions (CTO) of a coronary artery is not well established. In stable patients with a CTO, we investigated whether CPC levels are associated with (a) collateral development and (b) ischemic burden, as measured by circulating high sensitivity troponin-I (hsTn-I) levels. METHODS CPCs were enumerated by flow cytometry as CD45med+ blood mononuclear cells expressing CD34 and both CD34 and CD133 epitopes. The association between CPC counts and both Rentrop collateral grade (0, 1, 2, or 3) and hsTn-I levels were evaluated using multivariate regression analysis, after adjusting for demographic and clinical characteristics. RESULTS In 89 patients (age 65.5, 72% male, 27% Black), a higher CPC count was positively associated with a higher Rentrop collateral grade; [CD34+ adjusted odds ratio (OR) 1.49 95% confidence interval (CI) (0.95, 2.34) P = 0.082] and [CD34+/CD133+ OR 1.57 95% CI (1.05, 2.36) P = 0.028]. Every doubling of CPC counts was also associated with lower hsTn-I levels [CD34+ β -0.35 95% CI (-0.49, -0.15) P = 0.002] and [CD34+/CD133+ β -0.27 95% CI (-0.43, -0.08) P = 0.009] after adjustment. CONCLUSION Individuals with higher CPC counts have greater collateral development and lower ischemic burden in the presence of a CTO.
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Affiliation(s)
- Daniel A Gold
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Pratik B Sandesara
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Bryan Kindya
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Matthew E Gold
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Vardhmaan Jain
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Nishant Vatsa
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Shivang R Desai
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Adithya Yadalam
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Alexander Razavi
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Malika Elhage Hassan
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Yi-An Ko
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Chang Liu
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Ayman Alkhoder
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Alireza Rahbar
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Mohammad S Hossain
- Division of Hematology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Edmund K Waller
- Division of Hematology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Wissam A Jaber
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - William J Nicholson
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Arshed A Quyyumi
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
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Hosoda C, Mitani S, Sakata A, Kasuda S, Onodera Y, Takabayashi Y, Shima M, Tatsumi K. MEK inhibitor PD0325901 upregulates CD34 expression in endothelial cells via inhibition of ERK phosphorylation. Regen Ther 2024; 26:654-662. [PMID: 39281105 PMCID: PMC11401103 DOI: 10.1016/j.reth.2024.08.009] [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: 07/08/2024] [Revised: 08/04/2024] [Accepted: 08/18/2024] [Indexed: 09/18/2024] Open
Abstract
Introduction CD34-positive endothelial progenitor cells (EPCs) promote angiogenesis and are a promising tool for regenerative cell therapy of ischemic diseases. However, the number and quality of CD34-positive cells decrease owing to various external and internal factors; thus, an efficient method is needed to establish CD34-positive EPCs. The generation of functional cells by reprogramming, that is, manipulating cell fate via gene transfer and/or treatment with chemical compounds, has recently been reported. Therefore, we aimed to generate CD34-positive cells by the reprogramming of endothelial cells (ECs). Methods Based on previous reports, seven candidate chemical compounds were selected to reprogram human umbilical vein ECs (HUVECs) to CD34-positive cells. Following stimulation with the chemical compounds, the expression of CD34 was evaluated using quantitative PCR, flow cytometry, and immunocytochemistry. Results HUVECs treated with the compounds exhibited increased CD34 expression. We cultured cells in alternate media lacking one of the seven compounds and found no CD34 expression in cells treated with PD0325901-free media, suggesting that PD0325901-a MEK inhibitor-mainly contributed to the increase in CD34 expression. We found that 98% of cells were CD34-positive after PD0325901 treatment alone for 7 d. Western blotting revealed that the phosphorylation of ERK was suppressed in PD0325901-treated cells. No upregulation of CD34 was observed in fibroblast cell lines, even after PD0325901 treatment. These results suggested that PD0325901 induces CD34-positive cells by inhibiting ERK phosphorylation in ECs. Conclusions CD34 expression was strongly induced in ECs by treatment with the MEK inhibitor PD0325901 in vitro. Our study provides a useful reference for the establishment of CD34-positive EPCs and will contribute to the development of regenerative therapies, especially for ischemic diseases.
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Affiliation(s)
- Chihiro Hosoda
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Seiji Mitani
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Asuka Sakata
- Medicinal Biology of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Shogo Kasuda
- Department of Legal Medicine, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yu Onodera
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yoko Takabayashi
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Midori Shima
- Medicinal Biology of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Kohei Tatsumi
- Advanced Medical Science of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
- Medicinal Biology of Thrombosis and Hemostasis, Nara Medical University, Kashihara, Nara 634-8521, Japan
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Ding H, Hou X, Gao Z, Guo Y, Liao B, Wan J. Challenges and Strategies for Endothelializing Decellularized Small-Diameter Tissue-Engineered Vessel Grafts. Adv Healthc Mater 2024; 13:e2304432. [PMID: 38462702 DOI: 10.1002/adhm.202304432] [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: 12/13/2023] [Revised: 02/26/2024] [Indexed: 03/12/2024]
Abstract
Vascular diseases are the leading cause of ischemic necrosis in tissues and organs, necessitating using vascular grafts to restore blood supply. Currently, small vessels for coronary artery bypass grafts are unavailable in clinical settings. Decellularized small-diameter tissue-engineered vessel grafts (SD-TEVGs) hold significant potential. However, they face challenges, as simple implantation of decellularized SD-TEVGs in animals leads to thrombosis and calcification due to incomplete endothelialization. Consequently, research and development focus has shifted toward enhancing the endothelialization process of decellularized SD-TEVGs. This paper reviews preclinical studies involving decellularized SD-TEVGs, highlighting different strategies and their advantages and disadvantages for achieving rapid endothelialization of these vascular grafts. Methods are analyzed to improve the process while addressing potential shortcomings. This paper aims to contribute to the future commercial viability of decellularized SD-TEVGs.
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Affiliation(s)
- Heng Ding
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Nanjing Medical University, Nanjing, 211166, P. R. China
| | - Xiaojie Hou
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Zhen Gao
- Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100069, China
| | - Yingqiang Guo
- Department of Cardiovascular Surgery and Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
| | - Juyi Wan
- Department of Cardiovascular Surgery, The Affiliated Hospital, Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Key Laboratory of cardiovascular remodeling and dysfunction, Luzhou, Sichuan, 646000, China
- Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases), Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, 646000, China
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Giordano FA, Layer JP, Leonardelli S, Friker LL, Turiello R, Corvino D, Zeyen T, Schaub C, Müller W, Sperk E, Schmeel LC, Sahm K, Oster C, Kebir S, Hambsch P, Pietsch T, Bisdas S, Platten M, Glas M, Seidel C, Herrlinger U, Hölzel M. L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial. Nat Commun 2024; 15:4210. [PMID: 38806504 PMCID: PMC11133480 DOI: 10.1038/s41467-024-48416-9] [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: 09/29/2023] [Accepted: 04/30/2024] [Indexed: 05/30/2024] Open
Abstract
The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.
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Affiliation(s)
- Frank A Giordano
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
| | - Julian P Layer
- Department of Radiation Oncology, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Sonia Leonardelli
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Lea L Friker
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
- Institute of Neuropathology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Roberta Turiello
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Dillon Corvino
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Thomas Zeyen
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Christina Schaub
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Wolf Müller
- Institute of Neuropathology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Elena Sperk
- Department of Radiation Oncology, University Medical Center Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | | | - Katharina Sahm
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Christoph Oster
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sied Kebir
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Peter Hambsch
- Department of Radiation Oncology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Torsten Pietsch
- Institute of Neuropathology, University Hospital Bonn, University of Bonn, Bonn, Germany
| | - Sotirios Bisdas
- Lysholm Department of Neuroradiology, University College London, London, UK
| | - Michael Platten
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
- Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Mannheim, Germany
- DKTK Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center, Heidelberg, Germany
| | - Martin Glas
- Division of Clinical Neurooncology, Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS) and West German Cancer Center, German Cancer Consortium, Partner Site Essen, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Clemens Seidel
- Department of Radiation Oncology, University Hospital Leipzig, University of Leipzig, Leipzig, Germany
| | - Ulrich Herrlinger
- Department of Neurooncology, Center for Neurology, University Hospital Bonn, Bonn, Germany
| | - Michael Hölzel
- Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn, University of Bonn, Bonn, Germany.
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8
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Zhu Y, Cai G, Lin L, Fu H, Zhang C, Zeng L, Tu C, Yang Z. Age-associated declined function of endothelial progenitor cells and its correlation with plasma IL-18 or IL-23 concentrations in patients with ST-segment elevation myocardial infarction. Front Cardiovasc Med 2024; 11:1351567. [PMID: 38854655 PMCID: PMC11157231 DOI: 10.3389/fcvm.2024.1351567] [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: 12/12/2023] [Accepted: 05/03/2024] [Indexed: 06/11/2024] Open
Abstract
BACKGROUND ST-segment elevation myocardial infarction (STEMI) persists to be prevalent in the elderly with a dismal prognosis. The capacity of endothelial progenitor cells (EPCs) is reduced with aging. Nevertheless, the influence of aging on the functionality of EPCs in STEMI is not fully understood. METHOD This study enrolled 20 younger STEMI patients and 21 older STEMI patients. We assessed the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events Risk (GRACE) scores in two groups. Then, we detected EPC migration, proliferation, adhesion, and plasma interleukin (IL)-18 and IL-23 concentrations in two groups. In addition, we analyzed the interconnection between age, EPC function, plasma IL-18 and IL-23 concentrations, and GRACE or TIMI scores in STEMI patients. RESULT GRACE and TIMI scores in older STEMI patients were higher than in younger STEMI patients, whereas EPC function declined. GRACE and TIMI scores were found to have an inverse relationship with the EPC function. In older STEMI patients, plasma concentrations of IL-18 and IL-23 increased. Plasma IL-18 and IL-23 concentrations were adversely connected to EPC capacity and positively related to GRACE and TIMI scores. Moreover, age was positively correlated with plasma IL-18 or IL-23 concentrations, as well as GRACE or TIMI scores. However, age was adversely correlated with EPC function. CONCLUSION In patients with STEMI, aging results in declined EPC function, which may be associated with inflammatory cytokines. The current investigation may offer new perception about mechanism and therapeutic targets of aging STEMI.
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Affiliation(s)
- Yuanting Zhu
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
| | - Guoyi Cai
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
| | - Luyang Lin
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
| | - Hongna Fu
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
| | - Cong Zhang
- Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Department of Gastroenterology, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lijin Zeng
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
| | - Chang Tu
- Department of Cardiology, SSL Central Hospital of Dongguan City, Dongguan, China
| | - Zhen Yang
- Division of Emergency Medicine, Department of Emergency Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation and Vascular Diseases, Sun Yat-sen University, Guangzhou, China
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9
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Brett VE, Dignat George F, James C. Circulating endothelial cells in pathophysiology. Curr Opin Hematol 2024; 31:148-154. [PMID: 38362895 DOI: 10.1097/moh.0000000000000814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
PURPOSE OF REVIEW The purpose of this review is to synthesize recent insights into the roles and importance of circulating endothelial cells (CECs) as indicators of the severity, progression, and prognosis of vascular-related diseases. RECENT FINDINGS Recent studies have identified elevated counts of CECs in pathological conditions, notably inflammatory or cardiovascular diseases such as acute myocardial infarction and heart failure, underscoring their potential as sensitive indicators of disease. Furthermore, the rise in CEC levels in cancer patients, particularly with disease advancement, points to their role in cancer-associated angiogenesis and response to treatment. SUMMARY This review underscores the evolving significance of CECs as markers for evaluating the gravity and advancement of diseases with vascular injury, including cardiovascular diseases, cancer, inflammatory conditions, and thromboembolic events. These last years, efforts made to standardize flow cytometry detection of CEC and the development of highly sensitive techniques to isolate, quantify or phenotype rare cells open promising avenues for clinical application. This may yield extensive knowledge regarding the mechanisms by which endothelial cells contribute to a variety of vascular-related disorders and their clinical value as emerging biomarkers.
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Affiliation(s)
- Victor Emmanuel Brett
- University of Bordeaux, Institut national de la santé et de la recherche médicale, Biologie des maladies cardio-vasculaires, U1034
- Laboratory of Hematology, Bordeaux University Hospital, Pessac
| | - Francoise Dignat George
- Aix Marseille Univ, INSERM, INRAE, C2VN, UFR de Pharmacie
- Hematology and Vascular Biology Department, CHU La Conception, Assistance Publique-Hôpitaux de Marseille, Marseille, France
| | - Chloe James
- University of Bordeaux, Institut national de la santé et de la recherche médicale, Biologie des maladies cardio-vasculaires, U1034
- Laboratory of Hematology, Bordeaux University Hospital, Pessac
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10
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Kwon JY, Maeng YS. Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction). Int J Mol Sci 2024; 25:4444. [PMID: 38674031 PMCID: PMC11050478 DOI: 10.3390/ijms25084444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/12/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare-through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence-the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.
