In Situ Maturated Early-Stage Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Improve Cardiac Function by Enhancing Segmental Contraction in Infarcted Rats

Abstract

The scant ability of cardiomyocytes to proliferate makes heart regeneration one of the biggest challenges of science. Current therapies do not contemplate heart re-muscularization. In this scenario, stem cell-based approaches have been proposed to overcome this lack of regeneration. We hypothesize that early-stage hiPSC-derived cardiomyocytes (hiPSC-CMs) could enhance the cardiac function of rats after myocardial infarction (MI). Animals were subjected to the permanent occlusion of the left ventricle (LV) anterior descending coronary artery (LAD). Seven days after MI, early-stage hiPSC-CMs were injected intramyocardially. Rats were subjected to echocardiography pre-and post-treatment. Thirty days after the injections were administered, treated rats displayed 6.2% human cardiac grafts, which were characterized molecularly. Left ventricle ejection fraction (LVEF) was improved by 7.8% in cell-injected rats, while placebo controls showed an 18.2% deterioration. Additionally, cell-treated rats displayed a 92% and 56% increase in radial and circumferential strains, respectively. Human cardiac grafts maturate in situ, preserving proliferation with 10% Ki67 and 3% PHH3 positive nuclei. Grafts were perfused by host vasculature with no evidence for immune rejection nor ectopic tissue formations. Our findings support the use of early-stage hiPSC-CMs as an alternative therapy to treat MI. The next steps of preclinical development include efficacy studies in large animals on the path to clinical-grade regenerative therapy targeting human patients.

Time-regulated transcripts with the potential to modulate human pluripotent stem cell-derived cardiomyocyte differentiation

“…The miRNAs exhibiting Profile 1 when overexpressed delayed maturation characteristics mainly associated with structural changes, whereas miR-124-3p regulated both structural and functional features. Altogether, we (1) identified a molecular signature for tracking in vitro cardiac differentiation over time; (2) provided evidence that the miRNA/gene pairs display biological relevance; and (3) showed that most of the top-scoring miRNAs influence the proliferation-maturation axis. The improved understanding of the interplay among miRNAs and gene targets may be instrumental in developing more robust human cardiac disease modeling systems and cardiac cell-based regenerative approaches.…”

“…Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are instrumental for the complete development of cardiac disease cell-modeling systems, patient-specific drug tests, and strategies to replace lost cardiomyocytes [1][2][3].…”

Cell-Based and Selected Cell-Free Therapies for Myocardial Infarction: How Do They Compare to the Current Treatment Options?

“…Over the past two decades, the iPSC-CMs generation, thanks to the improvement of differentiation and purification techniques, has opened the door for clinical applications. The underlying mechanism of MI and the therapeutic effect of iPSC-CMs have been demonstrated in several small and large animal models of MI, such as mice [ 118 , 119 ], rats [ 120 , 121 ], and pigs [ 121 , 122 , 123 ]. A significant study published by Chong et al regarding the use of ESC-CMs in a non-human-primate model (pigtail macaque) of myocardial ischemia-reperfusion resulted in remuscularization of heart tissue but incomplete cell maturation [ 50 ].…”

Development of an efficient Computational Model for classification of Tissue remodeling

“…Article [14] signifies that the meager capacity to remodel makes heart recovery one of the greatest difficulties. Current treatments don't think about heart re-muscularization.…”