Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
J Cell Sci. 2013 Dec 1;126(Pt 23):5422-31. doi: 10.1242/jcs.133314. Epub 2013 Oct 7.
Human mesenchymal stem cell (hMSC) aging may lead to a reduced tissue regeneration capacity and a decline in physiological functions. However, the molecular mechanisms controlling hMSC aging in the context of prelamin A accumulation are not completely understood. In this study, we demonstrate that the accumulation of prelamin A in the nuclear envelope results in cellular senescence and potential downstream regulatory mechanisms responsible for prelamin A accumulation in hMSCs. We show for the first time that ZMPSTE24, which is involved in the post-translational maturation of lamin A, is largely responsible for the prelamin A accumulation related to cellular senescence in hMSCs. Direct binding of miR-141-3p to the 3'UTR of ZMPSTE24 transcripts was confirmed using a 3'UTR-luciferase reporter assay. We also found that miR-141-3p, which is overexpressed during senescence as a result of epigenetic regulation, is able to decrease ZMPSTE24 expression levels, and leads to an upregulation of prelamin A in hMSCs. This study provides new insights into mechanisms regulating MSC aging and may have implications for therapeutic application to reduce age-associated MSC pool exhaustion.
人类间充质干细胞（hMSC）衰老可能导致组织再生能力下降和生理功能衰退。然而，在核纤层蛋白 A 积累的背景下，控制 hMSC 衰老的分子机制尚不完全清楚。在这项研究中，我们证明了核膜中 prelamin A 的积累导致细胞衰老，以及潜在的下游调节机制负责 hMSCs 中 prelamin A 的积累。我们首次表明，参与核纤层蛋白 A 翻译后成熟的 ZMPSTE24 在很大程度上负责 hMSCs 中与细胞衰老相关的 prelamin A 积累。使用 3'UTR-荧光素酶报告基因检测证实了 miR-141-3p 与 ZMPSTE24 转录物 3'UTR 的直接结合。我们还发现，miR-141-3p 在衰老过程中由于表观遗传调控而过表达，能够降低 ZMPSTE24 的表达水平，并导致 hMSCs 中 prelamin A 的上调。这项研究为调节 MSC 衰老的机制提供了新的见解，并可能对减少与年龄相关的 MSC 池耗竭的治疗应用具有重要意义。
