p300 的减少通过 p53/p21 信号通路促进 hUC-MSCs 的细胞衰老和生长抑制。
Decline of p300 contributes to cell senescence and growth inhibition of hUC-MSCs through p53/p21 signaling pathway.
机构信息
Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China; Stem Cell Biology and Therapy Laboratory of Ministry of Education Key Laboratory for Pediatrics, The Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China; China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing, 400014, China.
出版信息
Biochem Biophys Res Commun. 2019 Jul 12;515(1):24-30. doi: 10.1016/j.bbrc.2019.05.061. Epub 2019 May 20.
Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) in vitro expansion for long term may undergo epigenetic and genetic alterations that subsequently induce cellular senescence and associated growth inhibition. Increasing evidence implicated that aberrant histone acetylation modulates gene expression responsible for MSCs aging. Whether the dysregulation of p300 and its KAT activity is involved in the aging process of MSCs was still unexplored. In this study, we found a significant decrease of p300 but elevated p53/p21 levels in senescent hUC-MSCs at late-passage. Then we used two different approaches: (i) downregulation of p300 by siRNA and (ii) inhibition of the acetyltransferase(KAT) activity by C646 to determine the role of p300 in regulating MSCs senescence. We showed that inhibition of p300 induce premature senescence and decrease proliferation potential in hUC-MSCs. Moreover, upregulations of p53 and p21 expressions were confirmed in p300 knockdown and C646-treated hUC-MSCs. Taken together, these results suggest that p300 plays an important role in aging process of MSCs associated with activation of p53/p21 signaling pathway.
人脐带间充质基质细胞（hUC-MSCs）在体外长期扩增过程中可能会经历表观遗传和遗传改变，随后诱导细胞衰老和相关的生长抑制。越来越多的证据表明，异常的组蛋白乙酰化调节负责 MSC 衰老的基因表达。p300 及其 KAT 活性的失调是否参与 MSC 的衰老过程仍未被探索。在这项研究中，我们发现衰老的 hUC-MSCs 在晚期传代时 p300 显著减少，但 p53/p21 水平升高。然后我们使用了两种不同的方法：（i）用 siRNA 下调 p300 和（ii）用 C646 抑制乙酰转移酶（KAT）活性来确定 p300 在调节 MSC 衰老中的作用。我们表明，抑制 p300 会诱导 hUC-MSCs 过早衰老并降低增殖潜能。此外，在 p300 敲低和 C646 处理的 hUC-MSCs 中，p53 和 p21 的表达上调得到了证实。综上所述，这些结果表明 p300 在与 p53/p21 信号通路激活相关的 MSC 衰老过程中发挥重要作用。
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