Spatial transcriptomic analysis deciphers adipocyte-to-fibroblast transformation in bleomycin-induced murine skin fibrosis  

作　　者：Yixiang Zhang Jiahao He Fangzhou Xie Shengzhou Shan Jiaqi Qin Chuandong Wang Qingfeng Li Yun Xie Bin Fang 

机构地区：[1]Department of Plastic&Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [2]Shanghai Institute for Plastic and Reconstructive Surgery,Shanghai,China.Department of Plastic&Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China [3]Department of Orthopedic Surgery,Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine(SJTUSM),Shanghai 200092,China

出　　处：《Chinese Medical Journal》2024年第22期2745-2757,共13页中华医学杂志(英文版)

基　　金：supported from grants from the National Natural Science Foundation of China(No.82102327);Clinical Research Program of 9th People’s Hospital,Shanghai JiaoTong University School of Medicine(No.JYLJ202103)。

摘　　要：Background:Scleroderma is characterized by inflammation and fibrosis,predominantly occurring in the skin and extending to various parts of the body.The pathophysiology of scleroderma is multifaceted,with the current understanding including endothelial damage,inflammatory cell infiltration,and fibroblast activation in its progression.Nonetheless,the mechanism of cellular interactions and the precise spatial distribution of these cellular events within the fibrotic tissues remain elusive,highlighting a critical gap in our comprehensive understanding of scleroderma’s pathogenesis.Methods:In this study,we administered bleomycin intradermally to the dorsal skin of four individual murine models.Subsequently,skin tissues were harvested at predetermined intervals for comprehensive spatial transcriptomic analysis to determine the spatial dynamics influencing scleroderma pathogenesis.To validate the possible results from bioinformatic analysis,further in vitro and in vivo experiments were conducted.Results:Analysis of the spatial transcriptome revealed significant alterations in cell clusters during the progression of scleroderma.Gene Ontology analysis identified disruptions in lipid metabolism as the disease advanced.Pseudotime analysis provided evidence for a phenotypic transition from adipocytes to fibroblasts.In vitro studies demonstrated increased expression of Col1a1 andα-SMA as the disease progressed.These fibroblasts have been identified as key contributors to the increasing inflammation.Co-culturing TGF-βinduced adipocytes with RAW264.7 cells resulted in overexpression of pro-inflammatory cytokines in the RAW264.7 cells.Both in vitro and in vivo experiments confirmed adipocyte loss and fibroblast formation,with transformed fibroblasts showing pronounced pro-inflammatory characteristics,highlighting their crucial role in the disease mechanism.Conclusions:Our study showed the spatial distribution and dynamic alterations of various cell types during scleroderma progression.Crucially,we identified the transformati

关 键 词：Spatial transcriptome SCLERODERMA ADIPOCYTES Fibroblasts 

分 类 号：R73[医药卫生—肿瘤]