Objectives Cellular senescence and endothelial-to-mesenchymal transition (EndMT) are profibrotic cellular processes involved in systemic sclerosis (SSc), but how they respond to treatment is largely unknown. Methods Skin biopsies from diffuse cutaneous SSc (dcSSc) patients who underwent either autologous haematopoietic stem cell transplantation (aHSCT) or cyclophosphamide pulse (iv CYC) treatment were collected before and 6 months after randomisation in the Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial. The extent of fibrosis, inflammation, senescence, EndMT and tissue remodelling were examined in histopathology. Results Fourteen pairs of skin biopsies were analysed. Decrease in modified Rodnan skin score (mRSS) was more pronounced in aHSCT-treated patients compared with iv CYC at 6 months (median change -14 [IQR -16–-9] vs -6 [IQR -9–-4], respectively, p= 0.028). Histologically, expression of uPAR on fibroblasts, P21 on vessels and EndMT decreased after treatment in both groups, yet the reduction was more pronounced in the aHSCT group. Poor skin response was associated with high baseline CTGF on fibroblasts and low baseline P21 on vessels, with an odds ratio (OR) of 1.43 and 0.41, respectively. Furthermore, poor response was also seen in patients with a rise in CTGF on fibroblasts (OR 1.29) and P21 on vessels (OR 3.02) after treatment, p< 0.001. Conclusion Both aHSCT and iv CYC in dcSSc reduced skin thickening clinically and attenuated EndMT, but affected cellular senescence not significantly different. EndMT and uPAR were associated with fibro-remodelling activity, whereas senescence, CTGF, uPAR and vascularity were associated with treatment response.

中文翻译：

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接受环磷酰胺或 aHSCT 治疗的系统性硬化症患者的皮肤细胞衰老和 EndMT


目的 细胞衰老和内皮-间充质转化 （EndMT） 是参与系统性硬化症 （SSc） 的促纤维化细胞过程，但它们对治疗的反应在很大程度上是未知的。方法 在自体干细胞移植国际硬皮病 （ASTIS） 试验中，收集接受自体造血干细胞移植 （aHSCT） 或环磷酰胺脉冲 （IV CYC） 治疗的弥漫性皮肤 SSc （dcSSc） 患者的皮肤活检。在组织病理学中检查纤维化、炎症、衰老、EndMT 和组织重塑的程度。结果 共分析 14 对皮肤活检。与 iv CYC 相比，aHSCT 治疗患者在 6 个月时改良 Rodnan 皮肤评分 （mRSS） 的下降更为明显 （中位变化分别为 -14 [IQR -16–-9] 和 -6 [IQR -9–-4]，p = 0.028）。组织学上，两组治疗后成纤维细胞 uPAR 表达、血管 P21 表达和 EndMT 表达均降低，但 aHSCT 组降低更明显。皮肤反应差与成纤维细胞高基线 CTGF 和血管低基线 P21 相关，比值比 （OR） 分别为 1.43 和 0.41。此外，治疗后成纤维细胞 CTGF 升高 （OR 1.29） 和血管 P21 升高 （OR 3.02） 的患者反应不佳，p< 0.001。结论 aHSCT 和 iv CYC 在 dcSSc 中均能减轻临床皮肤增厚并减轻 EndMT，但对细胞衰老的影响无显著差异。EndMT 和 uPAR 与纤维重塑活性相关，而衰老、 CTGF 、 uPAR 和血管分布与治疗反应相关。