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.

Keywords: direct reprogramming; engineered heart tissue; iPSC-CMs; immune reduction; myocadiac infarction; progenitor cells; regenerative heart repair; stem cells.

Figure 1

Recent advanced methodologies for regenerative heart disease treatment. hiPSCs differentiate and maturate into hiPSC-CMs for transplantation and further functionalize for engineered heart tissue process (right side). Current genetic direct reprogramming techniques, in vitro and in situ, for cardiac fibroblast cells reprogramming into induced cardiomyocytes (iCMs), and induced cardiac progenitor cells (iCPCs) through transcriptional factors by viruses, microRNAs, and small molecules.

Figure 2

Current development of cardiac differentiation process by hiPSC for cardiomyocyte generation based on Wnt, TGF-β, FGF, and retinoic acid signaling pathway. Culture methods such as inductive co-culture with embryoid body culture.

Figure 3

Molecular mechanisms of cardiac reprogramming. (A) Various reprogramming routes for converting fibroblasts into cardiovascular cells in Waddington’s epigenetic landscape model. (B) The transcriptional and epigenetic mechanisms involved in iCPC reprogramming. (C) Potential interactions between reprogramming pioneer factors and epigenetic modifiers, and establishment of an auto-regulatory loop of TFs. PSC: pluripotent stem cells; EB: embryonic body; CPC: cardiovascular progenitor cell; CM: cardiomyocytes; SMC: smooth muscle cell; EC: endothelial cell; TF: transcription factor; CE: cardiac enhancer.

Figure 4

Administration methods for delivery of reprogramming factors and chemical molecules for reprogramming-based therapy.