Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA.
Nat Med. 2011 Nov 20;17(12):1594-601. doi: 10.1038/nm.2542.
Stem cell-based regenerative medicine is a promising approach in tissue reconstruction. Here we show that proinflammatory T cells inhibit the ability of exogenously added bone marrow mesenchymal stem cells (BMMSCs) to mediate bone repair. This inhibition is due to interferon γ (IFN-γ)-induced downregulation of the runt-related transcription factor 2 (Runx-2) pathway and enhancement of tumor necrosis factor α (TNF-α) signaling in the stem cells. We also found that, through inhibition of nuclear factor κB (NF-κB), TNF-α converts the signaling of the IFN-γ-activated, nonapoptotic form of TNF receptor superfamily member 6 (Fas) in BMMSCs to a caspase 3- and caspase 8-associated proapoptotic cascade, resulting in the apoptosis of these cells. Conversely, reduction of IFN-γ and TNF-α concentrations by systemic infusion of Foxp3(+) regulatory T cells, or by local administration of aspirin, markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL/6 mice. These data collectively show a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.
基于干细胞的再生医学是组织重建的一种很有前途的方法。在这里，我们表明促炎 T 细胞抑制外源性骨髓间充质干细胞 (BMMSCs) 介导骨修复的能力。这种抑制是由于干扰素 γ (IFN-γ) 诱导的 Runt 相关转录因子 2 (Runx-2) 通路下调和干细胞中肿瘤坏死因子 α (TNF-α) 信号的增强所致。我们还发现，通过抑制核因子 κB (NF-κB)，TNF-α 将 IFN-γ 激活的、非凋亡形式的 TNF 受体超家族成员 6 (Fas) 在 BMMSCs 中的信号转导转换为 caspase 3 和 caspase 8 相关的促凋亡级联，导致这些细胞凋亡。相反，通过系统输注 Foxp3(+)调节性 T 细胞或局部给予阿司匹林来减少 IFN-γ 和 TNF-α 浓度，可显著改善 C57BL/6 小鼠的 BMMSC 基于骨再生和颅骨缺损修复。这些数据共同表明，在 BMMSC 为基础的组织工程中，受体 T 细胞具有以前未被认识到的作用。
