Cellular reprogramming of fibroblasts in heart regeneration

Advances in the Generation of Constructed Cardiac Tissue Derived from Induced Pluripotent Stem Cells for Disease Modeling and Therapeutic Discovery

“…Efforts to understand and treat CVD face the challenges of complex pathogenesis and the heart's absence of regenerative capacity. Limited therapeutic options necessitate reliance on scarce donor organs and immunosuppression [8,[10][11][12]16,[23][24][25][26][27]. Preclinical studies have attempted to remuscularize infarcted hearts by regenerating new cardiomyocytes (CMs) from stem cells and non-CMs or by modulating the proliferation-maturation axis of existing CMs [1,17,[26][27][28][29][30][31], the constituent cells of cardiac muscle [1,31] (Figure 1).…”

“…Limited therapeutic options necessitate reliance on scarce donor organs and immunosuppression [8,[10][11][12]16,[23][24][25][26][27]. Preclinical studies have attempted to remuscularize infarcted hearts by regenerating new cardiomyocytes (CMs) from stem cells and non-CMs or by modulating the proliferation-maturation axis of existing CMs [1,17,[26][27][28][29][30][31], the constituent cells of cardiac muscle [1,31] (Figure 1). Recent studies have also aimed to revascularize damaged tissue or reprogram fibrotic scar tissue into healthy musculature and vasculature [3,6,8,12,15,20,26,27,30,32,33].…”

“…Over 99% of transplanted cells in solution quickly die for various reasons: host immune reactions, inflammation, protease release, low cell density, deficient cell-cell interactions needed to promote cell survival, and poor cell-type diversity, which limits host integration [1,10,27,30,34,35]. Critically, transplanting immature tissue poses an arrhythmia risk from improper CM electrical integration [10,24,27,30,31,34]. Even acellular factors face rapid clearance following treatment [10,30,34,35].…”

“…Cells 2024, 13, x FOR PEER REVIEW 2 of 25 tissue into healthy musculature and vasculature [3,6,8,12,15,20,26,27,30,32,33]. Despite continued efforts, cellular therapies encounter viability issues.…”

“…Infusions and injections of cell solutions containing mesenchymal stem cells (MSCs), iPSCs, and iPSC-derived CMs (iPSC-CMs) have shown modest recovery in some in vivo models [3,8,12] but highly variable results in human clinical trials for CVD, as poor cell retention and host integration challenge long-term treatment efficacy [1,3,8,10,12,27]. Over 99% of transplanted cells in solution quickly die for various reasons: host immune reactions, inflammation, protease release, low cell density, deficient cell-cell interactions needed to promote cell survival, and poor cell-type diversity, which limits host integration [1,10,27,30,34,35]. Critically, transplanting immature tissue poses an arrhythmia risk from improper CM electrical integration [10,24,27,30,31,34].…”