Abstract

Multipotent mesenchymal stromal cells (MMSCs) are promising to treat a variety of traumatic and degenerative diseases. However, in vitro-passage aging induces cell cycle arrest and a series of genetic and biological changes, which greatly limits ex vivo cell number expansion and further clinical application of MMSCs. In most cases, DNA damage and DNA damage response (DDR) act as the main cause and executor of cellular senescence respectively. Mechanistically, DNA damage signals induce cell cycle arrest and DNA damage repair via DDR. If the DNA damage is indelible, MMSCs would entry into a permanent cell cycle arrest. It should be noted that apart from DDR signaling, certain proliferation or metabolism pathways are also occupied in DNA damage related cell cycle arrest. New findings of these aspects will also be summarized in this study. In summary, we aim to provide a comprehensive review of DDR associated cell cycle regulation and other major molecular signaling in the senescence of MMSCs. Above knowledge could contribute to improve the limited capacity of in vitro expansion of MMSCs, and then promote their clinical applications.

中文翻译：

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DNA损伤反应控制老年多能间充质基质细胞的细胞周期限制

摘要

多能间充质基质细胞（MMSC）有望用于治疗各种创伤性和退行性疾病。然而，体外衰老诱导细胞周期停滞以及一系列遗传和生物学变化，这极大地限制了离体细胞数量的扩展以及MMSC的进一步临床应用。在大多数情况下，DNA损伤和DNA损伤反应（DDR）分别是细胞衰老的主要原因和执行者。从机理上讲，DNA损伤信号通过DDR诱导细胞周期停滞和DNA损伤修复。如果DNA损伤无法消除，则MMSC将进入永久性细胞周期停滞期。应该注意的是，除了DDR信号传导外，DNA损伤相关的细胞周期阻滞中也存在某些增殖或代谢途径。这些方面的新发现也将在本研究中进行总结。综上所述，我们旨在提供有关DDR相关细胞周期调控和MMSC衰老中其他主要分子信号传导的全面综述。上述知识可能有助于提高MMSC体外扩增的有限能力，然后促进其临床应用。