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Affiliation(s)
- Ja-Young Kwon
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
| | - Yong-Sun Maeng
- Department of Obstetrics and Gynecology, Institute of Women’s Life Medical Science, Yonsei University Health System, Seoul 03722, Republic of Korea;
- Department of Obstetrics and Gynecology, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 03722, Republic of Korea
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11
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Ng CY, Cheung C. Origins and functional differences of blood endothelial cells. Semin Cell Dev Biol 2024; 155:23-29. [PMID: 37202277 DOI: 10.1016/j.semcdb.2023.05.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 05/05/2023] [Accepted: 05/05/2023] [Indexed: 05/20/2023]
Abstract
The interests in blood endothelial cells arise from their therapeutic potential in vascular repair and regeneration. Our understanding of blood endothelial cells that exist in the circulation has been evolving significantly from the original concept of endothelial progenitor cells. Many studies have uncovered heterogeneities of blood endothelial subtypes where some cells express both endothelial and hematopoietic antigens, and others possess either mature or immature endothelial markers. Due to the lack of definitive cell marker identities, there have been momentums in the field to adopt a technical-oriented labeling system based on the cells' involvement in postnatal neovascularization and cell culture derivatives. Our review streamlines nomenclatures for blood endothelial subtypes and standardizes understanding of their functional differences. Broadly, we will discuss about myeloid angiogenic cells (MACs), endothelial colony-forming cells (ECFCs), blood outgrowth endothelial cells (BOECs) and circulating endothelial cells (CECs). The strategic location of blood endothelial cells confers them essential roles in supporting physiological processes. MACs exert angiogenic effects through paracrine mechanisms, while ECFCs are recruited to sites of vascular injury to participate directly in new vessel formation. BOECs are an in vitro derivative of ECFCs. CECs are shed into the bloodstream from damaged vessels, hence reflective of endothelial dysfunction. With clarity on the functional attributes of blood endothelial subtypes, we present recent advances in their applications in disease modelling, along with serving as biomarkers of vascular tissue homeostasis.
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Affiliation(s)
- Chun-Yi Ng
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Christine Cheung
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
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12
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Mahara A, Shirai M, Soni R, Le HT, Shimizu K, Hirano Y, Yamaoka T. Vascular tissue reconstruction by monocyte subpopulations on small-diameter acellular grafts via integrin activation. Mater Today Bio 2023; 23:100847. [PMID: 37953756 PMCID: PMC10632538 DOI: 10.1016/j.mtbio.2023.100847] [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: 06/29/2023] [Revised: 10/17/2023] [Accepted: 10/26/2023] [Indexed: 11/14/2023] Open
Abstract
Although the clinical application of cell-free tissue-engineered vascular grafts (TEVGs) has been proposed, vascular tissue regeneration mechanisms have not been fully clarified. Here, we report that monocyte subpopulations reconstruct vascular-like tissues through integrin signaling. An Arg-Glu-Asp-Val peptide-modified acellular long-bypass graft was used as the TEVG, and tissue regeneration in the graft was evaluated using a cardiopulmonary pump system and porcine transplantation model. In 1 day, the luminal surface of the graft was covered with cells that expressed CD163, CD14, and CD16, which represented the monocyte subpopulation, and they exhibited proliferative and migratory abilities. RNA sequencing showed that captured cells had an immune-related phenotype similar to that of monocytes and strongly expressed cell adhesion-related genes. In vitro angiogenesis assay showed that tube formation of the captured cells occurred via integrin signal activation. After medium- and long-term graft transplantation, the captured cells infiltrated the tunica media layer and constructed vascular with a CD31/CD105-positive layer and an αSMA-positive structure after 3 months. This finding, including multiple early-time observations provides clear evidence that blood-circulating monocytes are directly involved in vascular remodeling.
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Affiliation(s)
- Atsushi Mahara
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Kishibe Shimmachi, Suita Osaka, 564-8565, Japan
| | - Manabu Shirai
- Omics Research Center, National Cerebral and Cardiovascular Center Research Institute, Kishibe Shimmachi, Suita Osaka, 564-8565, Japan
| | - Raghav Soni
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Kishibe Shimmachi, Suita Osaka, 564-8565, Japan
| | - Hue Thi Le
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Kishibe Shimmachi, Suita Osaka, 564-8565, Japan
| | - Kaito Shimizu
- Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamatecho, Suita, Osaka, 565-8680, Japan
| | - Yoshiaki Hirano
- Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamatecho, Suita, Osaka, 565-8680, Japan
| | - Tetsuji Yamaoka
- Department of Biomedical Engineering, National Cerebral and Cardiovascular Center Research Institute, Kishibe Shimmachi, Suita Osaka, 564-8565, Japan
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13
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Chen Y, Wan G, Li Z, Liu X, Zhao Y, Zou L, Liu W. Endothelial progenitor cells in pregnancy-related diseases. Clin Sci (Lond) 2023; 137:1699-1719. [PMID: 37986615 PMCID: PMC10665129 DOI: 10.1042/cs20230853] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/09/2023] [Accepted: 10/31/2023] [Indexed: 11/22/2023]
Abstract
Placental neovascularization plays a crucial role in fetomaternal circulation throughout pregnancy and is dysregulated in several pregnancy-related diseases, including preeclampsia, gestational diabetes mellitus, and fetal growth restriction. Endothelial progenitor cells (EPCs) are a heterogeneous population of cells that differentiate into mature endothelial cells, which influence vascular homeostasis, neovascularization, and endothelial repair. Since their discovery in 1997 by Asahara et al., the role of EPCs in vascular biology has garnered a lot of interest. However, although pregnancy-related conditions are associated with changes in the number and function of EPCs, the reported findings are conflicting. This review discusses the discovery, isolation, and classification of EPCs and highlights discrepancies between current studies. Overviews of how various diseases affect the numbers and functions of EPCs, the role of EPCs as biomarkers of pregnancy disorders, and the potential therapeutic applications involving EPCs are also provided.
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Affiliation(s)
- Yangyang Chen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Gui Wan
- Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Zeyun Li
- The First Clinical School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoxia Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yin Zhao
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Li Zou
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weifang Liu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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14
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Jiang H, Wang X, Guo L, Tan X, Gui X, Liao Z, Li Z, Chen X, Wu X. Effect of sunitinib against Echinococcus multilocularis through inhibition of VEGFA-induced angiogenesis. Parasit Vectors 2023; 16:407. [PMID: 37936208 PMCID: PMC10631006 DOI: 10.1186/s13071-023-05999-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 10/04/2023] [Indexed: 11/09/2023] Open
Abstract
BACKGROUND Alveolar echinococcosis (AE) is a lethal zoonosis caused by the fox tapeworm Echinococcus multilocularis. The disease is difficult to treat, and an effective therapeutic drug is urgently needed. Echinococcus multilocularis-associated angiogenesis is required by the parasite for growth and metastasis; however, whether antiangiogenic therapy is effective for treating AE is unclear. METHODS The in vivo efficacy of sunitinib malate (SU11248) was evaluated in mice by secondary infection with E. multilocularis. Enzyme-linked immunosorbent assays (ELISAs) were used to evaluate treatment effects on serum IL-4 and vascular endothelial growth factor A (VEGFA) levels after SU11248 treatment. Gross morphological observations and immunohistochemical staining were used to evaluate the impact of SU11248 on angiogenesis and the expression of pro-angiogenic factors VEGFA and VEGF receptor 2 (VEGFR2) in the metacestode tissues. Furthermore, the anthelmintic effects of SU11248 were tested on E. multilocularis metacestodes in vitro. The effect of SU11248 on the expression of VEGFA, VEGFR2, and phosphorylated VEGFR2 (p-VEGFR2) in liver cells infected with protoscoleces in vitro was detected by western blotting, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). The influence of SU11248 on endothelial progenitor cell (EPC) proliferation and migration was determined using CCK8 and transwell assays. RESULTS In vivo, SU11248 treatment markedly reduced neovascular lesion formation and substantially inhibited E. multilocularis metacestode growth in mice. Further, it exhibited high anti-hydatid activity as efficiently as albendazole (ABZ), and the treatment resulted in reduced protoscolex development. In addition, VEGFA, VEGFR2, and p-VEGFR2 expression was significantly decreased in the metacestode tissues after SU11248 treatment. However, no effect of SU11248 on serum IL-4 levels was observed. In vitro, SU11248 exhibited some anthelmintic effects and damaged the cellular structure in the germinal layer of metacestodes at concentrations below those generally considered acceptable for treatment (0.12-0.5 μM). Western blotting, RT-qPCR, and ELISA showed that in co-cultured systems, only p-VEGFR2 levels tended to decrease with increasing SU11248 concentrations. Furthermore, SU11248 was less toxic to Reuber rat hepatoma (RH) cells and metacestodes than to EPCs, and 0.1 μM SU11248 completely inhibited EPC migration to the supernatants of liver cell and protoscolex co-cultures. CONCLUSIONS SU11248 is a potential candidate drug for the treatment of AE, which predominantly inhibits parasite-induced angiogenesis. Host-targeted anti-angiogenesis treatment strategies constitute a new avenue for the treatment of AE.
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Affiliation(s)
- Huijiao Jiang
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Xiaoyi Wang
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Lijiao Guo
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Xiaowu Tan
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Xianwei Gui
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Zhenyu Liao
- Department of Immunology, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
- Department of Experimental Medicine, Jintang First People's Hospital West China Hospital Sichuan University Jintang Hospital, Chengdu, 610400, Sichuan, China
| | - Zhiwei Li
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China
| | - Xueling Chen
- Department of Immunology, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China.
| | - Xiangwei Wu
- National Health Commission of the People's Republic of China Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832000, Xinjiang, China.
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Kuroda R, Niikura T, Matsumoto T, Fukui T, Oe K, Mifune Y, Minami H, Matsuoka H, Yakushijin K, Miyata Y, Kawamoto S, Kagimura T, Fujita Y, Kawamoto A. Phase III clinical trial of autologous CD34 + cell transplantation to accelerate fracture nonunion repair. BMC Med 2023; 21:386. [PMID: 37798633 PMCID: PMC10557317 DOI: 10.1186/s12916-023-03088-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND We previously demonstrated that CD34 + cell transplantation in animals healed intractable fractures via osteogenesis and vasculogenesis; we also demonstrated the safety and efficacy of this cell therapy in an earlier phase I/II clinical trial conducted on seven patients with fracture nonunion. Herein, we present the results of a phase III clinical trial conducted to confirm the results of the previous phase studies using a larger cohort of patients. METHODS CD34 + cells were mobilized via administration of granulocyte colony-stimulating factor, harvested using leukapheresis, and isolated using magnetic cell sorting. Autologous CD34 + cells were transplanted in 15 patients with tibia nonunion and 10 patients with femur nonunion, who were followed up for 52 weeks post transplantation. The main outcome was a reduction in time to heal the tibia in nonunion patients compared with that in historical control patients. We calculated the required number of patients as 15 based on the results of the phase I/II study. An independent data monitoring committee performed the radiographic assessments. Adverse events and medical device failures were recorded. RESULTS All fractures healed during the study period. The time to radiological fracture healing was 2.8 times shorter in patients with CD34 + cell transplantation than in the historical control group (hazard ratio: 2.81 and 95% confidence interval 1.16-6.85); moreover, no safety concerns were observed. CONCLUSIONS Our findings strongly suggest that autologous CD34 + cell transplantation is a novel treatment option for fracture nonunion. TRIAL REGISTRATION UMIN-CTR, UMIN000022814. Registered on 22 June 2016.
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Affiliation(s)
- Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan.
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Tomoaki Fukui
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Keisuke Oe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Yutaka Mifune
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, 650-0017, Japan
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Chuo-Ku, Kobe, 650-0017, Japan
| | - Hiroshi Matsuoka
- Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Chuo-Ku, Kobe, 650-0017, Japan
| | - Kimikazu Yakushijin
- Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Chuo-Ku, Kobe, 650-0017, Japan
| | - Yoshiharu Miyata
- Division of Medical Oncology/Hematology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, Chuo-Ku, Kobe, 650-0017, Japan
| | - Shinichiro Kawamoto
- Department of Transfusion Medicine and Cell Therapy, Kobe University Hospital, Chuo-Ku, Kobe, 650-0017, Japan
| | - Tatsuo Kagimura
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-Ku, Kobe, 650-0047, Japan
| | - Yasuyuki Fujita
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-Ku, Kobe, 650-0047, Japan
| | - Atsuhiko Kawamoto
- Translational Research Center for Medical Innovation, Foundation for Biomedical Research and Innovation at Kobe, Chuo-Ku, Kobe, 650-0047, Japan
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16
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Zhao ZA, Yan L, Wen J, Satyanarayanan SK, Yu F, Lu J, Liu YU, Su H. Cellular and molecular mechanisms in vascular repair after traumatic brain injury: a narrative review. BURNS & TRAUMA 2023; 11:tkad033. [PMID: 37675267 PMCID: PMC10478165 DOI: 10.1093/burnst/tkad033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Revised: 02/01/2023] [Accepted: 05/26/2023] [Indexed: 09/08/2023]
Abstract
Traumatic brain injury (TBI) disrupts normal brain function and is associated with high morbidity and fatality rates. TBI is characterized as mild, moderate or severe depending on its severity. The damage may be transient and limited to the dura matter, with only subtle changes in cerebral parenchyma, or life-threatening with obvious focal contusions, hematomas and edema. Blood vessels are often injured in TBI. Even in mild TBI, dysfunctional cerebral vascular repair may result in prolonged symptoms and poor outcomes. Various distinct types of cells participate in vascular repair after TBI. A better understanding of the cellular response and function in vascular repair can facilitate the development of new therapeutic strategies. In this review, we analyzed the mechanism of cerebrovascular impairment and the repercussions following various forms of TBI. We then discussed the role of distinct cell types in the repair of meningeal and parenchyma vasculature following TBI, including endothelial cells, endothelial progenitor cells, pericytes, glial cells (astrocytes and microglia), neurons, myeloid cells (macrophages and monocytes) and meningeal lymphatic endothelial cells. Finally, possible treatment techniques targeting these unique cell types for vascular repair after TBI are discussed.
