Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-05-07 DOI:10.1038/s41413-024-00324-w
Xinshu Zhang, Yao Xiao, Bo Hu, Yanhao Li, Shaoyang Zhang, Jian Tian, Shuo Wang, Zaijin Tao, Xinqi Zeng, Ning-Ning Liu, Baojie Li, Shen Liu
{"title":"Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration","authors":"Xinshu Zhang, Yao Xiao, Bo Hu, Yanhao Li, Shaoyang Zhang, Jian Tian, Shuo Wang, Zaijin Tao, Xinqi Zeng, Ning-Ning Liu, Baojie Li, Shen Liu","doi":"10.1038/s41413-024-00324-w","DOIUrl":null,"url":null,"abstract":"<p>Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1<sup>+</sup> macrophages, RGCC<sup>+</sup> endothelial cells, ACKR1<sup>+</sup> endothelial cells and ADAM12<sup>+</sup> fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2<sup>+</sup> macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2<sup>+</sup> macrophages migration at the injured peritendinous site by transplantation of bone marrow from <i>Lysm-Cre;R26R</i><sup><i>tdTomato</i></sup> mice to lethally irradiated <i>Ackr1</i><sup><i>−/−</i></sup> mice (<i>Ackr1</i><sup><i>−/−</i></sup> chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2<sup>+</sup> macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2<sup>+</sup> macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.</p>","PeriodicalId":9134,"journal":{"name":"Bone Research","volume":null,"pages":null},"PeriodicalIF":14.3000,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bone Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41413-024-00324-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0

Abstract

Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1−/− mice (Ackr1−/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

Abstract Image

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
对人体肌腱粘附的多组学分析表明,ACKR1调控的巨噬细胞迁移参与了再生过程
肌腱粘连是肌腱损伤后常见的并发症,在没有有效抗纤维化疗法的情况下,会形成累积性纤维化组织,导致严重残疾。巨噬细胞被广泛认为是肌腱周围粘连形成过程中的纤维化诱因。然而,不同的巨噬细胞集群具有不同的功能,并受到多重调控,而这两点目前都还是未知数。在我们目前的研究中,我们对人类和小鼠肌腱损伤后不同阶段的肌腱粘连组织进行了多组学分析,包括单细胞 RNA 测序和蛋白质组学。我们对超过 74000 个人类单细胞的转录组进行了分析。结果发现,SPP1+巨噬细胞、RGCC+内皮细胞、ACKR1+内皮细胞和ADAM12+成纤维细胞参与了肌腱粘连的形成。有趣的是,尽管肌腱粘连中存在特定的纤维化集群,但利用人体细胞进行的体外实验发现,FOLR2+巨噬细胞是抗纤维化集群。此外,通过将Lysm-Cre;R26RtdTomato小鼠的骨髓移植到经致命照射的Ackr1-/-小鼠(Ackr1-/-嵌合体;缺乏ACKR1)和对照小鼠(WT嵌合体)体内,验证了ACKR1能调节FOLR2+巨噬细胞在损伤的腱周部位的迁移。与 WT 嵌合体相比,我们还观察到 FOLR2+ 巨噬细胞的减少,这表明 ACKR1 特别参与了 FOLR2+ 巨噬细胞的迁移。综上所述,我们的研究不仅通过多组学分析描述了肌腱粘附的纤维化微环境图谱,还发现了一个新的巨噬细胞抗纤维化集群及其起源。这些结果为人类肌腱粘连提供了潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
期刊最新文献
IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2. Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect Osteopetrosis-like disorders induced by osteoblast-specific retinoic acid signaling inhibition in mice A monoallelic variant in CCN2 causes an autosomal dominant spondyloepimetaphyseal dysplasia with low bone mass Periostin+ myeloid cells improved long bone regeneration in a mechanosensitive manner
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1