Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence-Based Pipeline.

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence-Based Pipeline.
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DOI:
10.3389/fbioe.2022.914450
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发表时间:
2022
影响因子:
5.7
通讯作者:
Zhang, Jianyi
Zhang, Jianyi
中科院分区:
工程技术2区
文献类型:
--
作者:
Nguyen, Thanh;Wei, Yuhua;Nakada, Yuji;Zhou, Yang;Zhang, Jianyi

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Adult mammalian cardiomyocytes have very limited capacity to proliferate and repair the myocardial infarction. However, when apical resection (AR) was performed in pig hearts on postnatal day (P) 1 (ARP1) and acute myocardial infarction (MI) was induced on P28 (MIP28), the animals recovered with no evidence of myocardial scarring or decline in contractile performance. Furthermore, the repair process appeared to be driven by cardiomyocyte proliferation, but the regulatory molecules that govern the ARP1-induced enhancement of myocardial recovery remain unclear. Single-nucleus RNA sequencing (snRNA-seq) data collected from fetal pig hearts and the hearts of pigs that underwent ARP1, MIP28, both ARP1 and MI, or neither myocardial injury were evaluated via autoencoder, cluster analysis, sparse learning, and semisupervised learning. Ten clusters of cardiomyocytes (CM1–CM10) were identified across all experimental groups and time points. CM1 was only observed in ARP1 hearts on P28 and was enriched for the expression of T-box transcription factors 5 and 20 (TBX5 and TBX20, respectively), Erb-B2 receptor tyrosine kinase 4 (ERBB4), and G Protein-Coupled Receptor Kinase 5 (GRK5), as well as genes associated with the proliferation and growth of cardiac muscle. CM1 cardiomyocytes also highly expressed genes for glycolysis while lowly expressed genes for adrenergic signaling, which suggested that CM1 were immature cardiomyocytes. Thus, we have identified a cluster of cardiomyocytes, CM1, in neonatal pig hearts that appeared to be generated in response to AR injury on P1 and may have been primed for activation of CM cell-cycle activation and proliferation by the upregulation of TBX5, TBX20, ERBB4, and GRK5.
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