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Affiliation(s)
- Zi-Ai Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
- Department of Neurology, General Hospital of Northern Theater Command, 83# Wen-Hua Road, Shenyang 110840, China
| | - Lingli Yan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Jing Wen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Senthil Kumaran Satyanarayanan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Feng Yu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Jiahong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
| | - Yong U Liu
- Laboratory of Neuroimmunology in Health and Disease Institute, Guangzhou First People’s Hospital School of Medicine, South China University of Technology, Guangzhou Higher Education Mega Center, Panyu District, Guangzhou 511400, China
| | - Huanxing Su
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
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Chen X, Dong N, Xu X, Zhou Y, Shi J, Qiao W, Hong H. Re-endothelialization of Decellularized Scaffolds With Endothelial Progenitor Cell Capturing Aptamer: A New Strategy for Tissue-Engineered Heart Valve. ASAIO J 2023; 69:885-893. [PMID: 37506117 DOI: 10.1097/mat.0000000000001979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2023] Open
Abstract
Tissue-engineered heart valve (TEHV) is a promising alternative to current heart valve substitute. Decellularized porcine aortic heart valves (DAVs) are the most common scaffolds of TEHV. Hard to endothelialization is one of the disadvantages of DAVs. Therefore, we aimed to immobilize endothelial progenitor cell (EPC)-aptamer onto DAVs for accelerating endothelialization. In this study, three groups of scaffolds were constructed: DAVs, aptamer-immobilized DAVs (aptamer-DAVs), and glutaraldehyde crosslinked DAVs (GA-DAVs). The results of flow cytometry revealed that EPC-aptamer was specific to EPCs and was immobilized onto DAVs. Cells adhesion experiments demonstrated that EPCs adhered more tightly onto aptamer-DAVs group than other two groups of scaffolds. And cell proliferation assay indicated that EPCs seeded onto aptamer-DAVs group grew faster than DAVs group and GA-DAVs group. Moreover, dynamic capture experiment in flow conditions revealed that the number of EPCs captured by aptamer-DAVs group was more than other two groups. In conclusion, aptamer-DAVs could specifically promote adhesion and proliferation of EPCs and had ability to capture EPCs in simulated flow condition. This could promote re-endothelialization of scaffolds.
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Affiliation(s)
- Xue Chen
- From the Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Arango-Rodríguez ML, Mateus LC, Sossa CL, Becerra-Bayona SM, Solarte-David VA, Ochoa Vera ME, Viviescas LTG, Berrio AMV, Serrano SE, Vargas O, Isla AC, Benitez A, Rangel G. A novel therapeutic management for diabetes patients with chronic limb-threatening ischemia: comparison of autologous bone marrow mononuclear cells versus allogenic Wharton jelly-derived mesenchymal stem cells. Stem Cell Res Ther 2023; 14:221. [PMID: 37626416 PMCID: PMC10464344 DOI: 10.1186/s13287-023-03427-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Chronic limb-threatening ischemia (CLTI) represents the final stage of peripheral arterial disease. Approximately one-third of patients with CLTI are not eligible for conventional surgical treatments. Furthermore, patients with advanced stage of CLTI are prone to amputation and death. Thus, an effective therapeutic strategy is urgently needed. In this context, autologous bone marrow mononuclear cell (auto-BM-MNC) and allogeneic mesenchymal stem cells represent a promising therapeutic approach for treating CLTI. In this study, we compared the safety and beneficial therapeutic effect of auto-BM-MNC versus allogeneic Wharton jelly-derived mesenchymal stem cells (allo-WJ-MSCs) in diabetic patients with CLTI. METHODS We performed a randomized, prospective, double-blind and controlled pilot study. Twenty-four diabetic patients in the advanced stage of CLTI (4 or 5 in Rutherford's classification) and a transcutaneous oxygen pressure (TcPO2) below 30 mmHg were randomized to receive 15 injections of (i) auto-BM-MNC (7.197 × 106 ± 2.984 × 106 cells/mL) (n = 7), (ii) allo-WJ-MSCs (1.333 × 106 cells/mL) (n = 7) or (iii) placebo solution (1 mL) (n = 10), which were administered into the periadventitial layer of the arterial walls under eco-Doppler guidance. The follow-up visits were at months 1, 3, 6, and 12 to evaluate the following parameters: (i) Rutherford's classification, (ii) TcPO2, (iii) percentage of wound closure, (iv) pain, (v) pain-free walking distance, (vi) revascularization and limb-survival proportion, and (vii) life quality (EQ-5D questionnaire). RESULTS No adverse events were reported. Patients with CLTI who received auto-BM-MNC and allo-WJ-MSCs presented an improvement in Rutherford's classification, a significant increase in TcPO2 values, a reduction in the lesion size in a shorter time, a decrease in the pain score and an increase in the pain-free walking distance, in comparison with the placebo group. In addition, the participants treated with auto-BM-MNC and allo-WJ-MSCs kept their limbs during the follow-up period, unlike the placebo group, which had a marked increase in amputation. CONCLUSIONS Our results showed that patients with CLTI treated with auto-BM-MNC and allo-WJ-MSCs conserved 100% of their limb during 12 months of the follow-up compared to the placebo group, where 60% of participants underwent limb amputation in different times. Furthermore, we observed a faster improvement in the allo-WJ-MSC group, unlike the auto-BM-MNC group. Trial registration This study was retrospectively registered at ClinicalTrials.gov (NCT05631444).
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Affiliation(s)
- Martha L Arango-Rodríguez
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia.
| | - Ligia C Mateus
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Claudia L Sossa
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
- Programa para el Tratamiento y Estudio de Enfermedades Hematológicas y Oncológicas de Santander (PROTEHOS), 681004153, Floridablanca, Colombia
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Silvia M Becerra-Bayona
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Víctor Alfonso Solarte-David
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
- Facultad de Ingeniería, Universidad Autónoma de Bucaramanga - UNAB, 680003, Bucaramanga, Colombia
| | - Miguel Enrique Ochoa Vera
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Lady T Giratá Viviescas
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Ana M Vera Berrio
- Banco Multitejidos y Centro de Terapias Avanzadas, Clínica FOSCAL Internacional, 681004, Floridablanca, Colombia
| | - Sergio Eduardo Serrano
- Facultad de Ciencias de la Salud, Universidad Autónoma de Bucaramanga - UNAB, 681003, Bucaramanga, Colombia
| | - Oliverio Vargas
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Andrés Catalá Isla
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Alape Benitez
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
| | - Germán Rangel
- Fundación Oftalmológica de Santander Carlos Ardila Lulle, 681004, Floridablanca, Colombia
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Ben Fraj S, Naserian S, Lorenzini B, Goulinet S, Mauduit P, Uzan G, Haouas H. Human Umbilical Cord Blood Endothelial Progenitor Cell-Derived Extracellular Vesicles Control Important Endothelial Cell Functions. Int J Mol Sci 2023; 24:9866. [PMID: 37373015 DOI: 10.3390/ijms24129866] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Circulating endothelial progenitor cells (EPCs) play a pivotal role in the repair of diseases in which angiogenesis is required. Although they are a potentially valuable cell therapy tool, their clinical use remains limited due to suboptimal storage conditions and, especially, long-term immune rejection. EPC-derived extracellular vesicles (EPC-EVs) may be an alternative to EPCs given their key role in cell-cell communication and expression of the same parental markers. Here, we investigated the regenerative effects of umbilical cord blood (CB) EPC-EVs on CB-EPCs in vitro. After amplification, EPCs were cultured in a medium containing an EVs-depleted serum (EV-free medium). Then, EVs were isolated from the conditioned medium with tangential flow filtration (TFF). The regenerative effects of EVs on cells were investigated by analyzing cell migration, wound healing, and tube formation. We also analyzed their effects on endothelial cell inflammation and Nitric Oxide (NO) production. We showed that adding different doses of EPC-EVs on EPCs does not alter the basal expression of the endothelial cell markers nor change their proliferative potential and NO production level. Furthermore, we demonstrated that EPC-EVs, when used at a higher dose than the physiological dose, create a mild inflammatory condition that activates EPCs and boosts their regenerative features. Our results reveal for the first time that EPC-EVs, when used at a high dose, enhance EPC regenerative functions without altering their endothelial identity.
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Affiliation(s)
- Sawssen Ben Fraj
- National Institute of Applied Sciences and Technology (INSAT), Carthage University, Tunis 1080, Tunisia
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
- LR18ES40, Inflammation, Environment and Signalization Pathologies, Faculty of Medicine, University of Monastir, Monastir 5000, Tunisia
| | - Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
- CellMedEx, 94100 Saint Maur Des Fossés, France
| | | | - Sylvie Goulinet
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Philippe Mauduit
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, 94800 Villejuif, France
| | - Houda Haouas
- National Institute of Applied Sciences and Technology (INSAT), Carthage University, Tunis 1080, Tunisia
- LR18ES40, Inflammation, Environment and Signalization Pathologies, Faculty of Medicine, University of Monastir, Monastir 5000, Tunisia
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20
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Balikji J, Mackus M, Garssen J, Hoogbergen MM, Verster JC. Immune Fitness, Migraine, and Headache Complaints in Individuals with Self-Reported Impaired Wound Healing. Int J Gen Med 2023; 16:2245-2253. [PMID: 37293517 PMCID: PMC10246567 DOI: 10.2147/ijgm.s413258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Accepted: 04/25/2023] [Indexed: 06/10/2023] Open
Abstract
Background Having chronic wounds and impaired wound healing are associated with psychological distress. The current study aims to evaluate migraine and headache complaints in young adults with self-reported impaired wound healing. Methods A survey was conducted among N=1935 young adults (83.6% women), 18-30 years old, living in the Netherlands. Wound healing status was verified, immune fitness was assessed using a single-item rating scale, and ID Migraine was completed. In addition, several questions were answered on past year's headache experiences (including frequency, quantity, type, location, and severity). Results In both the control group (p < 0.001) and the IWH group (p = 0.002) immune fitness was significantly lower among those that reported headaches compared to those that reported no headaches. Individuals with self-reported impaired wound healing (IWH) scored significantly higher on the ID Migraine scale, and individuals of the IWH group scored significantly more often positive for migraine (ie, an ID Migraine score ≥2). They reported a younger age of onset of experiencing headaches, and significantly more often reported having a beating or pounding headache than the control group. Compared to the control group, the IWH group reported being significantly more limited in their daily activities compared to the control group. Conclusion Headaches and migraines are more frequently reported by individuals with self-reported impaired wound healing, and their reported immune fitness is significantly poorer compared to healthy controls. These headache and migraine complaints significantly limit them in their daily activities.
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Affiliation(s)
- Jessica Balikji
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
| | - Marlou Mackus
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
| | - Johan Garssen
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
- Division of Plastic Surgery, Catharina Ziekenhuis, Eindhoven, 5623 EJ, the Netherlands
| | - Maarten M Hoogbergen
- Global Centre of Excellence Immunology, Nutricia Danone Research, Utrecht, 3584 CT, the Netherlands
| | - Joris C Verster
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, 3584 CG, the Netherlands
- Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, 3122, Australia
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Suda M, Paul KH, Minamino T, Miller JD, Lerman A, Ellison-Hughes GM, Tchkonia T, Kirkland JL. Senescent Cells: A Therapeutic Target in Cardiovascular Diseases. Cells 2023; 12:1296. [PMID: 37174697 PMCID: PMC10177324 DOI: 10.3390/cells12091296] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/27/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Senescent cell accumulation has been observed in age-associated diseases including cardiovascular diseases. Senescent cells lack proliferative capacity and secrete senescence-associated secretory phenotype (SASP) factors that may cause or worsen many cardiovascular diseases. Therapies targeting senescent cells, especially senolytic drugs that selectively induce senescent cell removal, have been shown to delay, prevent, alleviate, or treat multiple age-associated diseases in preclinical models. Some senolytic clinical trials have already been completed or are underway for a number of diseases and geriatric syndromes. Understanding how cellular senescence affects the various cell types in the cardiovascular system, such as endothelial cells, vascular smooth muscle cells, fibroblasts, immune cells, progenitor cells, and cardiomyocytes, is important to facilitate translation of senotherapeutics into clinical interventions. This review highlights: (1) the characteristics of senescent cells and their involvement in cardiovascular diseases, focusing on the aforementioned cardiovascular cell types, (2) evidence about senolytic drugs and other senotherapeutics, and (3) the future path and clinical potential of senotherapeutics for cardiovascular diseases.
