Matured hiPSC-derived cardiomyocytes possess dematuration plasticity

Area of Science:

• Cardiology
• Stem Cell Biology
• Pharmacology

Background:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are vital for studying heart regeneration.
• L-type calcium channel blockers can induce proliferation in mature hiPSC-CMs, but the mechanism is unknown.
• Cardiomyocyte maturation involves centrosome disassembly, a process potentially reversible in hiPSC-CMs.

Purpose of the Study:

• To investigate the mechanism by which L-type calcium channel blockers induce hiPSC-CM proliferation.
• To explore the plasticity of mature hiPSC-CMs in response to pharmacological compounds.
• To identify factors that can induce centrosome reassembly and cell cycle activity in hiPSC-CMs.

Main Methods:

• Small molecule screening to identify compounds inducing centrosome reassembly in hiPSC-CMs.
• Assessing cell cycle activity in hiPSC-CMs and neonatal rat ventricular myocytes (NRVMs) after compound treatment.
• Differential bulk and single-cell RNA transcriptome analysis to evaluate cellular changes.

Main Results:

• Nitrendipine (L-type calcium channel blocker) and 1-NA-PP1 (Src kinase inhibitor) induced centrosome reassembly in a subpopulation of hiPSC-CMs.
• Centrosome-positive hiPSC-CMs showed increased cell cycle activity compared to centrosome-negative cells.
• Transcriptome analysis revealed that mature hiPSC-CMs, but not NRVMs, undergo dematuration upon treatment with nitrendipine or 1-NA-PP1.

Conclusions:

• Mature hiPSC-CMs exhibit plasticity and can dedifferentiate in response to L-type calcium channel blockers and Src kinase inhibitors.
• This dedifferentiation mechanism differs from that in primary cardiomyocytes (NRVMs).
• The plasticity of hiPSC-CMs has significant implications for experimental systems studying cardiomyocyte maturation and heart regeneration.