Optimal transplantation strategy using human induced pluripotent stem cell‐derived cardiomyocytes for acute myocardial infarction in nonhuman primates

Abstract

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC‐CMs) have the potential to be a therapeutic option for myocardium restoration. However, hiPSC‐CMs of varying maturation and transplantation routes exhibit different reactivity and therapeutic effects. We previously demonstrated that the saponin+ compound induces more mature hiPSC‐CMs. The safety and efficacy of multi‐route transplantation of saponin+ compound‐induced hiPSC‐CMs in a nonhuman primate with myocardial infarction will be investigated for the first time in this study. Our findings indicate that optimized hiPSC‐CMs transplanted via intramyocardial and intravenous routes may affect myocardial functions by homing or mitochondrial transfer to the damaged myocardium to play a direct therapeutic role as well as indirect beneficial roles via anti‐apoptotic and pro‐angiogenesis mechanisms mediated by different paracrine growth factors. Due to significant mural thrombosis, higher mortality, and unilateral renal shrinkage, intracoronary transplantation of hiPSC‐CMs requires closer attention to anticoagulation and caution in clinical use. Collectively, our data strongly indicated that intramyocardial transplantation of hiPSC‐CMs is the ideal technique for clinical application; multiple cell transfers are recommended to achieve steady and protracted efficacy because intravenous transplantation's potency fluctuates. Thus, our study offers a rationale for choosing a therapeutic cell therapy and the best transplantation strategy for optimally induced hiPSC‐CMs.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes Therapy for Ischemic Heart Disease in Animal Model: A Meta-Analysis

“…Mortality outcomes were either documented or could be accurately determined in a total of 19 studies (Figure 2) [9,10,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. There was no difference in the mortality risk between the iPSC-CM and control groups, with OR = 0.61; 95% CI: 0.3 to 1.24, p = 0.17 (Figure 3).…”

“…There was no difference in the mortality risk between the iPSC-CM and control groups, with OR = 0.61; 95% CI: 0.3 to 1.24, p = 0.17 (Figure 3). [9,10,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Blue box represents the point estimate of the effect for a single study, the black diamond represents the overall effect estimate of the meta-analysis.…”

“…Four studies examined the potential risk of arrhythmia following iPSC-CM treatment, comprising one study involving small animals [9] and three studies involving large animals [19,30,31]. No significant difference was observed in the occurrence of sustained ventricular arrhythmias between the cell-based group and the control group, with an odds ratio of 10.46, a 95% confidence interval ranging from 0.94 to 115.83, and a p-value of 0.06 (Figure 4).…”

“…No significant difference was observed in the occurrence of sustained ventricular arrhythmias between the cell-based group and the control group, with an odds ratio of 10.46, a 95% confidence interval ranging from 0.94 to 115.83, and a p-value of 0.06 (Figure 4). [9,10,12,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]. Blue box represents the point estimate of the effect for a single study, the black diamond represents the overall effect estimate of the meta-analysis.…”

“…There was notable heterogeneity (p < 0.001) and high inconsistency (I 2 : 95%) in the small animal studies (Figure 5). [9,19,30,31]. Blue box represents the point estimate of the effect for a single study, the black diamond represents the overall effect estimate of the meta-analysis.…”