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Affiliation(s)
- Masayoshi Suda
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
| | - Karl H. Paul
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
- Department of Physiology and Pharmacology, Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine, 3-1-3 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
- Japan Agency for Medical Research and Development-Core Research for Evolutionary Medical Science and Technology (AMED-CREST), Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Jordan D. Miller
- Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, 200 First St., S.W., Rochester, MN 55905, USA
| | - Amir Lerman
- Department of Cardiovascular Medicine, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - Georgina M. Ellison-Hughes
- Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy’s Campus, King’s College London, London SE1 1UL, UK
- Centre for Stem Cells and Regenerative Medicine, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, Guy’s Campus, King’s College London, London SE1 1UL, UK
| | - Tamar Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
| | - James L. Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
- Division of General Internal Medicine, Department of Medicine, Mayo Clinic, 200 First St., S.W., Rochester, MN 55905, USA
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Bertozzo VDHE, da Silva Costa SM, Ito MT, da Cruz PRS, Souza BB, Rios VM, Viturino MGM, de Castro JNP, Rodrigues TAR, Lanaro C, de Albuquerque DM, Saez RC, Olalla Saad ST, Ozelo MC, Costa FF, de Melo MB. Comparative transcriptome analysis of endothelial progenitor cells of HbSS patients with and without proliferative retinopathy. Exp Biol Med (Maywood) 2023; 248:677-684. [PMID: 37012663 PMCID: PMC10408552 DOI: 10.1177/15353702231157927] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 01/18/2023] [Indexed: 04/05/2023] Open
Abstract
Among sickle cell anemia (SCA) complications, proliferative sickle cell retinopathy (PSCR) is one of the most important, being responsible for visual impairment in 10-20% of affected eyes. The aim of this study was to identify differentially expressed genes (DEGs) present in pathways that may be implicated in the pathophysiology of PSCR from the transcriptome profile analysis of endothelial progenitor cells. RNA-Seq was used to compare gene expression profile of circulating endothelial colony-forming cells (ECFCs) from HbSS patients with and without PSCR. Furthermore, functional enrichment analysis and protein-protein interaction (PPI) networks were performed to gain further insights into biological functions. The differential expression analysis identified 501 DEGs, when comparing the groups with and without PSCR. Furthermore, functional enrichment analysis showed associations of the DEGs in 200 biological processes. Among these, regulation of mitogen-activated protein (MAP) kinase activity, positive regulation of phosphatidylinositol 3-kinase (PI3K), and positive regulation of Signal Transducer and Activator of Transcription (STAT) receptor signaling pathway were observed. These pathways are associated with angiogenesis, cell migration, adhesion, differentiation, and proliferation, important processes involved in PSCR pathophysiology. Moreover, our results showed an over-expression of VEGFC (vascular endothelial growth factor-C) and FLT1 (Fms-Related Receptor Tyrosine Kinase 1) genes, when comparing HbSS patients with and without PSCR. These results may indicate a possible association between VEGFC and FLT1 receptor, which may activate signaling pathways such as PI3K/AKT and MAPK/ERK and contribute to the mechanisms implicated in neovascularization. Thus, our findings contain preliminary results that may guide future studies in the field, since the molecular mechanisms of PSCR are still poorly understood.
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Affiliation(s)
- Victor de Haidar e Bertozzo
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Sueli Matilde da Silva Costa
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Mirta Tomie Ito
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Pedro Rodrigues Sousa da Cruz
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Bruno Batista Souza
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Vinicius Mandolesi Rios
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | | | | | - Thiago Adalton Rosa Rodrigues
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
| | - Carolina Lanaro
- Hematology and Hemotherapy Center, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | | | - Roberta Casagrande Saez
- Hematology and Hemotherapy Center, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | - Sara Teresinha Olalla Saad
- Hematology and Hemotherapy Center, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | - Margareth Castro Ozelo
- Hematology and Hemotherapy Center, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | - Fernando Ferreira Costa
- Hematology and Hemotherapy Center, University of Campinas (UNICAMP), Campinas 13083-970, São Paulo, Brazil
| | - Mônica Barbosa de Melo
- Center for Molecular Biology and Genetic Engineering (CBMEG), University of Campinas (UNICAMP), Campinas 13083-875, São Paulo, Brazil
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Abstract
BACKGROUND Retinal neovascularization is the major cause of vision loss that affects both adults and young children including premature babies. It has been a major pathology in several retinal diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Current treatment modalities such as anti-VEGF therapy, laser are not suitable for every patient and response to these therapies is highly variable. Thus, there is a need to investigate newer therapeutic targets for DR, ROP and AMD, based on a clear understanding of disease pathology and regulatory mechanisms involved. METHOD Appropriate articles published till February 2021 were extracted from PUBMED using keywords like ocular angiogenesis, DR, ROP, AMD, miRNA, mRNA, and cirMiRNA and containvaluable information regarding the involvement of miRNA in causing neovascularization. After compiling the list of miRNA regulating mRNA expression in angiogenesis and neovascularaization, their interactions were studied using online available tool MIENTURNET (http://userver.bio.uniroma1.it/apps/mienturnet/). The pathways involved in these processes were also predicted using the same tool. RESULTS Most of the studies have explored potential targets like HIF1-α, PDGF, TGFβ, FGF, etc., for their involvement in pathological angiogenesis in different retinal diseases. The regulatory role of microRNA (miRNA) has also been explored in various retinal ocular pathologies. This review highlights regulatory mechanism of cellular and circulatory miRNAs and their interactions with the genes involved in retinal neovascularization. The role of long noncoding RNA (ncRNA) in the regulation of genes involved in different pathways is also noteworthy and discussed in this review. CONCLUSION This review highlights the potential regulatory mechanism/pathways involved in retinal neovascularization and its implications in retinal diseases and for identifying new drug targets.
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Affiliation(s)
- Sushma Vishwakarma
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India.,Manipal Academy of Higher Education, Manipal, India
| | - Inderjeet Kaur
- Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad, India
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Wan J, Bao Y, Hou LJ, Li GJ, Du LJ, Ma ZH, Yang GK, Hou Y, Li ZX, Yang Y. lncRNA ANRIL accelerates wound healing in diabetic foot ulcers via modulating HIF1A/VEGFA signaling through interacting with FUS. J Gene Med 2023; 25:e3462. [PMID: 36346049 DOI: 10.1002/jgm.3462] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/06/2022] [Accepted: 10/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Diabetic foot ulcer (DFU) is a frequently diagnosed complication of diabetes, and remains a heathcare burden worldwide. However, the pathogenesis of DFU is still largely unclear. The objective of this study is to delineate the function and underlying mechanism of lncRNA antisense non coding RNA in the INK4 locus (ANRIL) in endothelial progenitor cells (EPCs) and DFU mice. METHODS The DFU mouse model was established, and EPCs were subjected to high glucose (HG) treatment to mimic diabetes. qRT-PCR or western blot was employed to detected the expression of ANRIL, HIF1A, FUS and VEGFA. CCK-8 and Annexin V/PI staining were used to monitor cell proliferation and apoptosis. Wound healing, Transwell invasion and tube formation assays were conducted to assess cell migration, invasion and angiogenesis, respectively. The association between ANRIL and FUS was verified by RNA pull-down and RIP assays. Luciferase and ChIP assays were employed to investigate HIF1A-mediated transcriptional regulation of VEGFA and ANRIL. The histological alterations of DFU wound healing were observed by H&E and Masson staining. RESULTS ANRIL was downregulated in peripheral blood samples of DFU patients, DFU mice and HG-treated EPCs. Mechanistically, ANRIL regulated HIFA mRNA stability via recruiting FUS. VEGFA and ANRIL were transcriptionally regulated by HIF1A. Functional experiments revealed that HG suppressed EPC proliferation, migration, invasion and tube formation, but promoted apoptosis via ANRIL/HIF1A axis. ANRIL accelerated DFU wound healing via modulating HIF1A expression in vivo. CONCLUSION ANRIL accelerated wound healing in DFU via modulating HIF1A/VEGFA signaling in a FUS-dependent manner.
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Affiliation(s)
- Jia Wan
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Yan Bao
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Li-Juan Hou
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Guo-Jian Li
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Ling-Juan Du
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Zhen-Huan Ma
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Guo-Kai Yang
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Yi Hou
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Zhao-Xiang Li
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
| | - Yong Yang
- Department of Vascular Surgery, The Affiliated Hospital of Yunnan University, Kunming, Yunnan Province, P.R. China
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Salyers ZR, Coleman M, Le D, Ryan TE. AAV-mediated expression of PFKFB3 in myofibers, but not endothelial cells, improves ischemic muscle function in mice with critical limb ischemia. Am J Physiol Heart Circ Physiol 2022; 323:H424-H436. [PMID: 35867710 PMCID: PMC11834898 DOI: 10.1152/ajpheart.00121.2022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 01/18/2023]
Abstract
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a powerful driver of angiogenesis through its modulation of glycolytic metabolism within endothelial cells. Recent work has demonstrated that PFKFB3 modulates the response to muscle ischemia, however the cell specificity of these effects is not fully understood. In this study, we tested the impact of viral mediated expression of PFKFB3, driven by gene promoters specific for myofibers or endothelial cells, on ischemic hindlimb revascularization and muscle function. We hypothesized that both endothelium- and muscle-specific expression of PFKFB3 would attenuate limb pathology following femoral artery ligation. Male and female BALB/cJ mice were injected with adeno-associated virus encoding the either a green fluorescent protein (GFP) or PFKFB3 driven by either the human skeletal actin (ACTA1) or cadherin-5 (Cdh5) promoters. Four weeks after AAV treatment, mice were subjected to unilateral femoral artery ligation and limb perfusion and muscle function were assessed. Both endothelium- and muscle-specific PFKFB3 expression resulted in significantly more perfused capillaries within the ischemic limb muscle, but neither changed myofiber size/area. Muscle-specific, but not endothelium-specific, PFKFB3 expression significantly improved maximal force production in ischemic muscle (P = 0.0005). Notably, there was a significant effect of sex on maximal force levels in both cohorts of mice (P = 0.0075 and P = 0.0481), indicating that female mice had higher ischemic muscle strength compared with male mice, regardless of treatment group. Taken together, these data demonstrate that although both muscle- and endothelium-specific expression of PFKFB3 enhanced ischemic revascularization, only muscle-specific PFKFB3 expression improved muscle function.NEW & NOTEWORTHY Critical limb ischemia (CLI) carries a significant risk for limb amputation, and treatment options remain limited. We tested the impact of expression of PFKFB3 in myofibers or endothelial cells on limb pathology in mice with CLI. Although both muscle and endothelium-specific PFKFB3 expression increased perfused capillary density, only muscle-specific PFKFB3 expression improve contractile function. Regardless of treatment, female mice demonstrated better recovery from limb ischemic compared with male mice.
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Affiliation(s)
- Zachary R. Salyers
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL
| | - Madeline Coleman
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL
| | - Dennis Le
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL
| | - Terence E. Ryan
- Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL
- Center for Exercise Science, University of Florida, Gainesville, FL
- Myology Institute, University of Florida, Gainesville, FL
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Bauer CJ, Findlay M, Koliamitra C, Zimmer P, Schick V, Ludwig S, Gurtner GC, Riedel B, Schier R. Preoperative exercise induces endothelial progenitor cell mobilisation in patients undergoing major surgery – A prospective randomised controlled clinical proof-of-concept trial. Heliyon 2022; 8:e10705. [PMID: 36200018 PMCID: PMC9529507 DOI: 10.1016/j.heliyon.2022.e10705] [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: 12/29/2021] [Revised: 05/10/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
Introduction Prehabilitation is increasingly recognised as a therapeutic option to reduce postoperative complications. Investigating the beneficial effects of exercise on cellular mechanisms, we have previously shown that a single episode of exhaustive exercise effectively stimulates endothelial progenitor cells (a cell population associated with vascular maintenance, repair, angiogenesis, and neovascularization) in correlation with fewer postoperative complications, despite the ongoing debate about the appropriate cell surface marker profiles of these cells (common phenotypical definitions include CD45dim, CD133+, CD34+ and/or CD31+). In order to translate these findings into clinical application, a feasible prehabilitation programme achieving both functional and cellular benefits in a suitable timeframe to expedite surgery is necessary. Objective The objective of this study was to test the hypothesis that a four-week prehabilitation programme of vigorous-intensity interval exercise training is feasible, increases physical capacity (primary outcome) and the circulatory number of endothelial progenitor cells within peripheral blood. Methods In this unblinded, parallel-group, randomised controlled proof-of-concept clinical trial (German Clinical Trial Register number: DRKS00000527) conducted between 01st December 2014 and 30th November 2016, fifteen female adult patients scheduled for incontinence surgery with abdominal laparotomy at the University Hospital Cologne were allocated to either an exercise (n = 8, exclusion of 1 patient, analysed n = 7) or non-exercise group (n = 7, exclusion of 1 patient, analysed n = 6). The exercise group's intervention consisted of a vigorous-intensity interval training for four weeks preoperatively. Cardiopulmonary Exercise Testing accompanied by peripheral blood collection was performed before and after the (non-)training phase. Cellular investigations were conducted by flow cytometry and cluster-based analyses. Results Vigorous-intensity interval training over four weeks was feasible in the exercise group (successful completion by 8 out of 8 patients without any harms), with significant improvements in patients' functional capacity (increased oxygen uptake at anaerobic threshold [intervention group mean + 1.71 ± 3.20 mL/min/kg vs. control group mean −1.83 ± 2.14 mL/min/kg; p = 0.042] and peak exercise [intervention group mean + 1.71 ± 1.60 mL/min/kg vs. control group mean −1.67 ± 1.37 mL/min/kg; p = 0.002]) and a significant increase in the circulatory number of endothelial progenitor cells (proportionate CD45dim/CD14dim/CD133+/CD309+/CD34+/CD31 + subpopulation within the circulating CD45-pool [p = 0.016]). Conclusions We introduce a novel prehabilitation concept that shows effective stimulation of an endothelial progenitor cell subpopulation within four weeks of preoperative exercise, serving as a clinical cell-mediated intervention with the aim to reduce surgical complications. Funding Institutional funding. DFG (German Research Foundation, 491454339) support for the Article Processing Charge.
