Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation

Abstract

Cardiovascular diseases are the leading cause of mortality and reduced quality of life globally. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a personalized platform to study inherited heart diseases, drug-induced cardiac toxicity, and cardiac regenerative therapy. However, the immaturity of CMs obtained by current strategies is a major hurdle in utilizing hiPSC-CMs at their fullest potential. Here, the major findings and limitations of current maturation methodologies to enhance the utility of hiPSC-CMs in the battle against a major source of morbidity and mortality are reviewed. The most recent knowledge of the potential signaling pathways involved in the transition of fetal to adult CMs are assimilated. In particular, we take a deeper look on role of nutrient sensing signaling pathways and the potential role of cap-independent translation mediated by the modulation of mTOR pathway in the regulation of cardiac gap junctions and other yet to be identified aspects of CM maturation. Moreover, a relatively unexplored perspective on how our knowledge on the effects of preterm birth on cardiovascular development can be actually utilized to enhance the current understanding of CM maturation is examined. Furthermore, the interaction between the evolving neonatal human heart and brown adipose tissue as the major source of neonatal thermogenesis and its endocrine function on CM development is another discussed topic which is worthy of future investigation. Finally, the current knowledge regarding transcriptional mediators of CM maturation is still limited. The recent studies have produced the groundwork to better understand CM maturation in terms of providing some of the key factors involved in maturation and development of metrics for assessment of maturation which proves essential for future studies on in vitro PSC-CMs maturation.

Gene-Edited Human-Induced Pluripotent Stem Cell Lines to Elucidate DAND5 Function throughout Cardiac Differentiation

“…Curiously, it has been shown in cardiac microtissues that the localisation of Cx43 gap junctions is important for sarcomere organisation [89]. Concomitantly, the TEM images obtained from both DAND5 hiPSC-CMs suggested that the contractile machinery of these CMs is composed of low-density myofibrils and Z-bodies associated with immature CMs rather than more-mature sarcomeric structures with clear Z-disks such as those found in adult CMs [76,91]. Nevertheless, myofibrils in the DAND5-C hiPSC-CM appear to be more uniform and thicker than those displayed by the DAND5-KO hiPSC-CM, evidencing the different phenotype displayed by these DAND5 hiPSC-CM lines.…”

Cardiomyocyte external mechanical unloading activates modifications of α‐actinin differently from sarcomere‐originated unloading

“…In the case of loading, the mechanical force deforms proteins in the extracellular matrix, the focal adhesions, the numerous interior mechanosensors, and activation of signaling mediators including ERK1/2, FAK, and PKCƐ [ 28 , 30 – 32 ]. Instead of NRVMs, hiPS-CMs [ 19 , 33 ] would provide better relevance to the human than use of rodent cells. There are many 3D models that are superior to 2D in terms of cell structure and function.…”

hiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca2+-activated K+ (SK) ion channel variants associated with atrial fibrillation

“…This aspect is important to consider when investigating SK currents, which are present in hiPSC-CMs ( Zhao et al, 2018 ), given their spatiotemporal relationship with Ca 2+ sources for activation. To overcome limitations related to hiPSC-CM immaturity, tremendous efforts have gone into maturing hiPSC-CMs to improve their electro-contractile profiles, including long-term culture ( Lundy et al, 2013 ; Lewandowski et al, 2018 ), biophysical modification such as extracellular matrices ( Herron et al, 2016 ; Ogasawara et al, 2017 ) and polydimethylsiloxane (PDMS)-based polymers ( Thavandiran et al, 2013 ) with low tensile strength ( McCain et al, 2014 ; Ribeiro et al, 2015 ), metabolic and hormonal supplementation ( Nakano et al, 2017 ; Parikh et al, 2017 ; Horikoshi et al, 2019 ; Yang et al, 2019 ; Feyen et al, 2020 ), electrical stimulation ( Chan et al, 2013 ), and 3D tissue engineering ( Huethorst et al, 2016 ; Lemoine et al, 2017 ; Correia et al, 2018 ; Ulmer et al, 2018 ; Silbernagel et al, 2020 ), which have been previously reviewed in more detail elsewhere ( Hamledari et al, 2022 ). Importantly, many of these approaches have successfully improved the electro-contractile properties, as shown by: a) increased KCNJ2 expression and I K1 current density along with lower RMP values ( Nunes et al, 2013 ; Herron et al, 2016 ; Abilez et al, 2018 ; Horváth et al, 2018 ; Feyen et al, 2020 ; Huang et al, 2020 ), b) higher expression of SCN5A and upstroke velocity ( Herron et al, 2016 ; Lemoine et al, 2017 ; Feyen et al, 2020 ), c) lower HCN4 expression and I f current density ( Ronaldson-Bouchard et al, 2018 ) with lower intrinsic beating rates, d) greater Ca 2+ handling, storage, and expression of associated proteins (RyR2, SERCA, NCX1, CASQ2) ( Richards et al, 2016 ; Ruan et al, 2016 ; Parikh et al, 2017 ; Shadrin et al, 2017 ; Ronaldson-Bouchard et al, 2018 ; Feyen et al, 2020 ; Huang et al, 2020 ), and e) T-tubule formation and improved sarcomere alignment ( Mills et al, 2017 ; ...…”

“…Frontiers in Cell and Developmental Biology frontiersin.org Correia et al, 2018;Ulmer et al, 2018;Silbernagel et al, 2020), which have been previously reviewed in more detail elsewhere (Hamledari et al, 2022). Importantly, many of these approaches have successfully improved the electro-contractile properties, as shown by: a) increased KCNJ2 expression and I K1 current density along with lower RMP values (Nunes et al, 2013;Herron et al, 2016;Abilez et al, 2018;Horváth et al, 2018;Feyen et al, 2020;Huang et al, 2020), b) higher expression of SCN5A and upstroke velocity (Herron et al, 2016;Lemoine et al, 2017;Feyen et al, 2020), c) lower HCN4 expression and I f current density (Ronaldson-Bouchard et al, 2018) with lower intrinsic beating rates, d) greater Ca 2+ handling, storage, and expression of associated proteins (RyR2, SERCA, NCX1, CASQ2) (Richards et al, 2016;Ruan et al, 2016;Parikh et al, 2017;Shadrin et al, 2017;Ronaldson-Bouchard et al, 2018;Feyen et al, 2020;Huang et al, 2020), and e) T-tubule formation and improved sarcomere alignment (Mills et al, 2017;Parikh et al, 2017;Ronaldson-Bouchard et al, 2018;Feyen et al, 2020;Huang et al, 2020).…”