背景:新鲜分离的未培养的脂肪组织来源的基质细胞(u-ADSCs),含有杂项细胞,例如相对丰富的间充质干细胞,对修复和再生治疗有吸引力。然而,从受疾病影响的宿主获得的u-ADSCs的详细特征和治疗效果尚不清楚.我们比较了从野生型小鼠和非酒精性脂肪性肝炎(NASH)小鼠模型获得的u-ADSC的特性。
方法:通过喂养C57BL/6J小鼠动脉粥样硬化高脂饮食4周(NASH(4w))或12周(NASH(12w))建立NASH模型,随后是u-ADSCs的分离和表征。将野生型u-ADSCs或NASH衍生的u-ADSCs给予NASH肝硬化小鼠,然后分析肝脏炎症细胞,抗原谱,纤维化,和基因表达。
结果:野生型u-ADSCs和NASH衍生的u-ADSCs在表面抗原谱中没有显示出明显的差异。在NASH(4w)u-ADSCs中,但不是NASH(12w)u-ADSCs,白细胞标记CD11b的频率,CD45和CD44升高;此外,我们观察到M1/M2巨噬细胞比例仅在NASH(12w)u-ADSCs中增加。仅在NASH-4wu-ADSCs中,细胞周期相关基因的表达水平高于u-ADSCs。对NASH相关肝硬化小鼠给予野生型u-ADSCs减少CD11b+的浸润,F4/80+,和Gr-1+炎症细胞,改善纤维化,对肝脏组织有修复作用,由基因表达谱和NAFLD活性评分确定。NASH(4w)u-ADSCs和NASH(12w)u-ADSCs对NASH相关性肝硬化的治疗效果与野生型u-ADSCs的疗效高度相似。包括减少炎症和纤维化。
结论:NASH衍生的u-ADSCs,与野生型u-ADSCs相似,适用于NASH小鼠的修复和再生治疗。
BACKGROUND: Freshly isolated uncultured adipose tissue-derived stromal cells (u-ADSCs), containing miscellaneous cells like the relatively abundant mesenchymal stem cells, are attractive for repair and regenerative therapy. However, the detailed characteristics and therapeutic efficacy of u-ADSCs obtained from disease-affected hosts are unknown. We compared the properties of u-ADSCs obtained from wild-type mice and from a mouse model of non-alcoholic steatohepatitis (NASH).
METHODS: The NASH model was established by feeding C57BL/6J mice an atherogenic high-fat diet for 4 (NASH (4w)) or 12 weeks (NASH (12w)), followed by the isolation and characterization of u-ADSCs. Wild-type u-ADSCs or NASH-derived u-ADSCs were administered to mice with NASH cirrhosis, followed by analyses of hepatic inflammatory cells, antigen profiles, fibrosis, and gene expression.
RESULTS: Wild-type u-ADSCs and NASH-derived u-ADSCs did not show marked differences in surface antigen profiles. In NASH (4w) u-ADSCs, but not NASH (12w) u-ADSCs, the frequencies of the leukocyte markers CD11b, CD45, and CD44 were elevated; furthermore, we observed an increase in the M1/M2 macrophage ratio only in NASH (12w) u-ADSCs. Only in NASH-4w u-ADSCs, the expression levels cell cycle-related genes were higher than those in u-ADSCs. Wild-type u-ADSCs administered to mice with NASH-related cirrhosis decreased the infiltration of CD11b+, F4/80+, and Gr-1+ inflammatory cells, ameliorated fibrosis, and had a restorative effect on liver tissues, as determined by gene expression profiles and the NAFLD activity score. The therapeutic effects of NASH (4w) u-ADSCs and NASH (12w) u-ADSCs on NASH-related cirrhosis were highly similar to the effect of wild-type u-ADSCs, including reductions in inflammation and fibrosis.
CONCLUSIONS: NASH-derived u-ADSCs, similar to wild-type u-ADSCs, are applicable for reparative and regenerative therapy in mice with NASH.