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Affiliation(s)
- Claus Juergen Bauer
- Department of Internal Medicine—Oncology, Hematology and Rheumatology, University Hospital Bonn, Bonn, Germany
| | - Michael Findlay
- Department of Surgery, Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Christina Koliamitra
- Institute for Cardiovascular Research and Sports Medicine, German Sports University Cologne, Cologne, Germany
| | - Philipp Zimmer
- Institute of Sports and Sports Medicine, TU Dortmund University, Dortmund, Germany
| | - Volker Schick
- Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Sebastian Ludwig
- Department of Obstetrics and Gynaecology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Geoffrey C. Gurtner
- Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, USA
| | - Bernhard Riedel
- Department of Anaesthetics, Perioperative Medicine and Pain Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Robert Schier
- Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Corresponding author.
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Hypoxia Promotes Angiogenic Effect in Extracranial Arteriovenous Malformation Endothelial Cells. Int J Mol Sci 2022; 23:ijms23169109. [PMID: 36012380 PMCID: PMC9408925 DOI: 10.3390/ijms23169109] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/04/2022] [Accepted: 08/12/2022] [Indexed: 11/17/2022] Open
Abstract
Arteriovenous malformation (AVM) is characterized by high-flow blood vessels connecting arteries and veins without capillaries. This disease shows increased angiogenesis and a pathophysiological hypoxic environment in proximal tissues. Here, we analyzed the effects of hypoxia on angiogenesis in the endothelial cells (ECs) of AVM and normal tissues. ECs from human normal and AVM tissues were evaluated using immunocytochemistry with CD31. In vitro tube formation under hypoxia was tested in both ECs using Matrigel. The relative expression of angiogenesis-related genes was measured using real-time PCR. Under normoxia, CD31 was significantly higher in AVM ECs (79.23 ± 0.65%) than in normal ECs (74.15 ± 0.70%). Similar results were observed under hypoxia in AVM ECs (63.85 ± 1.84%) and normal ECs (60.52 ± 0.51%). In the tube formation test under normoxic and hypoxic conditions, the junction count and total vessel length were significantly greater in AVM ECs than normal ECs. Under both normoxia and hypoxia, the angiogenesis-related gene FSTL1 showed a significantly higher expression in AVM ECs than in normal ECs. Under hypoxia, CSPG4 expression was significantly lower in AVM ECs than in normal ECs. Accordingly, the angiogenic effect was increased in AVM ECs compared with that in normal ECs. These results provide a basic knowledge for an AVM treatment strategy.
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Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD). Int J Mol Sci 2022; 23:ijms23168969. [PMID: 36012229 PMCID: PMC9409296 DOI: 10.3390/ijms23168969] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 11/17/2022] Open
Abstract
Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.
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El Hage R, Knippschild U, Arnold T, Hinterseher I. Stem Cell-Based Therapy: A Promising Treatment for Diabetic Foot Ulcer. Biomedicines 2022; 10:1507. [PMID: 35884812 PMCID: PMC9312797 DOI: 10.3390/biomedicines10071507] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/17/2022] [Accepted: 06/21/2022] [Indexed: 11/16/2022] Open
Abstract
Diabetic foot ulcer (DFU) is a severe complication of diabetes and a challenging medical condition. Conventional treatments for DFU have not been effective enough to reduce the amputation rates, which urges the need for additional treatment. Stem cell-based therapy for DFU has been investigated over the past years. Its therapeutic effect is through promoting angiogenesis, secreting paracrine factors, stimulating vascular differentiation, suppressing inflammation, improving collagen deposition, and immunomodulation. It is controversial which type and origin of stem cells, and which administration route would be the most optimal for therapy. We reviewed the different types and origins of stem cells and routes of administration used for the treatment of DFU in clinical and preclinical studies. Diabetes leads to the impairment of the stem cells in the diseased patients, which makes it less ideal to use autologous stem cells, and requires looking for a matching donor. Moreover, angioplasty could be complementary to stem cell therapy, and scaffolds have a positive impact on the healing process of DFU by stem cell-based therapy. In short, stem cell-based therapy is promising in the field of regenerative medicine, but more studies are still needed to determine the ideal type of stem cells required in therapy, their safety, proper dosing, and optimal administration route.
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Affiliation(s)
- Racha El Hage
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, Fehrbelliner Str. 38, 16816 Neuruppin, Germany;
| | - Uwe Knippschild
- Department of General and Visceral Surgery, Surgery Center, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (U.K.); (T.A.)
| | - Tobias Arnold
- Department of General and Visceral Surgery, Surgery Center, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; (U.K.); (T.A.)
| | - Irene Hinterseher
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, Fehrbelliner Str. 38, 16816 Neuruppin, Germany;
- Berlin Institute of Health, Vascular Surgery Clinic, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane und der Brandenburgischen Technischen Universität Cottbus—Senftenberg, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
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Canjuga D, Steinle H, Mayer J, Uhde AK, Klein G, Wendel HP, Schlensak C, Avci-Adali M. Homing of mRNA-Modified Endothelial Progenitor Cells to Inflamed Endothelium. Pharmaceutics 2022; 14:pharmaceutics14061194. [PMID: 35745767 PMCID: PMC9229815 DOI: 10.3390/pharmaceutics14061194] [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: 04/30/2022] [Revised: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 01/25/2023] Open
Abstract
Endothelial progenitor cells (EPCs) are one of the most important stem cells for the neovascularization of tissues damaged by ischemic diseases such as myocardial infarction, ischemic stroke, or critical limb ischemia. However, their low homing efficiency in the treatment of ischemic tissues limits their potential clinical applications. The use of synthetic messenger RNA (mRNA) for cell engineering represents a novel and promising technology for the modulation of cell behavior and tissue regeneration. To improve the therapeutic potential of EPCs, in this study, murine EPCs were engineered with synthetic mRNAs encoding C-X-C chemokine receptor 4 (CXCR4) and P-selectin glycoprotein ligand 1 (PSGL-1) to increase the homing and migration efficiency of EPCs to inflamed endothelium. Flow cytometric measurements revealed that the transfection of EPCs with CXCR4 and PSGL-1 mRNA resulted in increased expressions of CXCR4 and PSGL-1 on the cell surface compared with the unmodified EPCs. The transfection of EPCs with mRNAs did not affect cell viability. CXCR4-mRNA-modified EPCs showed significantly higher migration potential than unmodified cells in a chemotactic migration assay. The binding strength of the EPCs to inflamed endothelium was determined with single-cell atomic force microscopy (AFM). This showed that the mRNA-modified EPCs required a three-fold higher detachment force to be released from the TNF-α-activated endothelium than unmodified EPCs. Furthermore, in a dynamic flow model, significantly increased binding of the mRNA-modified EPCs to inflamed endothelium was detected. This study showed that the engineering of EPCs with homing factors encoding synthetic mRNAs increases the homing and migration potentials of these stem cells to inflamed endothelium. Thus, this strategy represents a promising strategy to increase the therapeutic potential of EPCs for the treatment of ischemic tissues.
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Affiliation(s)
- Denis Canjuga
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Heidrun Steinle
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Jana Mayer
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Ann-Kristin Uhde
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Gerd Klein
- Center for Medical Research, Department of Medicine II, University of Tuebingen, Waldhörnlestraße 22, 72072 Tuebingen, Germany;
| | - Hans Peter Wendel
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Christian Schlensak
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
| | - Meltem Avci-Adali
- Department of Thoracic and Cardiovascular Surgery, University Hospital Tuebingen, Calwerstraße 7/1, 72076 Tuebingen, Germany; (D.C.); (H.S.); (J.M.); (A.-K.U.); (H.P.W.); (C.S.)
- Correspondence: ; Tel.: +49-7071-29-86605; Fax: +49-7071-29-3617
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Heinisch PP, Bello C, Emmert MY, Carrel T, Dreßen M, Hörer J, Winkler B, Luedi MM. Endothelial Progenitor Cells as Biomarkers of Cardiovascular Pathologies: A Narrative Review. Cells 2022; 11:cells11101678. [PMID: 35626716 PMCID: PMC9139418 DOI: 10.3390/cells11101678] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/11/2022] [Accepted: 05/13/2022] [Indexed: 01/25/2023] Open
Abstract
Endothelial progenitor cells (EPC) may influence the integrity and stability of the vascular endothelium. The association of an altered total EPC number and function with cardiovascular diseases (CVD) and risk factors (CVF) was discussed; however, their role and applicability as biomarkers for clinical purposes have not yet been defined. Endothelial dysfunction is one of the key mechanisms in CVD. The assessment of endothelial dysfunction in vivo remains a major challenge, especially for a clinical evaluation of the need for therapeutic interventions or for primary prevention of CVD. One of the main challenges is the heterogeneity of this particular cell population. Endothelial cells (EC) can become senescent, and the majority of circulating endothelial cells (CEC) show evidence of apoptosis or necrosis. There are a few viable CECs that have properties similar to those of an endothelial progenitor cell. To use EPC levels as a biomarker for vascular function and cumulative cardiovascular risk, a correct definition of their phenotype, as well as an update on the clinical application and practicability of current isolation methods, are an urgent priority.
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Affiliation(s)
- Paul Philipp Heinisch
- Department of Congenital and Pediatric Heart Surgery, German Heart Center Munich, School of Medicine, Technical University of Munich, 80636 Munich, Germany;
- Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig-Maximilians-Universität, 80636 Munich, Germany
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (C.B.); (M.M.L.)
- Correspondence:
| | - Corina Bello
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (C.B.); (M.M.L.)
| | - Maximilian Y. Emmert
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, 13353 Berlin, Germany;
- Institute of Regenerative Medicine (IREM), University of Zurich, 8952 Schlieren, Switzerland
- Department of Cardiovascular Surgery, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Thierry Carrel
- Department of Cardiac Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Martina Dreßen
- Department of Cardiovascular Surgery, Institute Insure, German Heart Center Munich, School of Medicine & Health, Technical University of Munich, Lazarettstrasse 36, 80636 Munich, Germany;
| | - Jürgen Hörer
- Department of Congenital and Pediatric Heart Surgery, German Heart Center Munich, School of Medicine, Technical University of Munich, 80636 Munich, Germany;
- Division of Congenital and Pediatric Heart Surgery, University Hospital of Munich, Ludwig-Maximilians-Universität, 80636 Munich, Germany
| | - Bernhard Winkler
- Department of Cardiovascular Surgery, Hospital Hietzing, 1130 Vienna, Austria;
| | - Markus M. Luedi
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland; (C.B.); (M.M.L.)
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Bao XY, Fan YN, Wang QN, Wang XP, Yang RM, Zou ZX, Zhang Q, Li DS, Duan L, Yu XG. The Potential Mechanism Behind Native and Therapeutic Collaterals in Moyamoya. Front Neurol 2022; 13:861184. [PMID: 35557620 PMCID: PMC9086844 DOI: 10.3389/fneur.2022.861184] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Background and Purpose To explore the genetic basis and molecular mechanism of native arteriogenesis and therapeutic synangiosis in moyamoya disease (MMD). Methods An angiography-based study using patients from a prospective trial of encephaloduroarteriosynangiosis (EDAS) surgery was performed. The spontaneous collaterals grades were evaluated according to the system described by a new grading system. Blood samples were collected from all the recruited patients before EDAS and during the second hospitalization 3 months post-EDAS. We performed Boolean analysis using a combination of specific cell surface markers of CD34briCD133+CD45dimKDR+. Genotyping of p.R4810K was also performed. The correlation of age, sex, initial symptoms at diagnosis, collateral grade, Suzuki stages, the RNF213 genotype, time to peak (TTP), and endothelial progenitor cell (EPC) count with good collateral circulation was evaluated. Results Eighty-five patients with MMD were included in this study. The mutation rate of RNF213 p.R4810K in our study was 25.9% (22/85). The heterozygous mutations were occurred significantly more frequently in the cases that were presented with infarction, worse neurological status, severe posterior cerebral artery (PCA) stenosis, and longer TTP delay. Further, the heterozygous mutations occurred significantly more frequently in the poor collateral stage group. Lower grades were significantly correlated with severe ischemia symptoms, worse neurological status, and a longer TTP delay. The post-operative angiographic findings showed that a good Matsushima grade was correlated with heterozygous mutations, a lower collateral stage, and a longer TTP delay. The CD34briCD133+CD45dimKDR+ cell count in patients 3 months post-EDAS was significantly higher as compared to the count before EDAS in the good Matsushima grade group. However, this change was not observed in the poor Matsushima grade group. Conclusions These data imply that mutations of RNF213 p.R4810K affect the establishment of spontaneous collateral circulation, and EPCs are involved in the process of formation of new EDAS collaterals.
