脂肪干细胞通过诱导肝星状细胞衰老减轻肝纤维化：双病因模型验证
ADSCs attenuate Liver fibrosis via inducing HSC senescence: validation in dual-etiology models.
作者信息
Mulati Mukexina, Yang Ning, Xue Junlong, Li Liang, Zhang Xue, Liu Hui, Chu Jin, Lü Guodong, Kusuman Nuerbaiti, He Xiaolong, Aji Tuerganaili, Bi Xiaojuan, Lin Renyong
机构信息
State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
Department of Hepatobiliary and Hydatid Diseases, Digestive and Vascular Surgery Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
出版信息
PLoS Negl Trop Dis. 2025 May 22;19(5):e0013094. doi: 10.1371/journal.pntd.0013094. eCollection 2025 May.
BACKGROUND
Liver fibrosis (LF) results from various causes, which require finding conserved mechanisms to help treat related diseases. Although adipose-derived stem cells (ADSCs) transplantation can alleviate hepatic fibrosis, their mechanism remains unclear. Accordingly, we explored the efficacy and mechanisms behind ADSCs transplantation in two LF models.
METHODOLOGY
The carbon tetrachloride (CCl4)-induced liver injury and Echinococcus multilocularis (E. multilocularis) infection models were established, and ADSCs were transplanted. Mouse liver samples were harvested and analyzed histologically. Expression levels of fibrosis and senescence-related proteins were analyzed by immunohistochemistry. Hepatic stellate cells (HSCs) activation and cell senescence protein expression were evaluated via western blotting. Co-localization expression was determined by immunofluorescence. To assess the cellular senescence degree, we utilized senescence-associated β-galactosidase (SA-β-Gal) staining.
RESULT
In the CCl4-induced LF mouse model, the liver surface exhibited a rough texture. The hematoxylin and eosin (H&E) staining revealed hepatic parenchymal cell destruction accompanied by pseudolobule formation and fibrosis in the portal area. In the E. multilocularis infection model, multiple white foci were on the liver surface. The H&E staining revealed massive inflammatory cell infiltration around the foci with severe fibrosis, and Sirius Red confirmed collagen deposition; both had elevated HSCs activation (α-SMA expression). After ADSCs transplantation, the collagen deposition and HSCs activation significantly diminished, while the cellular senescence levels increased. Immunofluorescence co-localization of p21 and a-SMA showed that transplantation of ADSCs promoted senescence of activated HSCs (aHSCs). In vitro co-culture had similar results, accompanied by expression changes and TGF-β/Smad signaling inhibition.
CONCLUSION
Our findings indicate that ADSCs transplantation can mitigate fibrosis by inducing the senescence of aHSCs and reducing collagen production.
背景
肝纤维化（LF）由多种原因引起，需要找到保守机制以帮助治疗相关疾病。尽管脂肪来源干细胞（ADSCs）移植可减轻肝纤维化，但其机制仍不清楚。因此，我们在两种肝纤维化模型中探究了ADSCs移植背后的疗效和机制。
方法
建立四氯化碳（CCl4）诱导的肝损伤和多房棘球绦虫（E. multilocularis）感染模型，并进行ADSCs移植。采集小鼠肝脏样本并进行组织学分析。通过免疫组织化学分析纤维化和衰老相关蛋白的表达水平。通过蛋白质印迹法评估肝星状细胞（HSCs）的激活和细胞衰老蛋白表达。通过免疫荧光确定共定位表达。为评估细胞衰老程度，我们采用衰老相关β-半乳糖苷酶（SA-β-Gal）染色。
结果
在CCl4诱导的肝纤维化小鼠模型中，肝脏表面质地粗糙。苏木精-伊红（H&E）染色显示肝实质细胞破坏，伴有假小叶形成和门管区纤维化。在多房棘球绦虫感染模型中，肝脏表面有多个白色病灶。H&E染色显示病灶周围有大量炎性细胞浸润，伴有严重纤维化，天狼星红证实有胶原沉积；两者均有HSCs激活（α-SMA表达）升高。ADSCs移植后，胶原沉积和HSCs激活明显减少，而细胞衰老水平增加。p21和α-SMA的免疫荧光共定位显示，ADSCs移植促进了活化HSCs（aHSCs）的衰老。体外共培养有类似结果，伴有表达变化和TGF-β/Smad信号抑制。
结论
我们的研究结果表明，ADSCs移植可通过诱导aHSCs衰老和减少胶原产生来减轻纤维化。
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