MicroRNA-302 induces proliferation and inhibits oxidant-induced cell death in human adipose tissue-derived mesenchymal stem cells.
MicroRNA-302 induces proliferation and inhibits oxidant-induced cell death in human adipose tissue-derived mesenchymal stem cells.
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DOI：
10.1038/cddis.2014.344
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发表时间：
2014-08-21
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
间充质干细胞（MSCs）是一种异质细胞群，在体外作为可塑贴壁细胞增殖，具有成纤维细胞样形态，在体外形成菌落，可以分化为骨、软骨和脂肪细胞。皮下脂肪组织的丰富、容易和可重复获取以及简单的分离程序为人类脂肪组织来源的间充质干细胞（hasdc）在临床应用中提供了明显的优势。我们筛选了影响hascs增殖和存活的microrna （mirna）。转染miR-302d模拟物可增加hascs中的细胞增殖，并保护细胞免受氧化诱导的细胞死亡，这一点得到了流式细胞术分析的支持。miR-302d不影响Bcl-2家族成员或抗氧化分子的表达。Nrf2-Keap1系统是细胞防御氧化应激的主要机制之一，转染miR-302d模拟物未改变Nrf2-Keap1系统。为了确定miR-302d对hADSCs增殖和存活的作用靶点，我们使用过表达miR-302d的hADSCs进行了微阵列分析。Real-time PCR分析显示转染miR-302d mimic可抑制CDKN1A和CCL5的表达。用特定的siRNA下调CDKN1A模拟miR-302d对hascs增殖的影响，但不影响miR-302d诱导的细胞存活。下调CCL5与miR-302d一样保护氧化诱导的细胞死亡，抑制氧化诱导的活性氧（ROS）的产生，重组CCL5的加入抑制了miR-302d对氧化诱导的细胞死亡的保护作用。本研究表明，miR-302通过不同的靶点控制hascs的增殖和细胞存活，该miRNA可在体内增强hascs移植的治疗效果。
Mesenchymal stem cells (MSCs) are a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells, have a fibroblast-like morphology, form colonies in vitro and can differentiate into bone, cartilage and fat cells. The abundance, ease and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide clear advantages for the use of human adipose tissue-derived mesenchymal stem cells (hASDCs) in clinical applications. We screened microRNAs (miRNAs) that affected the proliferation and survival of hADSCs. Transfection of miR-302d mimic increased cell proliferation and protected cells from oxidant-induced cell death in hADSCs, which was supported by flow-cytometric analysis. miR-302d did not affect the expression of Bcl-2 family members or anti-oxidant molecules. The Nrf2-Keap1 system, which is one of the major mechanisms for the cellular defense against oxidative stress, was not altered by transfection of miR-302d mimic. To identify the target of the miR-302d actions on proliferation and survival of hADSCs, a microarray analysis was performed using miR-302d-overexpressing hADSCs. Real-time PCR analysis showed that transfection of miR-302d mimic inhibited the CDKN1A and CCL5 expression. Downregulation of CDKN1A with a specific siRNA mimicked the effect of miR-302d on hADSCs proliferation, but did not affect miR-302d-induced cell survival. Downregulation of CCL5 protected oxidant-induced cell death as miR-302d, inhibited oxidant-induced reactive oxygen species (ROS) generation and the addition of recombinant CCL5 inhibited the protective action of miR-302d on oxidant-induced cell death. This study indicates that miR-302 controls proliferation and cell survival of hADSCs through different targets and that this miRNA can be used to enhance the therapeutic efficacy of hADSCs transplantation in vivo.
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