Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts

• Published in: Bioactive materials Vol. 28; pp. 206 - 226
• Main Authors: Jiang, Yun, Zhang, Ling-Ling, Zhang, Fan, Bi, Wei, Zhang, Peng, Yu, Xiu-Jian, Rao, Sen-Le, Wang, Shi-Hui, Li, Qiang, Ding, Chen, Jin, Ying, Liu, Zhong-Min, Yang, Huang-Tian
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.10.2023; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Cardiac lineage cells; Cardiomyocyte regeneration; Extracellular matrix patch; Induced human pluripotent stem cells; Infarcted heart repair; Cardiac lineage cells; Extracellular matrix patch; Cardiomyocyte regeneration; Infarcted heart repair; Induced human pluripotent stem cells
• ISSN: 2452-199X; 2452-199X
• DOI: 10.1016/j.bioactmat.2023.05.015

Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts; however, their efficacy needs to be enhanced. Here we tested the hypotheses that the combination of decellularized porcine small intestinal submucosal extracellular matrix (SIS-ECM) with hCVPCs, hCMs, or dual of them (Mix, 1:1) could provide better therapeutic effects than the SIS alone, and dual hCVPCs with hCMs would exert synergic effects in cardiac repair. The data showed that the SIS patch well supported the growth of hCVPCs and hCMs. Epicardially implanted SIS-hCVPC, SIS-hCM, or SIS-Mix patches at 7-day post-myocardial infarction significantly ameliorated functional worsening, ventricular dilation and scar formation at 28- and 90-day post-implantation in C57/B6 mice, whereas the SIS only mildly improved function at 90-day post-implantation. Moreover, the SIS and SIS-cell patches improved vascularization and suppressed MI-induced cardiomyocyte hypertrophy and expression of Col1 and Col3, but only the SIS-hCM and the SIS-Mix patches increased the ratio of collagen III/I fibers in the infarcted hearts. Further, the SIS-cell patches stimulated cardiomyocyte proliferation via paracrine action. Notably, the SIS-Mix had better improvements in cardiac function and structure, engraftments, and cardiomyocyte proliferation. Proteomic analysis showed distinct biological functions of exclusive proteins secreted from hCVPCs and hCMs, and more exclusive proteins secreted from co-cultivated hCVPCs and hCMs than mono-cells involving in various functional processes essential for infarct repair. These findings are the first to demonstrate the efficacy and mechanisms of mono- and dual-hCVPC- and hCM-seeding SIS-ECM for repair of infarcted hearts based on the side-by-side comparison. Epicardial implantation of hCVPCs-, hCMs- and their mixture (Mix)-seeding SIS patches at sub-acute phase of myocardial infarction promotes repair of infarcted hearts through vascularization and muscularization via paracrine action, engraftment and proliferation. Moreover, the SIS patches seeded with dual hCVPCs and hCMs display better functional improvement and more cardiomyocytes in proliferation, which is associated with secreted more exclusive proteins related to repair and regeneration. [Display omitted] •This is the first parallel comparison of SIS, SIS-hCVPC, SIS-hCM, and SIS-hCVPC + hCM (Mix) patches for infarct repair.•Implantation of SIS-cell patches at 7 d post-MI ameliorates functional worsening and scar size, and the SIS-Mix is better.•The effects are associated with the improved cell retention, cardiomyocyte proliferation, and angiogenesis in the MI hearts.•Proteomic analyses reveal more unique proteins secreted from co-cultivated hCVPCs and hCMs.