Maturation of Stem Cell-Derived Cardiomyocytes: Foe in Translation Medicine

Abstract

With the in-depth study of heart development, many human cardiomyocytes (CMs) have been generated in a laboratory environment. CMs derived from pluripotent stem cells (PSCs) have been widely used for a series of applications such as laboratory studies, drug toxicology screening, cardiac disease models, and as an unlimited resource for cell-based cardiac regeneration therapy. However, the low maturity of the induced CMs significantly impedes their applicability. Scientists have been committed to improving the maturation of CMs to achieve the purpose of heart regeneration in the past decades. In this review, we take CMs maturation as the main object of discussion, describe the characteristics of CMs maturation, summarize the key regulatory mechanism of regulating maturation and address the approaches to promote CMs maturation. The maturation of CM is gradually improving due to the incorporation of advanced technologies and is expected to continue.

Improving rodents and humans cardiac cell maturity in vitro through polycaprolactone and polyurethane nanofibers

“…In human and rodent hearts, proteins, involved in the structure and function of cardiac tissue, can exist in different isoforms, and their expression levels differ between fetal and adult CMs. For example, the heavy chain of myosin with two isoforms, MYH6 and MYH7, builds thick filaments (myosin) of sarcomeres [41,60]. MYH7 expression was upregulated in mature human ventricular CMs, whereas MYH6 gene expression was upregulated in mature rodent cardiac cells [41,42].…”

“…During the development of the heart from the fetal to the adult stage, the electrophysiology of CMs is changed, which is based on the transport of sodium, potassium, and calcium ions [53][54][55]60]. Calcium ions play an essential role in the contraction of CMs.…”

Stem cell therapy for heart failure in the clinics: new perspectives in the era of precision medicine and artificial intelligence

“…( Qian et al, 2012 ). Cardiomyogenesis from iPSCs has been attempted previously ( Yang et al, 2017 ; Wu et al, 2023 ); however, iPSC-derived CMs (iPSC-CMs) largely expressed fetal phenotypes and failed to efficiently function as adult CMs ( Liao et al, 2021 ), limiting their clinical applicability. Recently, progress has been made to enhance the maturity of iPSC-CMs ( Li et al, 2022 ; Hsueh et al, 2023 ).…”

Novel method of differentiating human induced pluripotent stem cells to mature cardiomyocytes via Sfrp2

“…This protocol gives rise to a high number of cardiomyocytes. However, the phenotype is typically fetal-like which creates a significant issue for in vivo cell therapy as the immature cardiomyocytes can cause arrhythmia after implantation [7][8][9] .Several methods have been used in attempt to improve the maturation of iPSc-derived cardiomyocytes. These methods include mechanical stimuli, 3D-structures, chemical factors, as well as genetic regulation 10,11 .…”

“…This protocol gives rise to a high number of cardiomyocytes. However, the phenotype is typically fetal-like which creates a significant issue for in vivo cell therapy as the immature cardiomyocytes can cause arrhythmia after implantation [7][8][9] .…”