Hu Chao, Zhang Yan, Tang Kanglai, Luo Yuchun, Liu Yunpeng, Chen Wan
Department of Orthopedics, 101st Hospital of PLA, No. 101 North Xingyuan Road, Beitang District, Wuxi, Jiangsu, 214000, China.
Department of Orthopedics, Southwest Hospital, Third Military Medical University, Gaotanyan Street 30, Chongqing, 400038, China.
Cell Tissue Res. 2017 Apr;368(1):93-104. doi: 10.1007/s00441-016-2552-1. Epub 2017 Jan 13.
Tendon-derived stem cells (TDSCs) are multipotent adult stem cells with potential applications in tendon and tendon-bone junction repair. However, cellular characteristics change during in vitro passaging. Therefore, elucidation of the molecular and cellular mechanisms of tendon aging will be essential for the development of TDSC-based therapies. The aim of this study is to investigate the effect of CITED2, a nuclear regulator and transforming growth factor β2 (TGFβ2) on TDSC proliferation and senescence by comparing cells derived from Achilles tendon biopsies of young individuals (Y-TDSC) with those of older patients (O-TDSC). Our results showed that CITED2 mRNA and protein expression levels were significantly higher in Y-TDSCs than in O-TDSCs and O-TDSCs displayed decreased proliferation and increased senescence compared with Y-TDSCs. Furthermore, high levels of CITED2 protein expression in Y-TDSCs correlated with the downregulation of SP1 and p21 and the upregulation of MYC, potentially indicating the mechanism by which CITED2 upregulates TDSC proliferation. TGFβ2 was found to downregulate the expression of the CITED2 gene and knockdown of CITED2 abolished the effect of TGFβ2 on TDSC proliferation and senescence. Thus, the downregulation of CITED2 contributes to TGFβ-mediated senescence providing an insight into the molecular and cellular mechanisms that contribute to tendon aging and degeneration. Our findings may aid the development of cell-based therapies for tendon repair.
肌腱来源的干细胞（TDSCs）是多能成体干细胞，在肌腱和肌腱-骨结合处修复中具有潜在应用价值。然而，细胞特性在体外传代过程中会发生变化。因此，阐明肌腱衰老的分子和细胞机制对于基于TDSC的治疗方法的开发至关重要。本研究的目的是通过比较年轻个体跟腱活检组织来源的细胞（Y-TDSC）和老年患者的细胞（O-TDSC），研究核调节因子CITED2和转化生长因子β2（TGFβ2）对TDSC增殖和衰老的影响。我们的结果表明，Y-TDSCs中CITED2的mRNA和蛋白表达水平显著高于O-TDSCs，与Y-TDSCs相比，O-TDSCs的增殖减少且衰老增加。此外，Y-TDSCs中高水平的CITED2蛋白表达与SP1和p21的下调以及MYC的上调相关，这可能表明CITED2上调TDSC增殖的机制。发现TGFβ2可下调CITED2基因的表达，敲低CITED2可消除TGFβ2对TDSC增殖和衰老的影响。因此，CITED2的下调促成了TGFβ介导的衰老，这为导致肌腱衰老和退变的分子和细胞机制提供了见解。我们的研究结果可能有助于开发基于细胞的肌腱修复治疗方法。
