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Injury-induced Clusterin plus cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages

文献类型：期刊论文

作者Fan, Lei5; Tang, Qi5; Wang, Yutong5; Sun, Hang7; Li, Ge4,15; Yang, Yi5; Zhu, Huiying5; Liu, Zhaoyuan1; Wang, He2,3; Wang, Hongyan8
刊名CELL STEM CELL
出版日期2025-12-04
卷号32期号:12页码:36
ISSN号1934-5909
DOI10.1016/j.stem.2025.10.008
通讯作者Zhou, Zhigang(zhou_zhigang1980@163.com) ; Zeng, An(azeng@sibcb.ac.cn)
英文摘要Adult hearts scar after injury, while neonatal hearts regenerate. The mechanisms underlying this dichotomy remain unclear. Through comparative spatiotemporal single-cell analyses and dual recombinase-mediated lineage tracing, we uncovered an injury-induced Clusterin+ cardiomyocyte (Clu+ CM) population that coordinates reparative, anti-inflammatory macrophage activity. Following injury, Clu+ CMs emerge in the border zone of regenerative hearts but are scarce in non-regenerative contexts. These CMs secrete CLU, which binds to macrophage Toll-like receptor 4 (TLR4), attenuating inflammation and promoting reparative polarization through Cpt1a-dependent fatty acid oxidation. These macrophages secrete bone morphogenetic protein 2 (BMP2), activating bone morphogenetic protein receptor, type 1A (BMPR1A) signaling in CMs to drive proliferation. Reduced CLU levels in myocardial infarction patients correlate with impaired cardiac function, whereas Clu overexpression or transplantation of engineered CLU + human cardiac organoids recapitulates this regenerative modulation, enhancing myocardial repair in adult mice. Ourfindings reveal a critical cardioimmune mechanism whereby Clu+ CMs reprogram macrophages to resolve inflammation and stimulate CM proliferation, providing potential strategies for cardiac regeneration.
WOS关键词ISCHEMIA-REPERFUSION INJURY ; FATTY-ACID OXIDATION ; NF-KAPPA-B ; SINGLE-CELL ; MYOCARDIAL-INFARCTION ; MOSAIC ANALYSIS ; DOUBLE MARKERS ; ER STRESS ; EXPRESSION ; PROLIFERATION
资助项目National Key R&D Program of China[2021YFA1100202] ; National Key R&D Program of China[2020YFA0112502] ; National Natural Science Foundation of China[92168206] ; National Natural Science Foundation of China[32570997] ; National Natural Science Foundation of China[32070828] ; Science and Technology Commission of Shanghai Municipality[YDZX20243100004003] ; Science and Technology Commission of Shanghai Municipality[22ZR1468400] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1030000] ; CAS Pioneer Hundred Talents Program ; Shanghai Pujiang Program[20PJ1414600] ; Feng Foundation for Biomedical Research
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:001637762800002
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/322366]  
专题中国科学院上海药物研究所
通讯作者Zhou, Zhigang; Zeng, An
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Immunol, Shanghai 200025, Peoples R China
2.Tongji Univ, Shanghai Peoples Hosp 4, Dept Radiol, Sch Med, Shanghai 200083, Peoples R China
3.Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai 201203, Peoples R China
4.Peking Univ, Tsinghua Univ, Natl Inst Biol Sci Joint Grad Program, Acad Adv Interdisciplinary Studies, Beijing 100871, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci, Univ Chinese Acad Sci,Key Lab Multicell Syst, Shanghai 200031, Peoples R China
6.Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Crit Care Med, Shanghai 201620, Peoples R China
7.Jilin Univ, Coll Comp Sci & Technol, Key Lab Symbol Computat & Knowledge Engn, Minist Educ, Changchun 130012, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab RNA Innovat Sci & Engn, Shanghai 200031, Peoples R China
9.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Innovat Ctr Intervent Chron Dis & Promot Hlth, Shanghai 200031, Peoples R China
10.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Fan, Lei,Tang, Qi,Wang, Yutong,et al. Injury-induced Clusterin plus cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages[J]. CELL STEM CELL,2025,32(12):36.
APA Fan, Lei.,Tang, Qi.,Wang, Yutong.,Sun, Hang.,Li, Ge.,...&Zeng, An.(2025).Injury-induced Clusterin plus cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages.CELL STEM CELL,32(12),36.
MLA Fan, Lei,et al."Injury-induced Clusterin plus cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages".CELL STEM CELL 32.12(2025):36.

入库方式： OAI收割

来源：上海药物研究所

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