Mesenchymal-Stem-Cell-Induced Immunoregulation Involves FAS-Ligand-/FAS-Mediated T Cell Apoptosis

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• 作者：Kentaro Akiyama¹ ; ² ; ⁵ ; Chider Chen¹ ; ⁵ ; DanDan Wang³ ; ⁵ ; Xingtian Xu¹ ; Cunye Qu¹ ; Takayoshi Yamaza¹ ; Tao Cai⁴ ; WanJun Chen⁴ ; Lingyun Sun³ ; ^{lingyunsun2011@yahoo.com.cn} ; Songtao Shi¹ ; ^{songtaos@usc.edu}
• 刊名：Cell Stem Cell
• 出版年：2012
• 期刊代码：P15_19345909
• 类别：bio
• 出版时间：4 May, 2012
• 卷：10
• 期：5
• 页码：544-555
• 文件大小：2394 K

摘要

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Summary

Systemic infusion of bone marrow mesenchymal stem cells (BMMSCs) yields therapeutic benefit for a variety of autoimmune diseases, but the underlying mechanisms are poorly understood. Here we show that in mice systemic infusion of BMMSCs induced transient T聽cell apoptosis via the FAS ligand (FASL)-dependent FAS pathway and could ameliorate disease phenotypes in fibrillin-1 mutated systemic sclerosis (SS) and dextran-sulfate-sodium-induced experimental colitis. FASL^{鈭?鈭?/sup>} BMMSCs did not induce T聽cell apoptosis in recipients, and could not ameliorate SS and colitis. Mechanistic analysis revealed that FAS-regulated monocyte chemotactic protein 1 (MCP-1) secretion by BMMSCs recruited T聽cells for FASL-mediated apoptosis. The apoptotic T聽cells subsequently triggered macrophages to produce high levels of TGF尾, which in turn led to the upregulation of CD4⁺CD25⁺Foxp3⁺ regulatory T聽cells and, ultimately, immune tolerance. These data therefore demonstrate a previously unrecognized mechanism underlying BMMSC-based immunotherapy involving coupling via FAS/FASL to induce T聽cell apoptosis.