SARA suppresses myofibroblast precursor transdifferentiation in fibrogenesis in a mouse model of scleroderma.
SARA suppresses myofibroblast precursor transdifferentiation in fibrogenesis in a mouse model of scleroderma.
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DOI：
10.1172/jci.insight.160977
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发表时间：
2022-11-08
期刊：
影响因子：
8
通讯作者：
Hayashida T
中科院分区：
文献类型：
--
作者：
Corano Scheri K;Liang X;Dalal V;Le Poole IC;Varga J;Hayashida T
我们之前报道过Smad锚定受体激活（SARA）在维持上皮细胞表型中起关键作用。在这里，我们发现SARA在硬皮病小鼠模型中抑制了肌成纤维细胞前体细胞的转分化。在PDGFR-β+周细胞和泛白细胞（SARATg）中特异性过表达SARA的小鼠，与野生型窝鼠（SARAWT）相比，在博莱霉素注射反应中发生的皮肤纤维化明显减少。皮肤PDGFR-β+细胞的单细胞RNA-Seq分析表明，在纤维化刺激下，周细胞亚群具有肌成纤维细胞特征，而SARA过表达阻断了这种转变。此外，博莱霉素治疗后，SARAWT小鼠中表达与Th2细胞和巨噬细胞活化相关的分子簇富集，而SARATg小鼠中则没有。博莱霉素治疗的SARAWT小鼠和硬皮病（或系统性硬化症，SSc）患者皮肤中th2特异性Il-31表达增加。受体配体分析表明，在SARAWT小鼠中，淋巴细胞介导周细胞转分化，而SARA过表达会抑制周细胞的肌成纤维细胞活性。综上所述，这些数据表明，在SSc的发病机制中，肌成纤维细胞前体和免疫细胞之间可能存在一种新的串扰，其中SARA起着关键作用。
We previously reported that Smad anchor for receptor activation (SARA) plays a critical role in maintaining epithelial cell phenotype. Here, we show that SARA suppressed myofibroblast precursor transdifferentiation in a mouse model of scleroderma. Mice overexpressing SARA specifically in PDGFR-β+ pericytes and pan-leukocytes (SARATg) developed significantly less skin fibrosis in response to bleomycin injection compared with wild-type littermates (SARAWT). Single-cell RNA-Seq analysis of skin PDGFR-β+ cells implicated pericyte subsets assuming myofibroblast characteristics under fibrotic stimuli, and SARA overexpression blocked the transition. In addition, a cluster that expresses molecules associated with Th2 cells and macrophage activation was enriched in SARAWT mice, but not in SARATg mice, after bleomycin treatment. Th2-specific Il-31 expression was increased in skin of the bleomycin-treated SARAWT mice and patients with scleroderma (or systemic sclerosis, SSc). Receptor-ligand analyses indicated that lymphocytes mediated pericyte transdifferentiation in SARAWT mice, while with SARA overexpression the myofibroblast activity of pericytes was suppressed. Together, these data suggest a potentially novel crosstalk between myofibroblast precursors and immune cells in the pathogenesis of SSc, in which SARA plays a critical role.
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DOI：
10.1161/atvbaha.119.313715
发表时间：
2020-03-01
影响因子：
8.7
作者：
Bordenave, Jennifer;Tu, Ly;Guignabert, Christophe
通讯作者：
Guignabert, Christophe
影响因子：
4.4
作者：
Denton, Christopher P.
通讯作者：
Denton, Christopher P.
DOI：
10.1111/bpa.12888
发表时间：
2020-11
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Ding R;Hase Y;Ameen-Ali KE;Ndung'u M;Stevenson W;Barsby J;Gourlay R;Akinyemi T;Akinyemi R;Uemura MT;Polvikoski T;Mukaetova-Ladinska E;Ihara M;Kalaria RN
通讯作者：
Kalaria RN
影响因子：
3.7
作者：
Bhattacharyya S;Sargent JL;Du P;Lin S;Tourtellotte WG;Takehara K;Whitfield ML;Varga J
通讯作者：
Varga J
影响因子：
64.5
作者：
Chuang, Jen-Zen;Zhao, Yu;Sung, Ching-Hwa
通讯作者：
Sung, Ching-Hwa