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

Yun Jiang; Ling-Ling Zhang; Fan Zhang; Wei Bi; Peng Zhang; Xiu-Jian Yu; Sen-Le Rao; Shi-Hui Wang; Qiang Li; Chen Ding; Yin Jin; Zhong-Min Liu; Huang-Tian Yang

doi:10.1016/j.bioactmat.2023.05.015

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

Bioact Mater. 2023 May 27:28:206-226. doi: 10.1016/j.bioactmat.2023.05.015. eCollection 2023 Oct.

Authors

Yun Jiang^{1

2}, Ling-Ling Zhang², Fan Zhang³, Wei Bi², Peng Zhang^{1

2}, Xiu-Jian Yu², Sen-Le Rao², Shi-Hui Wang², Qiang Li^{1

2}, Chen Ding³, Yin Jin², Zhong-Min Liu¹, Huang-Tian Yang^{1

2

4}

Affiliations

¹ Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
² CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China.
³ State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China.
⁴ Institute for Stem Cell and Regeneration, CAS, Beijing, 100101, PR China.

Abstract

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.

Keywords: Cardiac lineage cells; Cardiomyocyte regeneration; Extracellular matrix patch; Induced human pluripotent stem cells; Infarcted heart repair.