A research group led by Prof. YANG Huang-Tian from Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS) and collaborators developed a strategy for promoting cardiac repair with engineered mono- and dual-human pluripotent stem cells (hPSCs)-derived cardiovascular progenitors (hCVPCs)- and cardiomyocytes (hCMs)-seeding extracellular matrix materials (ECM) patches. The cell-seeding patches display long-term functional improvements, smaller scar and reversed maladaptive remodeling in the infarcted hearts after epicardially implanted at the sub-acute phase of myocardial infarction (MI) and the dual cell-seeding patches show better therapeutic effects.

MI and resulting heart failure remain a leading cause of morbidity and mortality worldwide.Current treatments improve the symptoms and survival but cannot compensate for the MI-caused irreversible loss of contractile myocardial tissue due to extensive cardiomyocyte loss and vascular disruption. 

Cell therapy by implantation of stem/progenitor cells and their derived cardiovascular cells offers new opportunities for repair of infarcted hearts. Other laboratories and Prof. YANG’s team demonstrate the beneficial effects of implantation of hCVPCs and hCMs into infarcted hearts in murine, porcine, and non-human primate models of MI, but the low engraftment of hCVPCs and incidence of ventricular arrhythmias following intramyocardial injection of hCMs are observed. Thus, more studies are needed to determine suitable cell types, mechanisms underlying, and optimal approaches for enhancing the therapeutic efficacy and safety of cell therapy for infarcted hearts.

The intact porcine small intestinal submucosa extracellular matrix materials (SIS) have superior biocompatibility to support stem cell attachment and growth, and promote angiogenesis and cardiac function after implanted to MI hearts. However, it is unknown whether it can be used to construct hPSC-derived cardiovascular cell patches and whether these cell-seeding SIS patches can promote the repair of infarcted hearts better than the SIS-ECM alone.

In this study, the researchers did side-by-side comparison of epicardial implantation of the SIS patches alone and the SIS-seeded mono-hCVPC-, hCM-, and dual hCVPC + hCM (Mix) patches at 7 days post-MI in a mouse model for cardiac repair. The research team found that the SIS patches have good biocompatibility to hCVPCs and hCMs as well as improves the cell viability. The study revealed that epicardial implantation of mono- and dual-cell seeding SIS patches significantly preserves cardiac function and decreases scar formation at day 28 but not the SIS alone, concomitantly associated with increased vascularization and cardiomyocyte proliferation. The researchers also discovered that the SIS-Mix patches have better therapeutic effects characterized by more effective short- and long-term improvements of left ventricular performance and dilation, and enhancement of engraftment and cardiomyocyte proliferation. Moreover, 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.

Collectively, 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. The implantation of dual hCVPC- and hCM-seeding SIS patches exhibits synergistic and complementary effects in promoting infarct repair, which might be a promising therapeutic approach for ischemic hearts disease.

This study entitled  “Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts” was online published in Bioactive Materials on May 27, 2023. Dr. JIANG Yun is the first author, and Prof. YANG Huang-Tian is the corresponding author. The study was cooperated with Prof. JIN Ying from SINH, Prof. DING Chen from Fudan University, and LIU Zhong-Min from Shanghai East Hospital, Tongji University.

The study was funded by the grants from National Key R&D Program of China, Strategic Priority Research Program of CAS, and National Natural Science Foundation of China.

The Graphical Abstract of the epicardial implantation of hCVPCs-, hCMs- and their mixture (Mix)-seeding SIS patches for infarct healing.(Image by Prof. YANG Huang-Tian’s research team)

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn

Web: http://english.sinh.cas.cn/