Low-dose telomerase is required for the expansion and migration of placental mesenchymal stem cells
Low-dose telomerase is required for the expansion and migration of placental mesenchymal stem cells
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DOI：
10.1016/j.bbrc.2022.10.093
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发表时间：
2022-11-04
影响因子：
3.1
通讯作者：
Zeng, Sicong
中科院分区：
文献类型：
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作者：
He, Caixia;Zhang, Xiaorui;Zeng, Sicong
端粒酶在多能干细胞和大多数肿瘤中被激活，并且被认为是获得自我更新和长期增殖所必需的。胎盘间充质干细胞（PMSCs）由于其强大的自我更新能力和分化潜力，在再生医学中非常有前景。尽管胎盘中的端粒酶活性天然较低，但仍不清楚端粒酶活性是否是 PMSC 特性所必需的。我们在此分离并鉴定了携带 hTERT 复合杂合子变异的 PMSC 系（DC-PMSC），其丧失端粒酶活性，显示出 MSC 的典型表面表型，并且能够分化为多个细胞谱系。 DC-PMSCs表现出端粒侵蚀加速、衰老提前以及迁移和侵袭能力减弱。 RNA-seq鉴定出DCPMSCs和对照组之间的361个差异表达基因，其中大部分富集于细胞外基质、ECM和相关通路。 PMSC 中端粒酶亚基基因的敲除证实了表型并减弱了细胞外基质成分和基质金属蛋白酶的表达。我们的结果表明，低端粒酶活性对于 MSC 的特性并不重要，但它是群落维持和 PMSC 迁移所必需的。
Telomerase is activated in pluripotent stem cells and the majority of tumors and is postulated to be necessary for the acquisition of self-renewal and long-term proliferation. Placental mesenchymal stem cells (PMSCs) are very promising in regenerative medicine owing to their great capacity for self-renewal and differentiation potential. Although telomerase activity in the placenta is naturally low, it remains unclear whether telomerase activity is required for the properties of PMSCs. We herein isolated and identified a PMSC line carrying compound heterozygote variations in hTERT (DC-PMSCs) that lost telomerase activity, showed a typical surface phenotype of MSCs, and was able to differentiate into multiple cell lineages. DC-PMSCs showed accelerated telomere erosion, advanced senescence, and diminished migratory and invasive capabilities. RNA-seq identified 361 differentially expressed genes between DCPMSCs and control groups, most of which were enriched in extracellular matrix, ECM, and related pathways. Knockdown of telomerase subunit genes in PMSCs confirmed the phenotype and attenuated the expression of extracellular matrix components and matrix metalloproteases. Our results suggest that low telomerase activity is not essential for the properties of MSCs, but that it is required for community maintenance and for the migration of PMSCs.