Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells

Abstract

Compact cardiomyocytes that make up the ventricular wall of the adult heart represent an important therapeutic target population for modeling and treating cardiovascular diseases. Here, we established a differentiation strategy that promotes the specification, proliferation and maturation of compact ventricular cardiomyocytes from human pluripotent stem cells (hPSCs). The cardiomyocytes generated under these conditions display the ability to use fatty acids as an energy source, a high mitochondrial mass, well-defined sarcomere structures and enhanced contraction force. These ventricular cells undergo metabolic changes indicative of those associated with heart failure when challenged in vitro with pathological stimuli and were found to generate grafts consisting of more mature cells than those derived from immature cardiomyocytes following transplantation into infarcted rat hearts. hPSC-derived atrial cardiomyocytes also responded to the maturation cues identified in this study, indicating that the approach is broadly applicable to different subtypes of the heart. Collectively, these findings highlight the power of recapitulating key aspects of embryonic and postnatal development for generating therapeutically relevant cell types from hPSCs.

Retinoic acid signaling in heart development: Application in the differentiation of cardiovascular lineages from human pluripotent stem cells

“…It was shown that the proliferative effect of proepicardial cells on co-cultured ventricular cardiomyocytes was mediated at least in part by RA-dependent IGF2 signaling (Tan et al, 2021). IGF2 has also been utilized for the maturation of compact ventricular cells derived from hPSCs (Funakoshi et al, 2021). IGF2 was strongly decreased in both Raldh2 À/À and Rxra mutants and is implicated in ventricu-lar wall proliferation (Brade et al, 2011;Li et al, 2011).…”

Recent progress of iPSC technology in cardiac diseases

“…Furthermore, in the developing heart, it is well known that there are two distinct subpopulations in the ventricle: trabecular and compact cardiomyocytes. Recent reports demonstrated the successful generation of trabecular and compact ventricular PSC cardiomyocytes by manipulating neuregulin and Wnt signaling, respectively (Mikryukov et al 2021 ; Funakoshi et al 2021 ). The specified ventricular cardiomyocytes would be helpful to analyze trabeculation- and compaction-related diseases, such as LV non-compaction.…”

“…We recently developed an efficient maturation protocol using the combination of T3, Dex, PPARα agonist, and palmitate in low glucose-containing media. The PSC cardiomyocytes treated by this protocol showed structural maturation, withdrawal from the cell cycle, and the ability to utilize exogenous fatty acids efficiently as an energy source, which is one of the representative features of the adult-like metabolism in the heart (Funakoshi et al 2021 ). In addition to these factors, Sakamoto et al demonstrated that ERR signaling plays an essential role in postnatal cardiac maturation in mice (Sakamoto et al 2020 ).…”

“…Although no previous studies have identified the causes of the graft-related arrhythmia, one possible mechanism is the relatively immature phenotype of the transplanted cardiomyocytes, since they have fetal-like immature electrophysiological properties in vitro. We recently demonstrated that the maturation status in in vitro cardiomyocytes prior to the cell transplantation affected the graft quality, including the expression of CX43, a gap junction protein that increases the electrical stability of the grafted cells, suggesting that the transplantation of mature cardiomyocytes could reduce the occurrence of the graft-related arrhythmias (Funakoshi et al 2021 ). Studies transplanting mature cardiomyocytes into large animal may answer this question.…”

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

“…Several approaches were attempted to overcome the issue of hiPSC-CMs immaturity, such as the long-term culture [46,47], the use of hormones [48], metabolic substrates [49,50] and microRNAs [51]. Recently, it has been observed that inhibition of the mechanistic target of the rapamycin (mTOR) pathway enhances hiPSC-CMs maturation by shifting cells to a quiescent state, which enhances cardiomyocyte maturity.…”