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PRDM16 Modulates Aspects of Cell-Cycle Dynamics and Maturation in Human iPSC-Derived Cardiomyocytes

ABSTRACT: Understanding the molecular mechanisms that mediate entry into quiescent states of cardiac tissues, along with their associated metabolic rewiring, is crucial for comprehending the postnatal changes driving physiological hypertrophy and functional maturation. PRDM16 has been identified as a critical regulator of both proliferation and maturation in fetal-like human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Our study demonstrates that PRDM16 orchestrates the proliferative axis of hiPSC-CMs by modulating CDK1 and phospho-AKT levels, two key drivers of cardiac proliferation. Reduced PRDM16 expression significantly impairs the metabolic and structural maturation of hiPSC-CMs, leading to dysregulated sarcomeric protein expression ratios and compromised engineered heart tissue (EHT) function. Conversely, mild PRDM16 overexpression promotes metabolic shifts and structural protein changes toward maturation. These findings provide new insights into the molecular mechanisms governing cardiomyocyte development and highlight PRDM16 as a potential therapeutic target for enhancing cardiac regeneration and repair, since transient PRDM16 downregulation creates a roadblock to maturation in favor of proliferation. Overall, this work underscores the central role of PRDM16 in controlling the proliferation-maturation axis of cardiomyocyte biology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307782 | GEO | 2026/07/08

REPOSITORIES: GEO

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Project description:Human induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) are increasingly used to identify potential factors capable of inducing endogenous cardiomyocyte proliferation to regenerate the injured heart. L-type calcium channel blockers have previously been identified as a class of factors capable of inducing matured hiPSC-CMs to proliferate. However, the mechanism by which L-type calcium channel blockers promote hiPSC-CM proliferation remains unclear. Here we provide evidence that matured hiPSC-CMs possess plasticity to undergo dematuration in response to certain pharmacological compounds. Consistent with primary cardiomyocyte maturation during perinatal development, we found that centrosome disassembly occurs in hiPSC-CMs during plate-based, temporal, maturation. A small molecule screen identified Nitrendipine, an L-type calcium channel blocker, and 1-NA-PP1, a Src kinase inhibitor, as factors capable of inducing centrosome reassembly in a subpopulation of hiPSC-CMs. Furthermore, centrosome-positive hiPSC-CMs were more likely to exhibit cell cycle activity than centrosome-negative hiPSC-CMs. In contrast, neither Nitrendipine or 1-NA-PP1 induced centrosome reassembly, or cell cycle activity, in neonatal rat ventricular myocytes (NRVMs). Differential bulk transcriptome analysis indicated that matured hiPSC-CMs, but not NRVMs, treated with Nitrendipine or 1-NA-PP1 undergo dematuration. ScRNA transcriptome analysis supported that matured hiPSC-CMs treated with either Nitrendipine or 1-NA-PP1 undergo dematuration. Collectively, our results indicate that matured hiPSC-CMs, but not primary NRVMs, possess plasticity to undergo dematuration in response to certain pharmacological compounds such as L-type calcium channel blockers and Src-kinase inhibitors. This study shows that once mature, hiPSC-CMs may not maintain their maturity under experimental conditions and thus may have implications for experimental systems where the state of hiPSC-CM maturation is relevant.

Project description:Rationale: Inducing cardiomyocyte proliferation in situ is an attractive approach for achieving cardiac regeneration after myocardial injury. However, numerous inhibitory mechanisms are present in cardiomyocytes that silence the pro-proliferative signals for their expansion. We hypothesized that cell-cell contact exerts a major suppressive effect on cardiomyocyte proliferation. Objectives: This study aims to uncover the molecular mechanisms underlying cell contact-mediated inhibition of cardiomyocyte proliferation and leverage this knowledge to sustain proliferation of cardiomyocytes in 3D despite cell-cell contact. Methods and Results: Using human iPSC-derived cardiomyocytes (hiPSC-CMs) as a model system, we found that the proliferative capacity of hiPSC-CMs is initially increased proportional to cell density until cells form intercellular contacts. We found that cell-cell contact exerts a strong inhibitory effect on hiPSC-CM proliferation as cell density increases. Phosphoproteomics analysis and cellular phenotyping revealed that cell-cell contact accompanies adherens junction formation, enhanced sarcomere organization, and increased contractility. Disruption of adherens junctions or sarcomere assembly via siRNA-mediated knockdown of N-cadherin or ɑ-actinin, respectively, resulted in increased cell cycle activation of hiPSC-CMs. Furthermore, disruption of cell-cell contact enhanced nuclear translocation of β-catenin and TCF/LEF transcriptional activity that contributed to hiPSC-CM proliferation. However, this was not sufficient to drive division of hiPSC-CMs. Additional screening for putative secreted growth factors in the conditioned media from sparsely plated hiPSC-CMs revealed the enrichment of IGFBP2, which was sufficient to drive hiPSC-CM division in the presence of cell-cell contact in 3D constructs. Conclusions: Our findings demonstrate that cell-cell contact inhibits hiPSC-CM proliferation through adherens junction formation, sarcomeric assembly, and reduced IGFBP2 secretion. Importantly, exogenous supplementation of IGFBP2 can overcome cell contact-mediated inhibition of hiPSC-CM proliferation and facilitate the growth of 3D cardiac tissue. These insights provide valuable implications for advancing cardiac tissue engineering and regenerative therapies.

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PRDM16 Modulates Aspects of Cell-Cycle Dynamics and Maturation in Human iPSC-Derived Cardiomyocytes

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