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单细胞多组学分析鉴定出促进心脏修复的巨噬细胞亚群。

Single-cell multiomic analysis identifies macrophage subpopulations in promoting cardiac repair.

机构信息

Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.

Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

出版信息

J Clin Invest. 2024 Aug 27;134(19):e175297. doi: 10.1172/JCI175297.

DOI:10.1172/JCI175297
PMID:39190625
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11444165/
Abstract

Cardiac mononuclear phagocytic cells (Cardiac MPCs) participate in maintaining homeostasis and orchestrating cardiac responses upon injury. However, the function of specific MPC subtypes and the related cell fate commitment mechanisms remain elusive in regenerative and nonregenerative hearts due to their cellular heterogeneities. Using spatiotemporal single-cell epigenomic analysis of cardiac MPCs in regenerative (P1) and nonregenerative (P10) mouse hearts after injury, we found that P1 hearts accumulate reparative Arg1+ macrophages, while proinflammatory S100a9+Ly6c+ monocytes are uniquely abundant during nonregenerative remodeling. Moreover, blocking chemokine CXCR2 to inhibit the specification of the S100a9+Ly6c+-biased inflammatory fate in P10 hearts resulted in elevated wound repair responses and marked improvements in cardiac function after injury. Single-cell RNA-Seq further confirmed an increased Arg1+ macrophage subpopulation after CXCR2 blockade, which was accomplished by increased expression of wound repair-related genes and reduced expression of proinflammatory genes. Collectively, our findings provide instructive insights into the molecular mechanisms underlying the function and fate specification of heterogeneous MPCs during cardiac repair and identify potential therapeutic targets for myocardial infarction.

摘要

心脏单核吞噬细胞（Cardiac MPCs）参与维持内稳态，并在损伤时协调心脏反应。然而，由于其细胞异质性，在再生和非再生心脏中，特定 MPC 亚型的功能和相关细胞命运决定机制仍然难以捉摸。通过对再生（P1）和非再生（P10）小鼠心脏损伤后心脏单核吞噬细胞的时空单细胞表观基因组分析，我们发现 P1 心脏积累了修复性 Arg1+巨噬细胞，而在非再生重塑过程中，促炎 S100a9+Ly6c+单核细胞则特别丰富。此外，阻断趋化因子 CXCR2 以抑制 P10 心脏中 S100a9+Ly6c+-偏向炎症命运的特化，导致伤口修复反应增加，并在损伤后显著改善心脏功能。单细胞 RNA-Seq 进一步证实，CXCR2 阻断后 Arg1+巨噬细胞亚群增加，这是通过增加与伤口修复相关的基因表达和减少促炎基因表达来实现的。总之，我们的研究结果为心脏修复过程中异质性 MPCs 的功能和命运特化的分子机制提供了有指导意义的见解，并确定了心肌梗死的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/010f8c89c91c/jci-134-175297-g102.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/a6a25e2ff45e/jci-134-175297-g103.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/13dad538eae3/jci-134-175297-g104.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/c05e86e5878a/jci-134-175297-g105.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/fdb730bf4f48/jci-134-175297-g106.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/d0d531300e0c/jci-134-175297-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/c7280af2272c/jci-134-175297-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/b9c4c1c2de00/jci-134-175297-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/5bb287495b05/jci-134-175297-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/a2113232c1fd/jci-134-175297-g101.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/010f8c89c91c/jci-134-175297-g102.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/d0668c561454/jci-134-175297-g100.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/a6a25e2ff45e/jci-134-175297-g103.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/13dad538eae3/jci-134-175297-g104.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/c05e86e5878a/jci-134-175297-g105.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/fdb730bf4f48/jci-134-175297-g106.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/d0d531300e0c/jci-134-175297-g107.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/c7280af2272c/jci-134-175297-g108.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/b9c4c1c2de00/jci-134-175297-g109.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/5bb287495b05/jci-134-175297-g110.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/a2113232c1fd/jci-134-175297-g101.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5739/11444165/010f8c89c91c/jci-134-175297-g102.jpg

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