Advances in Cellular Reprogramming-Based Approaches for Heart Regenerative Repair

Abstract

Continuous loss of cardiomyocytes (CMs) is one of the fundamental characteristics of many heart diseases, which eventually can lead to heart failure. Due to the limited proliferation ability of human adult CMs, treatment efficacy has been limited in terms of fully repairing damaged hearts. It has been shown that cell lineage conversion can be achieved by using cell reprogramming approaches, including human induced pluripotent stem cells (hiPSCs), providing a promising therapeutic for regenerative heart medicine. Recent studies using advanced cellular reprogramming-based techniques have also contributed some new strategies for regenerative heart repair. In this review, hiPSC-derived cell therapeutic methods are introduced, and the clinical setting challenges (maturation, engraftment, immune response, scalability, and tumorigenicity), with potential solutions, are discussed. Inspired by the iPSC reprogramming, the approaches of direct cell lineage conversion are merging, such as induced cardiomyocyte-like cells (iCMs) and induced cardiac progenitor cells (iCPCs) derived from fibroblasts, without induction of pluripotency. The studies of cellular and molecular pathways also reveal that epigenetic resetting is the essential mechanism of reprogramming and lineage conversion. Therefore, CRISPR techniques that can be repurposed for genomic or epigenetic editing become attractive approaches for cellular reprogramming. In addition, viral and non-viral delivery strategies that are utilized to achieve CM reprogramming will be introduced, and the therapeutic effects of iCMs or iCPCs on myocardial infarction will be compared. After the improvement of reprogramming efficiency by developing new techniques, reprogrammed iCPCs or iCMs will provide an alternative to hiPSC-based approaches for regenerative heart therapies, heart disease modeling, and new drug screening.

Direct Reprogramming of Resident Non-Myocyte Cells and Its Potential for In Vivo Cardiac Regeneration

“…Although iPSC technology is currently unable to regenerate all cell types for specific customized cell therapies, it has indeed paved the path for providing tailored cells for disease modelling and drug screening [ 10 ]. In cardiovascular regenerative medicine, iPSC technology has enabled to provide CMs [ 11 , 12 ], but with the current differentiation methods they are mostly immature and heterogenous, creating related problems such as arrhythmogenicity, immunogenicity, and poor engraftment. Direct transplant of pluripotent stem cell (PSC)-derived CMs into the infarcted myocardium has shown limited therapeutic benefit in large animal models, mainly due to insufficient retention potential of transplanted cells for the long term, low engraftment rate, potential immunological reactions, risk of tumour induction, and inadequate electrical and mechanical coupling [ 13 , 14 ].…”