Single cell analysis reveals inhibition of angiogenesis attenuates the progression of heterotopic ossification in Mkx(-/-) mice.
Single cell analysis reveals inhibition of angiogenesis attenuates the progression of heterotopic ossification in Mkx(-/-) mice.
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DOI：
10.1038/s41413-021-00175-9
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发表时间：
2022-01-07
期刊：
影响因子：
12.7
通讯作者：
Ouyang H
中科院分区：
文献类型：
--
作者：
Lin J;Yang Y;Zhou W;Dai C;Chen X;Xie Y;Han S;Liu H;Hu Y;Tang C;Bunpetch V;Zhang D;Chen Y;Zou X;Chen D;Liu W;Ouyang H
肌腱异位骨化（HO）的特点是肌腱组织内骨形成，严重损害人们的日常生活。目前的疗法未能促进功能性组织修复，很大程度上是由于我们对 HO 发病机制的了解有限。在这里，我们研究了 HO 的病理机制并提出了一种潜在的治疗方法。免疫荧光分析显示，人肌腱 HO 组织中 Mohawk (MKX) 表达水平降低，与自发性 HO 以及 Mkx−/− 小鼠肌腱中骨软骨生成和血管生成基因表达上调一致。对野生型和 Mkx−/− 肌腱的单细胞 RNA 测序分析确定了三种细胞类型，并揭示了 Mkx−/− 肌腱细胞的肌腱形成过程中骨软骨形成基因的过度激活。单细胞分析表明，与骨形成密切相关的血管生成基因表达程序在 HO 期间在所有细胞类型中都被激活。此外，小分子抑制剂 BIBF1120 对血管生成的抑制作用减弱了 Mkx 突变小鼠和 HO 大鼠创伤模型跟腱中的骨形成和血管生成。这些发现为肌腱 HO 的细胞机制提供了新的见解，并强调了 BIBF1120 抑制血管生成作为 HO 的潜在治疗策略。
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.
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影响因子：
82.9
作者：
Bi, Yanming;Ehirchiou, Driss;Young, Marian F.
通讯作者：
Young, Marian F.
影响因子：
64.8
作者：
Kusumbe AP;Ramasamy SK;Adams RH
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Adams RH
AfterQC：fastq数据的自动过滤、修剪、错误消除和质量控制
影响因子：
3
作者：
Chen S;Huang T;Zhou Y;Han Y;Xu M;Gu J
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影响因子：
4.6
作者：
Gehwolf R;Wagner A;Lehner C;Bradshaw AD;Scharler C;Niestrawska JA;Holzapfel GA;Bauer HC;Tempfer H;Traweger A
通讯作者：
Traweger A
影响因子：
5.3
作者：
Docheva, D;Hunziker, EB;Brandau, O
通讯作者：
Brandau, O