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Affiliation(s)
- Xiang-Yang Bao
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
| | - Yan-Na Fan
- Department of Radiation Oncology, The Fifth Medical Center of Chinese PLA General Hospital (Former 307th Hospital of the PLA), Beijing, China
| | - Qian-Nan Wang
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Xiao-Peng Wang
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Ri-Miao Yang
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Zheng-Xing Zou
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Qian Zhang
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - De-Sheng Li
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Lian Duan
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
- *Correspondence: Lian Duan
| | - Xin-Guang Yu
- Department of Neurosurgery, Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
- Chinese PLA Medical School, Beijing, China
- Xin-Guang Yu
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MicroRNA-132-3p, Downregulated in Myeloid Angiogenic Cells from Hereditary Hemorrhagic Telangiectasia Patients, Is Enriched in the TGFβ and PI3K/AKT Signalling Pathways. Genes (Basel) 2022; 13:genes13040665. [PMID: 35456471 PMCID: PMC9027908 DOI: 10.3390/genes13040665] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/07/2022] [Accepted: 04/07/2022] [Indexed: 02/04/2023] Open
Abstract
Background. Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant genetic disorder characterized by life-threatening vascular dysplasia. Myeloid angiogenic cells (MACs), alternatively called early endothelial progenitor cells or circulating angiogenic cells, do not directly incorporate into developing blood vessels, but augment angiogenesis in a paracrine manner. MAC dysfunction has been reported in HHT. MicroRNAs (miRNAs) regulate cellular function by modulating gene expression post-transcriptionally. To date, the role of miRNAs in HHT MAC dysfunction has not been documented. Objective. The goal of this study was to comparatively profile miRNAs in HHT patient and control MACs to identify dysregulated miRNAs that may be responsible for the observed MAC dysfunction in HHT. Methodology/Results. Twenty-three dysregulated miRNAs (twenty-one upregulated and two downregulated) in HHT MACs were identified with a TaqMan miRNA microarray. Pathway enrichment analysis showed that the dysregulated miRNAs were significantly enriched in pathways involved in HHT pathogenesis, such as the transforming growth factor β (TGFβ), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and Hippo signalling pathways. Furthermore, miR-132-3p was determined to be significantly reduced in HHT MACs compared with controls by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis revealed that miR-132-3p is significantly enriched in the TGFβ and PI3K/AKT signalling pathways, targeting SMAD4, an effector of the TGFβ signalling pathway and RASA1, a negative regulator of the PI3K/AKT signalling pathway, respectively. Conclusion. MiRNA dysregulation, specifically reduced expression of miR-132-3p, in HHT MACs was identified. The dysregulated miRNAs are significantly enriched in the TGFβ, PI3K/AKT, and Hippo signalling pathways. These data suggest that alteration in miRNA expression may impair these pathways and contribute to MAC dysfunction in HHT.
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Albiero M, D'Anna M, Bonora BM, Zuccolotto G, Rosato A, Giorgio M, Iori E, Avogaro A, Fadini GP. Hematopoietic and Nonhematopoietic p66Shc Differentially Regulates Stem Cell Traffic and Vascular Response to Ischemia in Diabetes. Antioxid Redox Signal 2022; 36:593-607. [PMID: 34538132 DOI: 10.1089/ars.2021.0097] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Aims: Peripheral artery disease (PAD) is a severe complication of diabetes, characterized by defective traffic of hematopoietic stem/progenitor cells (HSPCs). We examined the hematopoietic versus nonhematopoietic role of p66Shc in regulating HSPC traffic and blood flow recovery after ischemia in diabetic mice. Results: Using streptozotocin-induced diabetes, chimeric mice with green fluorescent protein (GFP)+ bone marrow (BM), and the hind limb ischemia model, we found that the physiologic mobilization and homing of HSPCs were abolished by diabetes, along with impaired vascular recovery. Hematopoietic deletion of p66Shc, obtained by transplanting p66Shc-/- BM cells into wild-type (Wt) recipients, but not nonhematopoietic deletion, constrained hyperglycemia-induced myelopoiesis, rescued postischemic HSPC mobilization, and improved blood flow recovery in diabetic mice. In Wt diabetic mice transplanted with BM cells from GFP+p66Shc-/- mice, the amount of HSPCs homed to ischemic muscles was greater than in mice transplanted with GFP+p66Shc+/+ cells, with recruited cells displaying higher expression of adhesion molecules and Vegf. In 40 patients with diabetes, p66Shc gene expression in mononuclear cells was correlated with myelopoiesis and elevated in the presence of PAD. In 13 patients with diabetes and PAD, p66Shc expression in HSPC-mobilized peripheral blood cells was inversely correlated with VEGF expression. Innovation: For the first time, we dissect the role of hematopoietic versus nonhematopoietic p66Shc in regulating HSPC traffic and ischemic responses. Conclusion: Hematopoietic deletion of p66Shc was sufficient to rescue HSPC mobilization and homing in diabetes after ischemia and improved blood flow recovery. Inhibiting p66Shc in blood cells may be a novel strategy to counter PAD in diabetes. Antioxid. Redox Signal. 36, 593-607. Clinical Trial No.: NCT02790957.
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Affiliation(s)
- Mattia Albiero
- Department of Medicine, University of Padova, Padova, Italy.,Veneto Institute of Molecular Medicine, Padova, Italy
| | - Marianna D'Anna
- Department of Medicine, University of Padova, Padova, Italy.,Veneto Institute of Molecular Medicine, Padova, Italy
| | - Benedetta Maria Bonora
- Department of Medicine, University of Padova, Padova, Italy.,Veneto Institute of Molecular Medicine, Padova, Italy
| | - Gaia Zuccolotto
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Antonio Rosato
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.,Veneto Institute of Oncology - IOV IRCCS, Padua, Italy
| | - Marco Giorgio
- European Institute of Oncology (IEO), Milan, Italy.,Department of Biomedical Sciences, University of Padova, Padova, Italy
| | | | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
| | - Gian Paolo Fadini
- Department of Medicine, University of Padova, Padova, Italy.,Veneto Institute of Molecular Medicine, Padova, Italy
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Metikala S, Warkala M, Casie Chetty S, Chestnut B, Rufin Florat D, Plender E, Nester O, Koenig AL, Astrof S, Sumanas S. Integration of vascular progenitors into functional blood vessels represents a distinct mechanism of vascular growth. Dev Cell 2022; 57:767-782.e6. [PMID: 35276066 PMCID: PMC9365108 DOI: 10.1016/j.devcel.2022.02.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/17/2022] [Accepted: 02/16/2022] [Indexed: 01/01/2023]
Abstract
During embryogenesis, the initial vascular network forms by the process of vasculogenesis, or the specification of vascular progenitors de novo. In contrast, the majority of later-forming vessels arise by angiogenesis from the already established vasculature. Here, we show that new vascular progenitors in zebrafish embryos emerge from a distinct site along the yolk extension, or secondary vascular field (SVF), incorporate into the posterior cardinal vein, and contribute to subintestinal vasculature even after blood circulation has been initiated. We further demonstrate that SVF cells participate in vascular recovery after chemical ablation of vascular endothelial cells. Inducible inhibition of the function of vascular progenitor marker etv2/etsrp prevented SVF cell differentiation and resulted in the defective formation of subintestinal vasculature. Similar late-forming etv2+ progenitors were also observed in mouse embryos, suggesting that SVF cells are evolutionarily conserved. Our results characterize a distinct mechanism by which new vascular progenitors incorporate into established vasculature.
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Affiliation(s)
- Sanjeeva Metikala
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pathology and Cell Biology, USF Health Heart Institute, University of South Florida, Tampa, FL 33602, USA
| | - Michael Warkala
- Department of Cell Biology and Molecular Medicine, Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
| | - Satish Casie Chetty
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Molecular and Developmental Biology Graduate Program, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Brendan Chestnut
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Diandra Rufin Florat
- Department of Pathology and Cell Biology, USF Health Heart Institute, University of South Florida, Tampa, FL 33602, USA
| | - Elizabeth Plender
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Olivia Nester
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Andrew L Koenig
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Molecular and Developmental Biology Graduate Program, University of Cincinnati, Cincinnati, OH 45221, USA
| | - Sophie Astrof
- Department of Cell Biology and Molecular Medicine, Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103, USA
| | - Saulius Sumanas
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pathology and Cell Biology, USF Health Heart Institute, University of South Florida, Tampa, FL 33602, USA; University of Cincinnati College of Medicine, Department of Pediatrics, Cincinnati, OH 45229, USA.
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36
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Tian X, Zhou B. Coronary vessel formation in development and regeneration: origins and mechanisms. J Mol Cell Cardiol 2022; 167:67-82. [DOI: 10.1016/j.yjmcc.2022.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/12/2022] [Accepted: 03/22/2022] [Indexed: 10/18/2022]
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Dastouri M, Ozdag H, Akar AR, Can A. Differentiation and molecular characterization of endothelial progenitor and vascular smooth muscle cells from induced pluripotent stem cells. BIOIMPACTS : BI 2022; 13:289-300. [PMID: 37645025 PMCID: PMC10460769 DOI: 10.34172/bi.2022.24132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 08/31/2023]
Abstract
Introduction Pluripotent stem cells have been used by various researchers to differentiate and characterize endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) for the clinical treatment of vascular injuries. Studies continue to differentiate and characterize the cells with higher vascularization potential and low risk of malignant transformation to the recipient. Unlike previous studies, this research aimed to differentiate induced pluripotent stem (iPS) cells into endothelial progenitor cells (EPCs) and VSMCs using a step-wise technique. This was achieved by elucidating the spatio-temporal expressions of the stage-specific genes and proteins during the differentiation process. The presence of highly expressed oncogenes in iPS cells was also investigated during the differentiation period. Methods Induced PS cells were differentiated into lateral mesoderm cells (Flk1+). The Flk1+ populations were isolated on day 5.5 of the mesodermal differentiation period. Flk1+ cells were further differentiated into EPCs and VSMCs using VEGF165 and platelet-derived growth factor-BB (PDGF-BB), respectively, and then characterized using gene expression levels, immunocytochemistry (ICC), and western blot (WB) methods. During the differentiation steps, the expression levels of the marker genes and proto-oncogenic Myc and Klf4 genes were simultaneously studied. Results The optimal time for the isolation of Flk1+ cells was on day 5.5. EPCs and VSMCs were differentiated from Flk1+ cells and characterized with EPC-specific markers, including Kdr, Pecam1, CD133, Cdh5, Efnb2, Vcam1; and VSMC-specific markers, including Acta2, Cnn1, Des, and Myh11. Differentiated cells were validated based on their temporal gene expressions, protein synthesis, and localization at certain time points. Significant decreases in Myc and Klf4 gene expression levels were observed during the EPCs and VSMC differentiation period. Conclusion EPCs and VSMCs were successfully differentiated from iPS cells and characterized by gene expression levels, ICC, and WB. We observed significant decreases in oncogene expression levels in the differentiated EPCs and VSMCs. In terms of safety, the described methodology provided a better safety margin. EPCs and VSMC obtained using this method may be good candidates for transplantation and vascular regeneration.
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Affiliation(s)
- Mohammadreza Dastouri
- Ankara University Biotechnology Institute and SISBIYOTEK Advanced Research Unit, Gumusdere Yerleskesi, Kecioren Ankara, 06135, Turkey
| | - Hilal Ozdag
- Ankara University Biotechnology Institute and SISBIYOTEK Advanced Research Unit, Gumusdere Yerleskesi, Kecioren Ankara, 06135, Turkey
| | - Ahmet Ruchan Akar
- Ankara University School of Medicine, Department of Cardiovascular Surgery, Heart Center Dikimevi, Ankara, 06340, Turkey
| | - Alp Can
- Ankara University School of Medicine, Department of Histology and Embryology, Laboratories for Stem Cells and Reproductive Medicine, Sihhiye, Ankara, 06410, Turkey
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Akcan B, Örem A, Altinkaynak Y, Kural B, Örem C, Sönmez M, Serafini M. Endothelial Progenitor Cell Levels and Extent of Post-prandial Lipemic Response. Front Nutr 2022; 9:822131. [PMID: 35237643 PMCID: PMC8885282 DOI: 10.3389/fnut.2022.822131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/07/2022] [Indexed: 12/31/2022] Open
Abstract
Background and ObjectiveDue to the frequency of meal ingestion, individuals spend the majority of the day, ~18 h, in a status of post-prandial (PP) stress. Remnant-like lipoprotein particles (RLPs) are predominant in PP phase playing an important role in the development of atherosclerosis. Endothelial progenitor cells (EPCs) have been suggested to play a role in vessel wall homeostasis and in reducing atherosclerosis. However, there is no information about peripheral blood EPCs number following PP stress. We investigated the association between circulating EPCs levels and extent of PP lipemia in healthy subjects following a high-fat meal.Materials and MethodsA total of 84 healthy subjects (42 men, 42 women) aged 17–55 years were included in the study. PP lipemic response of subjects was determined by Oral Fat-Loading Test (OFLT). All the subjects were classified on the basis of their plasma TG levels after PP lipemic stressors in categories 1 (low), 2 (moderate), and 3 (high). Circulating EPCs numbers were measured by the flow cytometry method.ResultsThere was a significant difference in terms of lipid parameters between men and women: high-density lipoprotein cholesterol (HDL-C) was significantly lower in men than in women (p < 0.001). Total cholesterol (TC) (p = 0.004), low-density lipoprotein cholesterol (LDL-C) (p < 0.001), triglyceride (TG) (p < 0.001), and TG-AUC (p < 0.001) were significantly higher in men than in women. There was no significant difference between the genders in terms of CD34+KDR+ and CD34+KDR+CD133+cell number and MMP-9 levels. Vascular endothelial growth factor (VEGF) levels were significantly higher in men than women (p = 0.004). TC, LDL-C, and TG were significantly higher in the 3rd category than 1st and 2nd categories (p < 0.001) in women. Age, body mass index (BMI), fat rate, TG, TC, and LDL-C were significantly higher in the 3rd category than 1st category (p < 0.001, p = 0.002, p = 0.002, p = 0.01, p = 0.007, p = 0.004; respectively), in men. Circulating numbers of EPCs in men were significantly higher in the PP hyperlipidemia group than in the low TG levels category, independently from age (p < 0.05). Circulating EPC levels showed a positive correlation with OFLT response in men (r = 0.414, p < 0.05). Also, OFLT response showed a strong positive correlation with fasting TG levels (r = 0.930, p < 0.001). EPC levels in categories of women were not different.ConclusionIncreased EPCs levels in subjects with different PP hyperlipidemia may be associated with a response to endothelial injury, related to increased atherogenic remnant particles at the PP phase.
