Sasi Sharath P, Rahimi Layla, Yan Xinhua, Silver Marcy, Qin Gangjian, Losordo Douglas W, Kishore Raj, Goukassian David A
Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA;
Cardiovascular Research Center, GeneSys Research Institute, Boston, Massachusetts, USA; Tufts University School of Medicine, Boston, Massachusetts, USA;
FASEB J. 2015 Apr;29(4):1208-19. doi: 10.1096/fj.14-249813. Epub 2014 Dec 2.
We have previously shown that TNF-tumor necrosis factor receptor-2/p75 (TNFR2/p75) signaling plays a critical role in ischemia-induced neovascularization in skeletal muscle and heart tissues. To determine the role of TNF-TNFR2/p75 signaling in ischemia-induced inflammation and muscle regeneration, we subjected wild-type (WT) and TNFR2/p75 knockout (p75KO) mice to hind limb ischemia (HLI) surgery. Ischemia induced significant and long-lasting inflammation associated with considerable decrease in satellite-cell activation in p75KO muscle tissue up to 10 d after HLI surgery. To determine the possible additive negative roles of tissue aging and the absence of TNFR2/p75, either in the tissue or in the bone marrow (BM), we generated 2 chimeric BM transplantation (BMT) models where both young green fluorescent protein (GFP)-positive p75KO and WT BM-derived cells were transplanted into adult p75KO mice. HLI surgery was performed 1 mo after BMT, after confirming complete engraftment of the recipient BM with GFP donor cells. In adult p75KO with the WT-BMT, proliferative (Ki67(+)) cells were detected only by d 28 and were exclusively GFP(+), suggesting significantly delayed contribution of young WT-BM cell to adult p75KO ischemic tissue recovery. No GFP(+) young p75KO BM cells survived in adult p75KO tissue, signifying the additive negative roles of tissue aging combined with decreased/absent TNFR2/p75 signaling in postischemic recovery.
我们之前已经表明，肿瘤坏死因子-肿瘤坏死因子受体-2/p75（TNFR2/p75）信号通路在骨骼肌和心脏组织缺血诱导的新生血管形成中起关键作用。为了确定TNF-TNFR2/p75信号通路在缺血诱导的炎症和肌肉再生中的作用，我们对野生型（WT）和TNFR2/p75基因敲除（p75KO）小鼠进行了后肢缺血（HLI）手术。在HLI手术后长达10天的时间里，缺血在p75KO肌肉组织中诱导了显著且持久的炎症，同时卫星细胞活化显著减少。为了确定组织衰老以及组织或骨髓（BM）中TNFR2/p75缺失可能产生的叠加负面作用，我们构建了2种嵌合骨髓移植（BMT）模型，将年轻的绿色荧光蛋白（GFP）阳性p75KO和WT骨髓来源的细胞都移植到成年p75KO小鼠体内。在确认受体骨髓被GFP供体细胞完全植入后1个月进行HLI手术。在接受WT-BMT的成年p75KO小鼠中，仅在第28天检测到增殖（Ki67(+)）细胞，且这些细胞均为GFP(+)，这表明年轻的WT-BM细胞对成年p75KO缺血组织恢复的贡献显著延迟。在成年p75KO组织中没有存活的GFP(+)年轻p75KO BM细胞，这表明组织衰老与TNFR2/p75信号通路减少/缺失相结合在缺血后恢复中具有叠加负面作用。
