Recent advances in regulating the proliferation or maturation of human-induced pluripotent stem cell-derived cardiomyocytes

Abstract

In the last decade, human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM)-based cell therapy has drawn broad attention as a potential therapy for treating injured hearts. However, mass production of hiPSC-CMs remains challenging, limiting their translational potential in regenerative medicine. Therefore, multiple strategies including cell cycle regulators, small molecules, co-culture systems, and epigenetic modifiers have been used to improve the proliferation of hiPSC-CMs. On the other hand, the immaturity of these proliferative hiPSC-CMs could lead to lethal arrhythmias due to their limited ability to functionally couple with resident cardiomyocytes. To achieve functional maturity, numerous methods such as prolonged culture, biochemical or biophysical stimulation, in vivo transplantation, and 3D culture approaches have been employed. In this review, we summarize recent approaches used to promote hiPSC-CM proliferation, and thoroughly review recent advances in promoting hiPSC-CM maturation, which will serve as the foundation for large-scale production of mature hiPSC-CMs for future clinical applications.

Keywords: Cardiac differentiation; Cardiomyocytes; Human-induced pluripotent stem cells; Maturation; Proliferation.

Fig. 1

Comparison of hiPSC-CMs with adult CMs in terms of morphology, structure, gene expression, cell cycle, metabolism, and electrophysiology. NCX, sodium–calcium exchanger; RYR2, ryanodine receptor 2; MYH6, myosin heavy chain 6; MYH7, myosin heavy chain 7; TNNI1, troponin I1, slow skeletal type; TNNI3, troponin I3, cardiac type. Red arrows indicate upregulation, and blue arrows indicate downregulation. The figure was drawn by the authors in Adobe Illustrator

Fig. 2

Overview of strategies that promote hiPSC-CM proliferation or maturation. The blue half circle indicates methods to promote hiPSC-CM proliferation. The red half circle indicates methods to promote hiPSC-CM maturation. The red-blue gradient indicates methods that provide pipelines to promote hiPSC-CM maturation or proliferation. The figure was drawn by the authors in Adobe Illustrator