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Perdomo S, Brugnini A, Trias N, Menyou A, Silveira G, Ranero S, Lens D, Díaz L, Grille S. Mobilized and apheresis-collected endothelial progenitor cells with plerixafor. J Clin Apher 2022; 37:245-252. [PMID: 35114004 DOI: 10.1002/jca.21967] [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: 10/21/2021] [Revised: 01/11/2022] [Accepted: 01/13/2022] [Indexed: 11/10/2022]
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) are immature cells able to proliferate and contribute to endothelial repair, vascular homeostasis, neovascularization, and angiogenesis. It therefore seems likely that circulating EPCs have therapeutic potential in ischemic and vascular diseases. In this study we evaluated the efficiency of EPC mobilization and collection by large volume leukapheresis in subjects with hematological diseases, treated with plerixafor in association with G-CSF. METHODS Twenty-two patients with lymphoid malignancies underwent rHuG-CSF and plerixafor treatment followed by leukapheresis. Blood samples before and after treatment and apheresis liquid sample were taken and analyzed by flow cytometry in order to quantified EPC. RESULTS The percentage of CD34+ cells and EPCs among circulating total nuclear cells (TNCs) increased significantly by approximately 2-fold and 3-fold, respectively, after plerixafor treatment. Consequently, the absolute number of CD34+ cells and EPCs were increased 4-fold after plerixafor treatment. The median PB concentration of EPCs before and after treatment were 0.77/μL (0.31-2.15) and 3.41/μL (1.78-4.54), respectively, P < .0001. The total EPCs collected per patient were 3.3×107 (0.8×107 -6.8×107 ). CONCLUSION We have shown that plerixafor in combination with G-CSF allows the mobilization and collection of large amounts of EPCs along with CD34+ cells in lymphoid neoplasm patients. The possibility to collect and to store these cells could represent a promising therapeutic tool for the treatment of ischemic complications without the need of in vitro expansion.
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Affiliation(s)
- Susana Perdomo
- Servicio Médico Integral, Centro de Trasplante de Médula Ósea, Montevideo, Uruguay
| | - Andreina Brugnini
- Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Natalia Trias
- Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Alba Menyou
- Servicio Médico Integral, Centro de Trasplante de Médula Ósea, Montevideo, Uruguay
| | - Gonzalo Silveira
- Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Sabrina Ranero
- Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.,Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
| | - Daniela Lens
- Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Lilián Díaz
- Servicio Médico Integral, Centro de Trasplante de Médula Ósea, Montevideo, Uruguay
| | - Sofía Grille
- Servicio Médico Integral, Centro de Trasplante de Médula Ósea, Montevideo, Uruguay.,Laboratorio de Citometría y Biología Molecular, Departamento Básico de Medicina, Hospital de Clínicas, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.,Facultad de Medicina, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay
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40
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Saito N, Shirado T, Funabashi-Eto H, Wu Y, Mori M, Asahi R, Yoshimura K. Purification and characterization of human adipose-resident microvascular endothelial progenitor cells. Sci Rep 2022; 12:1775. [PMID: 35110646 PMCID: PMC8811023 DOI: 10.1038/s41598-022-05760-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 12/20/2021] [Indexed: 12/18/2022] Open
Abstract
Human adipose tissue is a rich source of adipose-derived stem cells (ASCs) and vascular endothelial progenitor cells (EPCs). However, no standardized method has been established for the isolation and purification of adipose-derived EPCs (AEPCs). The aim of this study was to establish a method for the isolation and purification of AEPCs. The stromal vascular fraction (SVF) was extracted from human lipoaspirates, and the CD45−CD31+ fraction of the SVF was collected by magnetic-activated cell sorting (MACS). The CD45−CD31+ fraction was cultured for 4.5 days, followed by a second MACS separation to collect the CD31+ fraction. Purified AEPCs were expanded without being overwhelmed by proliferating ASCs, indicating that a high level (> 95%) of AEPC purification is a key factor for their successful isolation and expansion. AEPCs exhibited typical endothelial markers, including CD31, von Willebrand factor, and the isolectin-B4 binding capacity. AEPCs formed colonies, comparable to cultured human umbilical vein endothelial cells (HUVECs). Both AEPCs and HUVECs formed capillary-like networks in the tube formation assay, with no significant difference in network lengths. We are the first to establish a purification and expansion method to isolate these cells. Because adipose tissue is a clinically accessible and abundant tissue, AEPCs may have potential advantages as a therapeutic tool for regenerative medicine.
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Affiliation(s)
- Natsumi Saito
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Takako Shirado
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Hitomi Funabashi-Eto
- Department of Plastic Surgery, Federation of National Public Service Personnel Mutual Aid Associations, Hamanomachi Hospital, 3-3-1, Nagahama, Chuou-ku, Fukuoka, 810-8539, Japan
| | - Yunyan Wu
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Masanori Mori
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Rintaro Asahi
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Kotaro Yoshimura
- Department of Plastic Surgery, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
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Yoshimi R, Nakajima H. Current State and Issues of Regenerative Medicine for Rheumatic Diseases. Front Med (Lausanne) 2022; 9:813952. [PMID: 35155499 PMCID: PMC8831787 DOI: 10.3389/fmed.2022.813952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/05/2022] [Indexed: 12/15/2022] Open
Abstract
The prognosis of rheumatic diseases is generally better than that of malignant diseases. However, some cases with poor prognoses resist conventional therapies and cause irreversible functional and organ damage. In recent years, there has been much research on regenerative medicine, which uses stem cells to restore the function of missing or dysfunctional tissues and organs. The development of regenerative medicine is also being attempted in rheumatic diseases. In diseases such as systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and rheumatoid arthritis, hematopoietic stem cell transplantation has been attempted to correct and reconstruct abnormalities in the immune system. Mesenchymal stem cells (MSCs) have also been tried for the treatment of refractory skin ulcers in SSc using the ability of MSCs to differentiate into vascular endothelial cells and for the treatment of systemic lupus erythematosus SLE using the immunosuppressive effect of MSCs. CD34-positive endothelial progenitor cells (EPCs), which are found in the mononuclear cell fraction of bone marrow and peripheral blood, can differentiate into vascular endothelial cells at the site of ischemia. Therefore, EPCs have been used in research on vascular regeneration therapy for patients with severe lower limb ischemia caused by rheumatic diseases such as SSc. Since the first report of induced pluripotent stem cells (iPSCs) in 2007, research on regenerative medicine using iPSCs has been actively conducted, and their application to rheumatic diseases is expected. However, there are many safety issues and bioethical issues involved in regenerative medicine research, and it is essential to resolve these issues for practical application and spread of regenerative medicine in the future. The environment surrounding regenerative medicine research is changing drastically, and the required expertise is becoming higher. This paper outlines the current status and challenges of regenerative medicine in rheumatic diseases.
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Li T, Zhang T. The Application of Nanomaterials in Angiogenesis. Curr Stem Cell Res Ther 2021; 16:74-82. [PMID: 32066364 DOI: 10.2174/1574888x15666200211102203] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 12/16/2019] [Accepted: 01/07/2020] [Indexed: 02/08/2023]
Abstract
Induction of angiogenesis has enormous potential in the treatment of ischemic diseases and
the promotion of bulk tissue regeneration. However, the poor activity of angiogenic cells and proangiogenic
factors after transplantation is the main problem that imposes its wide applications. Recent
studies have found that the development of nanomaterials has solved this problem to some extent.
Nanomaterials can be mainly classified into inorganic nanomaterials represented by metals, metal oxides
and metal hydroxides, and organic nanomaterials including DNA tetrahedrons, graphene, graphene
oxide, and carbon nanotubes. These nanomaterials can induce the release of angiogenic factors
either directly or indirectly, thereby initiating a series of signaling pathways to induce angiogenesis.
Moreover, appropriate surface modifications of nanomaterial facilitate a variety of functions, such as
enhancing its biocompatibility and biostability. In clinical applications, nanomaterials can promote the
proliferation and differentiation of endothelial cells or mesenchymal stem cells, thereby promoting the
migration of hemangioblast cells to form new blood vessels. This review outlines the role of nanomaterials
in angiogenesis and is intended to provide new insights into the clinical treatment of systemic
and ischemic diseases.
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Affiliation(s)
- Tianle Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Tao Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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Wang LT, He PC, Li AQ, Cao KX, Yan JW, Guo S, Jiang L, Yao L, Dai XY, Feng D, Xu YM, Tan N. Caffeine promotes angiogenesis through modulating endothelial mitochondrial dynamics. Acta Pharmacol Sin 2021; 42:2033-2045. [PMID: 33664417 PMCID: PMC8632980 DOI: 10.1038/s41401-021-00623-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/07/2021] [Indexed: 11/09/2022]
Abstract
Caffeine induces multiple vascular effects. In this study we investigated the angiogenic effect of physiological concentrations of caffeine with focus on endothelial cell behaviors (migration and proliferation) during angiogenesis and its mitochondrial and bioenergetic mechanisms. We showed that caffeine (10-50 μM) significantly enhanced angiogenesis in vitro, evidenced by concentration-dependent increases in tube formation, and migration of human umbilical vein endothelial cells (HUVECs) without affecting cell proliferation. Caffeine (50 μM) enhanced endothelial migration via activation of cAMP/PKA/AMPK signaling pathway, which was mimicked by cAMP analog 8-Br-cAMP, and blocked by PKA inhibitor H89, adenylate cyclase inhibitor SQ22536 or AMPK inhibitor compound C. Furthermore, caffeine (50 μM) induced significant mitochondrial shortening through the increased phosphorylation of mitochondrial fission protein dynamin-related protein 1 (Drp1) in HUVECs, which increased its activity to regulate mitochondrial fission. Pharmacological blockade of Drp1 by Mdivi-1 (10 μM) or disturbance of mitochondrial fission by Drp1 silencing markedly suppressed caffeine-induced lamellipodia formation and endothelial cell migration. Moreover, we showed that caffeine-induced mitochondrial fission led to accumulation of more mitochondria in lamellipodia regions and augmentation of mitochondrial energetics, both of which were necessary for cell migration. In a mouse model of hindlimb ischemia, administration of caffeine (0.05% in 200 mL drinking water daily, for 14 days) significantly promoted angiogenesis and perfusion as well as activation of endothelial AMPK signaling in the ischemic hindlimb. Taken together, caffeine induces mitochondrial fission through cAMP/PKA/AMPK signaling pathway. Mitochondrial fission is an integral process in caffeine-induced endothelial cell migration by altering mitochondrial distribution and energetics.
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Affiliation(s)
- Li-Tao Wang
- Guangdong Provincial People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510100, China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, China
| | - Peng-Cheng He
- Guangdong Provincial People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510100, China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, China
| | - An-Qi Li
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Kai-Xiang Cao
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Jing-Wei Yan
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shuai Guo
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Lei Jiang
- Guangdong Provincial People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510100, China
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, China
| | - Lin Yao
- School of Pharmaceutical Sciences, South China Research Center for Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Xiao-Yan Dai
- Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Du Feng
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yi-Ming Xu
- Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, 511436, China.
- State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou, 511436, China.
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Ning Tan
- Guangdong Provincial People's Hospital, School of Medicine, South China University of Technology, Guangzhou, 510100, China.
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510100, China.
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Chiang KJ, Chiu LC, Kang YN, Chen C. Autologous Stem Cell Therapy for Chronic Lower Extremity Wounds: A Meta-Analysis of Randomized Controlled Trials. Cells 2021; 10:3307. [PMID: 34943815 PMCID: PMC8699089 DOI: 10.3390/cells10123307] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 12/15/2022] Open
Abstract
Lower extremity chronic wounds (LECWs) commonly occur in patients with diabetes mellitus (DM) and peripheral arterial disease (PAD). Autologous stem cell therapy (ASCT) has emerged as a promising alternative treatment for those who suffered from LECWs. The purpose of this study was to assess the effects of ASCT on LECWs. Two authors searched three core databases, and independently identified evidence according to predefined criteria. They also individually assessed the quality of the included randomized controlled trials (RCTs), and extracted data on complete healing rate, amputation rate, and outcomes regarding peripheral circulation. The extracted data were pooled using a random-effects model due to clinical heterogeneity among the included RCTs. A subgroup analysis was further performed according to etiology, source of stem cells, follow-up time, and cell markers. A total of 28 RCTs (n = 1096) were eligible for this study. The pooled results showed that patients receiving ASCT had significantly higher complete healing rates (risk ratio (RR) = 1.67, 95% confidence interval (CI) 1.28-2.19) as compared with those without ASCT. In the CD34+ subgroup, ASCT significantly led to a higher complete healing rate (RR = 2.70, 95% CI 1.50-4.86), but there was no significant difference in the CD34- subgroup. ASCT through intramuscular injection can significantly improve wound healing in patients with LECWs caused by either DM or critical limb ischemia. Lastly, CD34+ is an important cell marker for potential wound healing. However, more extensive scale and well-designed studies are necessary to explore the details of ASCT and chronic wound healing.
