Cell Reprogramming, Transdifferentiation, and Dedifferentiation Approaches for Heart Repair

Abstract

Cardiovascular disease (CVD) remains the leading cause of death globally, with myocardial infarction (MI) being a major contributor. The current therapeutic approaches are limited in effectively regenerating damaged cardiac tissue. Up-to-date strategies for heart regeneration/reconstitution aim at cardiac remodeling through repairing the damaged tissue with an external cell source or by stimulating the existing cells to proliferate and repopulate the compromised area. Cell reprogramming is addressed to this challenge as a promising solution, converting fibroblasts and other cell types into functional cardiomyocytes, either by reverting cells to a pluripotent state or by directly switching cell lineage. Several strategies such as gene editing and the application of miRNA and small molecules have been explored for their potential to enhance cardiac regeneration. Those strategies take advantage of cell plasticity by introducing reprogramming factors that regress cell maturity in vitro, allowing for their later differentiation and thus endorsing cell transplantation, or promote in situ cell proliferation, leveraged by scaffolds embedded with pro-regenerative factors promoting efficient heart restoration. Despite notable advancements, important challenges persist, including low reprogramming efficiency, cell maturation limitations, and safety concerns in clinical applications. Nonetheless, integrating these innovative approaches offers a promising alternative for restoring cardiac function and reducing the dependency on full heart transplants.

Keywords: cardiovascular diseases; dedifferentiation; direct reprogramming; indirect reprogramming; transdifferentiation.

Figure 1

Innate mechanisms of response to myocardial infarction (MI). Following an MI, damaged cells and extracellular matrix (ECM) proteins release danger-associated molecular patterns (DAMPs) and alarmins, prompting an immune response and fibroblast activation, respectively. DAMPs will activate toll-like receptor/interleukin-1 (TLR/IL-1) signaling, triggering the nuclear factor (NF)-κB system and the subsequent release of chemokines, cytokines, and adhesion molecules. In response, immune cells will be recruited to the site of the lesion, clearing dead cells and debris. Concomitantly, alarmins will promote the conversion of fibroblasts into myofibroblasts, though the activation of the TGF-β pathway. Myofibroblasts will produce ECM proteins that will form a collagen-based scar, preventing cardiac rupture. Created with BioRender.com.

Figure 2

hiPSC-derived cardiomyocyte generation. Cardiac differentiation of hiPSCs through the modulation of Wnt, TGF-β, FGF, and RA signaling pathways. Inductive co-culture and embryoid body formation are employed in cardiac research to improve the physiological and metabolic relevance of in vitro hiPSC-derived CMs. Created with BioRender.com.

Figure 3

Direct cell reprogramming into cardiomyocytes (CMs). Induced reprogramming to pluripotency involves the complete regression of cell differentiation into a pluripotent status (iPSC), allowing for further differentiation into a cell type from a different cell lineage. On the other hand, direct cell reprogramming, encompassing transdifferentiation and dedifferentiation, does not require the intermediate step of generating a pluripotent cell type. Transdifferentiation involves the regression of a somatic cell to a less differentiated transitory state from where the cell may develop into a different lineage. Dedifferentiation consists in the generation of a less differentiated (more immature) cell type, in the same lineage of the initial somatic cell. Created with BioRender.com.

Figure 4

Cardiac fibroblast transdifferentiation into cardiomyocytes (CMs). Small molecules, miRNAs, and transcription factors are administered to induce the transition of cardiac fibroblasts (CFs) to induced cardiomyocytes (iCMs), leading to improved cardiac function and the resolution of excessive scar formation. Created with BioRender.com.

Figure 5

Strategies for the promotion of in vivo cardiac repair. The repair of an injured heart can be promoted by recurring to hydrogels or malleable solid scaffolds embedded with iCPCs, cellular co-cultures (i.e., EC and CM), or pro-angiogenic and growth factors, ultimately, transdifferentiation and dedifferentiation inductors for improved heart regeneration. Created with BioRender.com.