Department of Physiology, School of Medicine, Pusan National University, Yangsan, Gyeongnam, Korea.
Stem Cells Dev. 2012 Jul 1;21(10):1749-60. doi: 10.1089/scd.2011.0429. Epub 2011 Nov 21.
The reduction of adult stem cell self-renewal can be an important mechanism of aging. MicroRNAs have been reported to be involved in aging processes. Through a microarray approach, we have identified miR-486-5p, the expression of which is progressively expressed in human adipose tissue-derived mesenchymal stem cells (hAT-MSCs) with aging. Overexpression of miR-486-5p induces a premature senescence-like phenotype and inhibits proliferation of hAT-MSCs and inhibits adipogenic and osteogenic differentiation, whereas inhibition of miR-486-5p has the opposite effects. miR-486-5p regulates the expression of silent information regulator 1 (SIRT1), a major regulator of longevity and metabolic disorders. Decrease of SIRT1 deacetylase activity in hAT-MSCs is correlated with their passage number. miR-486-5p inhibits SIRT1 expression through a miR-486-5p binding site within the 3'-untranslated region of SIRT1. Overexpression of miR-486-5p inhibits SIRT1 deacetylase activity in hAT-MSCs, and transfection of miR-486-5p inhibitor shows the opposite effect. Downregulation of SIRT1 in hAT-MSCs induces senescence and inhibits cell proliferation. Exposure to high glucose increases miR-486-5p expression and inhibits SIRT1 expression in hAT-MSCs. Our data pinpoint miR-486-5p as an endogenous inhibitor of SIRT1 that promotes hAT-MSCs senescence and is potentially applicable to therapeutic manipulation of hAT-MSCs dysfunction in metabolic disorders.
成体干细胞自我更新的减少可能是衰老的一个重要机制。已有报道称 microRNAs 参与衰老过程。通过微阵列方法，我们已经鉴定出 miR-486-5p，其表达在衰老的人脂肪组织来源间充质干细胞（hAT-MSCs）中逐渐表达。miR-486-5p 的过表达诱导出一种早衰样表型，并抑制 hAT-MSCs 的增殖，同时抑制脂肪生成和成骨分化，而抑制 miR-486-5p 则有相反的效果。miR-486-5p 调节沉默信息调节因子 1（SIRT1）的表达，SIRT1 是长寿和代谢紊乱的主要调节因子。hAT-MSCs 中 SIRT1 脱乙酰酶活性的降低与它们的传代数有关。miR-486-5p 通过 SIRT1 3'非翻译区中的 miR-486-5p 结合位点来抑制 SIRT1 的表达。miR-486-5p 的过表达抑制了 hAT-MSCs 中的 SIRT1 脱乙酰酶活性，而 miR-486-5p 抑制剂的转染则表现出相反的效果。下调 hAT-MSCs 中的 SIRT1 会诱导衰老并抑制细胞增殖。高葡萄糖暴露会增加 hAT-MSCs 中 miR-486-5p 的表达并抑制 SIRT1 的表达。我们的数据指出 miR-486-5p 是 SIRT1 的内源性抑制剂，可促进 hAT-MSCs 衰老，并可能适用于代谢紊乱中 hAT-MSCs 功能障碍的治疗干预。
