Mitochondrial Maturation in Human Pluripotent Stem Cell Derived Cardiomyocytes

Abstract

Human pluripotent stem cells derived cardiomyocytes (PSC-CMs) have been widely used for disease modeling, drug safety screening, and preclinical cell therapy to regenerate myocardium. Most studies have utilized PSC-CM grown in vitro for a relatively short period after differentiation. These PSC-CMs demonstrated structural, electrophysiological, and mechanical features of primitive cardiomyocytes. A few studies have extended in vitro PSC-CM culture time and reported improved maturation of structural and electromechanical properties. The degree of mitochondrial maturation, however, remains unclear. This study characterized the development of mitochondria during prolonged in vitro culture. PSC-CM demonstrated an improved mitochondrial maturation with prolonged culture, in terms of increased mitochondrial relative abundance, enhanced membrane potential, and increased activity of several mitochondrial respiratory complexes. These are in parallel with the maturation of other cellular components. However, the maturation of mitochondria in PSC-CMs grown for extended in vitro culture exhibits suboptimal maturation when compared with the maturation of mitochondria observed in the human fetal heart during similar time interval.

IGF1 and NRG1 Enhance Proliferation, Metabolic Maturity, and the Force-Frequency Response in hESC-Derived Engineered Cardiac Tissues

“…Our results also show that hESC-cardiomyocyte metabolism can be manipulated with biochemical stimulation, but in a manner that increases mitochondrial content (biogenesis). Recent work has demonstrated that mitochondria number increases during maturation of hPSC-cardiomyocytes in long-term culture, and our results suggest a means to expedite this process [ 49 ]. Currently, the field is limited to metabolic measurements of hESC-cardiomyocytes in 2D cultures, and yet we believe these data accurately represent the metabolic behavior of engineered 3D tissues because they provide plausible explanations for the phenomena observed in 3D, namely an increased rate of medium acidification (apparent with overnight color change to yellow in phenol red-containing culture medium) and decreased force production.…”

Pioglitazone Protects Mesenchymal Stem Cells against P-Cresol-Induced Mitochondrial Dysfunction via Up-Regulation of PINK-1

“…CKD leads to cardiovascular disease and fibrosis through hyperhomocysteinemia, oxidant stress, dyslipidemia, and elevated inflammation [ 19 ]. Exposure to high concentrations of uremic compounds reduces cell proliferation, cell migration, and cell pluripotency in MSCs via mitochondrial dysfunction potential [ 20 , 21 , 22 , 23 ]. Recent studies have demonstrated that MSC-based therapy is one of the best candidates for regeneration and healing in CKD [ 24 , 25 ].…”

Changing Metabolism in Differentiating Cardiac Progenitor Cells—Can Stem Cells Become Metabolically Flexible Cardiomyocytes?

“…When stem/progenitor cells differentiate to cardiomyocytes they need to increase the number of their mitochondria and upregulate FA metabolism (Figure 3 ). A study comparing hiPSC-derived cardiomyocytes (hiPSC-CM) to hiPSCs, showed an increase in mitochondrial relative abundance and activity (mitochondria membrane potential) as a result of cardiac differentiation ( 160 ) and that additional mitochondrial maturation in hiPSC-CMs could be achieved by long-term culture (3 months). Comparison of substrate metabolism in ESCs with that in ESC-derived cardiomyocytes has shown increased oxidative metabolism after differentiation ( 161 ) and that the respiratory capacity of cardiomyocytes was higher than in ESCs, resulting in an increased ADP:ATP ratio in the cardiomyocytes ( 106 ).…”