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Affiliation(s)
- Kuan-Ju Chiang
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (K.-J.C.); (L.-C.C.)
| | - Li-Cheng Chiu
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; (K.-J.C.); (L.-C.C.)
| | - Yi-No Kang
- Department of Health Care Management, College of Health Technology, National Taipei University of Nursing Health Sciences, Taipei 112, Taiwan
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Research Center of Big Data and Meta-Analysis Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
- Institute of Health Policy & Management, College of Public Health, National Taiwan University, Taipei 100, Taiwan
| | - Chiehfeng Chen
- Evidence-Based Medicine Center, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Cochrane Taiwan, Taipei Medical University, Taipei 110, Taiwan
- Division of Plastic Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
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Francomano D, Sanguigni V, Capogrosso P, Deho F, Antonini G. New Insight into Molecular and Hormonal Connection in Andrology. Int J Mol Sci 2021; 22:ijms222111908. [PMID: 34769341 PMCID: PMC8584869 DOI: 10.3390/ijms222111908] [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: 07/25/2021] [Revised: 10/16/2021] [Accepted: 10/20/2021] [Indexed: 12/13/2022] Open
Abstract
Hormones and cytokines are known to regulate cellular functions in the testes. These biomolecules induce a broad spectrum of effects on various level of spermatogenesis, and among them is the modulation of cell junction restructuring between Sertoli cells and germ cells in the seminiferous epithelium. Cytokines and androgens are closely related, and both correct testicular development and the maintenance of spermatogenesis depend on their function. Cytokines also play a crucial role in the immune testicular system, activating and directing leucocytes across the endothelial barrier to the inflammatory site, as well as in increasing their adhesion to the vascular wall. The purpose of this review is to revise the most recent findings on molecular mechanisms that play a key role in male sexual function, focusing on three specific molecular patterns, namely, cytokines, miRNAs, and endothelial progenitor cells. Numerous reports on the interactions between the immune and endocrine systems can be found in the literature. However, there is not yet a multi-approach review of the literature underlying the role between molecular patterns and testicular and sexual function.
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Affiliation(s)
- Davide Francomano
- Division of Internal Medicine and Endocrinology, Madonna delle Grazie Hospital, 00049 Rome, Italy
- GCS Point Medical Center, 0010 Rome, Italy
- Correspondence:
| | - Valerio Sanguigni
- Department of Medicine of Systems, University of Rome Tor Vergata, 00100 Rome, Italy;
| | - Paolo Capogrosso
- ASST-Sette Laghi, Circolo & Fondazione Macchi Hospital, University of Insurbria, 21100 Varese, Italy; (P.C.); (F.D.)
| | - Federico Deho
- ASST-Sette Laghi, Circolo & Fondazione Macchi Hospital, University of Insurbria, 21100 Varese, Italy; (P.C.); (F.D.)
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Wang T, Zhou P, Xie X, Tomita Y, Cho S, Tsirukis D, Lam E, Luo HR, Sun Y. Myeloid lineage contributes to pathological choroidal neovascularization formation via SOCS3. EBioMedicine 2021; 73:103632. [PMID: 34688035 PMCID: PMC8546367 DOI: 10.1016/j.ebiom.2021.103632] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 01/08/2023] Open
Abstract
Background Pathological neovascularization in neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly. Increasing evidence shows that cells of myeloid lineage play important roles in controlling pathological endothelium formation. Suppressor of cytokine signaling 3 (SOCS3) pathway has been linked to neovascularization. Methods We utilised a laser-induced choroidal neovascularization (CNV) mouse model to investigate the neovascular aspect of human AMD. In several cell lineage reporter mice, bone marrow chimeric mice and Socs3 loss-of-function (knockout) and gain-of-function (overexpression) mice, immunohistochemistry, confocal, and choroidal explant co-culture with bone marrow-derived macrophage medium were used to study the mechanisms underlying pathological CNV formation via myeloid SOCS3. Findings SOCS3 was significantly induced in myeloid lineage cells, which were recruited into the CNV lesion area. Myeloid Socs3 overexpression inhibited laser-induced CNV, reduced myeloid lineage-derived macrophage/microglia recruitment onsite, and attenuated pro-inflammatory factor expression. Moreover, SOCS3 in myeloid regulated vascular sprouting ex vivo in choroid explants and SOCS3 agonist reduced in vivo CNV. Interpretation These findings suggest that myeloid lineage cells contributed to pathological CNV formation regulated by SOCS3. Funding This project was funded by NIH/NEI (R01EY030140, R01EY029238), BrightFocus Foundation, American Health Assistance Foundation (AHAF), and Boston Children's Hospital Ophthalmology Foundation for YS and the National Institutes of Health/National Heart, Lung and Blood Institute (U01HL098166) for PZ.
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Affiliation(s)
- Tianxi Wang
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Pingzhu Zhou
- Department of Cardiology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Xuemei Xie
- Division of Blood Bank, Department of Laboratory Medicine, Stem Cell Program, Boston Children's Hospital, Boston, MA, USA
| | - Yohei Tomita
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Steve Cho
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Demetrios Tsirukis
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Enton Lam
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Hongbo Robert Luo
- Division of Blood Bank, Department of Laboratory Medicine, Stem Cell Program, Boston Children's Hospital, Boston, MA, USA; Joint Program in Transfusion Medicine, Department of Pathology, Harvard Medical School, Boston, MA, USA; Dana-Farber/Harvard Cancer Center, Boston, MA, USA
| | - Ye Sun
- Department of Ophthalmology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
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47
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Gong H, Wang T, Xu Q. Resident stem cells in the heart. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:10-13. [PMID: 37724080 PMCID: PMC10471108 DOI: 10.1515/mr-2021-0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/18/2021] [Indexed: 09/20/2023]
Abstract
Cardiovascular disease is the leading cause of mobility and morality worldwide, in which the ischemic heart disease is the most common type of the diseases. During last decade, a major progress in the study of the pathogenesis of heart disease has been achieved. For example, the discovery of adult stem/progenitor cells in the heart and vessel tissues may play a role in tissue regeneration. However, the issue of 31 retractions for cardiac stem cell work has caused a "storm of trust" in the heart stem cell field, in which both founders and scientists have become cautious and conservative in stem cell research of the heart. Despite that the existence of adult cardiac stem cells has been denied, recent studies confirmed that there are many other resident stem/progenitor cells in adult heart. Although these cells cannot differentiate into cardiomyocytes, the role they played in heart repair after injury should not be ignored. The purpose of this short article is to briefly review the current research progress in resident stem/progenitor cells in the heart, to discuss how they function during cardiac repair and to point out unanswered questions in the research field.
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Affiliation(s)
- Hui Gong
- Department of Cardiology,
The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou,
Zhejiang, China
| | - Ting Wang
- Department of Cardiology,
The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou,
Zhejiang, China
| | - Qingbo Xu
- Department of Cardiology,
The First Affiliated Hospital,
Zhejiang University School of Medicine, Hangzhou,
Zhejiang, China
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48
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Zhou J, Chen S, Ren J, Zou H, Liu Y, Chen Y, Qiu Y, Zhuang W, Tao J, Yang J. Association of enhanced circulating trimethylamine N-oxide with vascular endothelial dysfunction in periodontitis patients. J Periodontol 2021; 93:770-779. [PMID: 34472093 DOI: 10.1002/jper.21-0159] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 06/22/2021] [Accepted: 08/10/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Accumulating evidences indicate that periodontitis is closely associated with endothelial dysfunction. Trimethylamine-N-oxide (TMAO), a harmful microbiota generated metabolite, has been implicated as a nontraditional risk factor for impaired endothelial function. However, whether increased circulating levels of TMAO in periodontitis patients induces endothelial dysfunction remains unknown. METHODS Patients with periodontitis and periodontally healthy controls were enrolled. Periodontal inflamed surface area (PISA) was calculated to assess the inflammatory burden posed by periodontitis. The circulating TMAO was measured by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Vascular endothelial function including peripheral endothelial progenitor cells (EPCs), brachial arterial flow-mediated vasodilation (FMD), and brachial-ankle pulse wave velocity (baPWV) were assessed. We also isolated and cultured EPCs from participants' peripheral blood to investigate the effect of TMAO on EPC functions in vitro. RESULTS One hundred and twenty two patients with Stage III-IV periodontitis and 81 healthy controls were included. Patients with periodontitis presented elevated TMAO (P = 0.002), lower EPCs (P = 0.025), and declined FMD levels (P = 0.005). The TMAO concentrations were correlated with reduced circulating EPCs and FMD levels. Moreover, TMAO can injury EPCs function in vitro, and may induce cell pyroptosis via Bax/caspase-3/GSDME pathway. CONCLUSIONS The present study demonstrates for the first time that circulating TMAO levels are increased in patients with Stage III-IV periodontitis, and correlated with vascular endothelial dysfunction. These findings may provide a novel insight into the mechanism of vascular endothelial dysfunction in patient with periodontitis via TMAO-downregulated EPC functions.
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Affiliation(s)
- Jiamin Zhou
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shan Chen
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jing Ren
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Huiqiong Zou
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yafang Liu
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yanbin Chen
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yumin Qiu
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Weijie Zhuang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Jun Tao
- Department of Hypertension and Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Junying Yang
- Department of Stomatology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Sidiropoulou S, Papadaki S, Tsouka AN, Koutsaliaris IK, Chantzichristos VG, Pantazi D, Paschopoulos ME, Hansson KM, Tselepis AD. The Effect of Platelet-Rich Plasma on Endothelial Progenitor Cell Functionality. Angiology 2021; 72:776-786. [PMID: 33678047 DOI: 10.1177/0003319721998895] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Platelets mediate circulating endothelial progenitor cell (EPC) recruitment and maturation, participating in vascular repair, however the underlying mechanism(s) remain unclear. We investigated the effect of platelet-rich plasma (PRP) on the functionality of CD34+-derived late-outgrowth endothelial cells (OECs) in culture. Confluent OECs were coincubated with PRP under platelet aggregation (with adenosine diphosphate; ADP) and nonaggregation conditions, in the presence/absence of the reversible P2Y12 platelet receptor antagonist ticagrelor. Outgrowth endothelial cell activation was evaluated by determining prostacyclin (PGI2) and monocyte chemoattractant protein-1 (MCP-1) release and intercellular adhesion molecule-1 (ICAM-1) membrane expression. Similar experiments were performed using human umbilical vein endothelial cells (HUVECs). Platelet-rich plasma increased ICAM-1 expression and PGI2 and MCP-1 secretion compared with autologous platelet-poor plasma, whereas ADP-aggregated platelets in PRP did not exhibit any effect. Platelet-rich plasma pretreated with ticagrelor prior to activation with ADP increased all markers to a similar extent as PRP. Similar results were obtained using HUVECs. In conclusion, PRP induces OEC activation, a phenomenon not observed when platelets are aggregated with ADP. Platelet inhibition with ticagrelor restores the PRP capability to activate OECs. Since EPC activation is important for endothelial regeneration and angiogenesis, we suggest that agents inhibiting platelet aggregation, such as ticagrelor, may promote platelet-EPC interaction and EPC function.
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Affiliation(s)
- Sofia Sidiropoulou
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Styliani Papadaki
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Aikaterini N Tsouka
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Ioannis K Koutsaliaris
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Vasileios G Chantzichristos
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Despoina Pantazi
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
| | - Minas E Paschopoulos
- Department of Obstetrics and Gynecology, School of Medicine, University of Ioannina, Ioannina, Greece
| | - Kenny M Hansson
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Alexandros D Tselepis
- Atherothrombosis Research Centre/Laboratory of Biochemistry, Department of Chemistry, School of Sciences, University of Ioannina, Ioannina, Greece
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50
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Hepatic cell mobilization for protection against ischemic myocardial injury. Sci Rep 2021; 11:15830. [PMID: 34349157 PMCID: PMC8339068 DOI: 10.1038/s41598-021-94170-z] [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: 06/16/2020] [Accepted: 06/29/2021] [Indexed: 11/29/2022] Open
Abstract
The heart is capable of activating protective mechanisms in response to ischemic injury to support myocardial survival and performance. These mechanisms have been recognized primarily in the ischemic heart, involving paracrine signaling processes. Here, we report a distant cardioprotective mechanism involving hepatic cell mobilization to the ischemic myocardium in response to experimental myocardial ischemia–reperfusion (MI-R) injury. A parabiotic mouse model was generated by surgical skin-union of two mice and used to induce bilateral MI-R injury with unilateral hepatectomy, establishing concurrent gain- and loss-of-hepatic cell mobilization conditions. Hepatic cells, identified based on the cell-specific expression of enhanced YFP, were found in the ischemic myocardium of parabiotic mice with intact liver (0.2 ± 0.1%, 1.1 ± 0.3%, 2.7 ± 0.6, and 0.7 ± 0.4% at 1, 3, 5, and 10 days, respectively, in reference to the total cell nuclei), but not significantly in the ischemic myocardium of parabiotic mice with hepatectomy (0 ± 0%, 0.1 ± 0.1%, 0.3 ± 0.2%, and 0.08 ± 0.08% at the same time points). The mobilized hepatic cells were able to express and release trefoil factor 3 (TFF3), a protein mitigating MI-R injury as demonstrated in TFF3−/− mice (myocardium infarcts 17.6 ± 2.3%, 20.7 ± 2.6%, and 15.3 ± 3.8% at 1, 5, and 10 days, respectively) in reference to wildtype mice (11.7 ± 1.9%, 13.8 ± 2.3%, and 11.0 ± 1.8% at the same time points). These observations suggest that MI-R injury can induce hepatic cell mobilization to support myocardial survival by releasing TFF3.
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