| Title | Single-cell analysis reveals an Angpt4-initiated EPDC-EC-CM cellular coordination cascade during heart regeneration |
| Authors | Wu, Zekai Shi, Yuan Cui, Yueli Xing, Xin Zhang, Liya Liu, Da Zhang, Yutian Dong, Ji Jin, Li Pang, Meijun Xiao, Rui-Ping Zhu, Zuoyan Xiong, Jing-Wei Tong, Xiangjun Zhang, Yan Wang, Shiqiang Tang, Fuchou Zhang, Bo |
| Affiliation | Peking Univ, Coll Life Sci, Genome Editing Res Ctr, Key Lab Cell Proliferat & Differentia,Minist Educ, Beijing 100871, Peoples R China Peking Univ, Coll Life Sci, Beijing Adv Innovat Ctr Genom ICG, Beijing 100871, Peoples R China Peking Univ, Inst Mol Med, Coll Future Technol, State Key Lab Membrane Biol, Beijing 100871, Peoples R China Peking Univ, Coll Life Sci, State Key Lab Membrane Biol, Beijing 100871, Peoples R China Peking Univ, Inst Cardiovasc Sci, Hlth Sci Ctr, Sch Basic Med Sci,Minist Educ, Beijing 100191, Peoples R China Peking Univ, Hlth Sci Ctr, Sch Basic Med Sci, Key Lab Mol Cardiovasc Sci,Minist Educ, Beijing 100191, Peoples R China Peking Univ, Inst Mol Med, Coll Future Technol, Beijing 100871, Peoples R China |
| Keywords | RNA-SEQ HEMATOPOIETIC STEM EPICARDIAL CELLS OUTFLOW TRACT ZEBRAFISH EXPRESSION QUANTIFICATION ANGIOPOIETIN-1 PROLIFERATION MIGRATION |
| Issue Date | May-2022 |
| Publisher | PROTEIN & CELL |
| Abstract | Mammals exhibit limited heart regeneration ability, which can lead to heart failure after myocardial infarction. In contrast, zebrafish exhibit remarkable cardiac regeneration capacity. Several cell types and signaling pathways have been reported to participate in this process. However, a comprehensive analysis of how different cells and signals interact and coordinate to regulate cardiac regeneration is unavailable. We collected major cardiac cell types from zebrafish and performed high-precision single-cell transcriptome analyses during both development and post-injury regeneration. We revealed the cellular heterogeneity as well as the molecular progress of cardiomyocytes during these processes, and identified a subtype of atrial cardiomyocyte exhibiting a stem-like state which may transdifferentiate into ventricular cardiomyocytes during regeneration. Furthermore, we identified a regeneration-induced cell (RIC) population in the epicardium-derived cells (EPDC), and demonstrated Angiopoietin 4 (Angpt4) as a specific regulator of heart regeneration. angpt4 expression is specifically and transiently activated in RIC, which initiates a signaling cascade from EPDC to endocardium through the Tie2-MAPK pathway, and further induces activation of cathepsin K in cardiomyocytes through RA signaling. Loss of angpt4 leads to defects in scar tissue resolution and cardiomyocyte proliferation, while overexpression of angpt4 accelerates regeneration. Furthermore, we found that ANGPT4 could enhance proliferation of neonatal rat cardiomyocytes, and promote cardiac repair in mice after myocardial infarction, indicating that the function of Angpt4 is conserved in mammals. Our study provides a mechanistic understanding of heart regeneration at single-cell precision, identifies Angpt4 as a key regulator of cardiomyocyte proliferation and regeneration, and offers a novel therapeutic target for improved recovery after human heart injuries. |
| URI | http://hdl.handle.net/20.500.11897/670328 |
| ISSN | 1674-800X |
| DOI | 10.1093/procel/pwac010 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 细胞增殖分化调控机理研究教育部重点实验室 分子医学研究所 膜生物学国家重点实验室 基础医学院 |
