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心肌细胞的出生后状态转变是心脏成熟的首要步骤。

Postnatal state transition of cardiomyocyte as a primary step in heart maturation.

机构信息

Shenzhen Key Laboratory of Cardiovascular Disease, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, 518057, China.

State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.

出版信息

Protein Cell. 2022 Nov;13(11):842-862. doi: 10.1007/s13238-022-00908-4. Epub 2022 Apr 8.

DOI:10.1007/s13238-022-00908-4
PMID:35394262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9237199/
Abstract

Postnatal heart maturation is the basis of normal cardiac function and provides critical insights into heart repair and regenerative medicine. While static snapshots of the maturing heart have provided much insight into its molecular signatures, few key events during postnatal cardiomyocyte maturation have been uncovered. Here, we report that cardiomyocytes (CMs) experience epigenetic and transcriptional decline of cardiac gene expression immediately after birth, leading to a transition state of CMs at postnatal day 7 (P7) that was essential for CM subtype specification during heart maturation. Large-scale single-cell analysis and genetic lineage tracing confirm the presence of transition state CMs at P7 bridging immature state and mature states. Silencing of key transcription factor JUN in P1-hearts significantly repressed CM transition, resulting in perturbed CM subtype proportions and reduced cardiac function in mature hearts. In addition, transplantation of P7-CMs into infarcted hearts exhibited cardiac repair potential superior to P1-CMs. Collectively, our data uncover CM state transition as a key event in postnatal heart maturation, which not only provides insights into molecular foundations of heart maturation, but also opens an avenue for manipulation of cardiomyocyte fate in disease and regenerative medicine.

摘要

心脏在出生后的成熟是心脏正常功能的基础，为心脏修复和再生医学提供了重要的见解。虽然静态的成熟心脏图谱为其分子特征提供了很多的了解，但在出生后心肌细胞成熟过程中很少发现几个关键事件。在这里，我们报告说，心肌细胞（CMs）在出生后立即经历了心脏基因表达的表观遗传和转录下降，导致 P7 时的 CM 过渡状态，这对于心脏成熟过程中的 CM 亚型特化至关重要。大规模单细胞分析和遗传谱系追踪证实了 P7 时存在过渡状态的 CM，它连接了未成熟状态和成熟状态。在 P1 心脏中沉默关键转录因子 JUN 显著抑制 CM 过渡，导致 CM 亚型比例失调，并降低成熟心脏的心脏功能。此外，将 P7-CM 移植到梗死心脏中表现出优于 P1-CM 的心脏修复潜力。总的来说，我们的数据揭示了 CM 状态转换是出生后心脏成熟的一个关键事件，它不仅为心脏成熟的分子基础提供了深入了解，也为疾病和再生医学中的心肌细胞命运操纵开辟了途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/4fbb2d21fa7f/13238_2022_908_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/e8cba936115f/13238_2022_908_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/b29509199bf1/13238_2022_908_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/5a3b4418e6a8/13238_2022_908_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/e9590a44cc12/13238_2022_908_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/00b3e545bfe9/13238_2022_908_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/4fbb2d21fa7f/13238_2022_908_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/e8cba936115f/13238_2022_908_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/b29509199bf1/13238_2022_908_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/5a3b4418e6a8/13238_2022_908_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/e9590a44cc12/13238_2022_908_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/00b3e545bfe9/13238_2022_908_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b58f/9237199/4fbb2d21fa7f/13238_2022_908_Fig6_HTML.jpg

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