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Single cell analysis reveals inhibition of angiogenesis attenuates the progression of heterotopic ossification in Mkx^(−/−)mice

查看全文 作　　者：Junxin [1,2,3]Lin;Yuwei [1,3]Yang;Wenyan [1,3]Zhou;Chao [3]Dai;Xiao [1,2,3,4]Chen;Yuanhao [1,2]Xie;Shan [1,3]Han;Huanhuan [1,3]Liu;Yejun [1,2]Hu;Chenqi [1,2]Tang;Varitsara [1,3]Bunpetch;Dandan [5]Zhang;Yishan [1,3]Chen;Xiaohui [1,3,6]Zou;Di [3,7]Chen;Wanlu [1,3]Liu;Hongwei [1,2,3,4]Ouyang 高影响力作者 机构地区：[1]Dr.Li Dak Sum&Yip Yio Chin Center for Stem Cells and Regenerative Medicine,and Department of Orthopedic Surgery of the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China;[2]Department of Sports Medicine,Zhejiang University School of Medicine,Hangzhou,China;[3]Zhejiang University-University of Edinburgh Institute,Zhejiang University School of Medicine,and Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province,Hangzhou,China;[4]China Orthopedic Regenerative Medicine Group(CORMed),Hangzhou,China;[5]Department of Pathology,Zhejiang University School of Medicine,Hangzhou,China;[6]Clinical Research Center,The First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,China;[7]Center for Reproductive Medicine,The Second Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou,China高影响力机构 出　　处：《Bone Research》索引2022年第10卷第4期,共11页高影响力期刊 基　　金：supported by the National Key R&D Program of China(2017YFA0104900);the National Natural Science Foundation of China(31830029,81501937 and 81522029);the Fundamental Research Funds for the Central Universities(K20200099). 摘　　要：Tendon heterotopic ossification(HO)is characterized by bone formation inside tendon tissue,which severely debilitates people in their daily life.Current therapies fail to promote functional tissue repair largely due to our limited understanding of HO pathogenesis.Here,we investigate the pathological mechanism and propose a potential treatment method for HO.Immunofluorescence assays showed that the Mohawk(MKX)expression level was decreased in human tendon HO tissue,coinciding with spontaneous HO and the upregulated expression of osteochondrogenic and angiogenic genes in the tendons of Mkx^(−/−)mice.Single-cell RNA sequencing analyses of wild-type and Mkx^(−/−)tendons identified three cell types and revealed the excessive activation of osteochondrogenic genes during the tenogenesis of Mkx^(−/−)tendon cells.Single-cell analysis revealed that the gene expression program of angiogenesis,which is strongly associated with bone formation,was activated in all cell types during HO.Moreover,inhibition of angiogenesis by the small-molecule inhibitor BIBF1120 attenuated bone formation and angiogenesis in the Achilles tendons of both Mkx mutant mice and a rat traumatic model of HO.These findings provide new insights into the cellular mechanisms of tendon HO and highlight the inhibition of angiogenesis with BIBF1120 as a potential treatment strategy for HO. 关 键 词：ANGIOGENESIS OSSIFICATION analysis
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