Stage-specific regulation of Gremlin1 on the differentiation and expansion of human urinary induced pluripotent stem cells into endothelial progenitors
Stage-specific regulation of Gremlin1 on the differentiation and expansion of human urinary induced pluripotent stem cells into endothelial progenitors
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Gremlin1 对人尿诱导多能干细胞向内皮祖细胞分化和扩增的阶段特异性调节
DOI：
10.1111/jcmm.15433
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发表时间：
2020-05-28
影响因子：
5.3
通讯作者：
Xiang, Qiuling
中科院分区：
文献类型：
--
作者：
Chen, Haixuan;Zhang, Zhen;Xiang, Qiuling
由存在于尿液中的脱落的肾上皮细胞产生的人尿诱导多能干细胞（hUiPSC）可以提供用于治疗缺血性疾病的内皮祖细胞的非侵入性来源。然而，它们的分化效率并不令人满意，并且分化的潜在机制仍然未知。Gremlin 1（GREM 1）是一个参与细胞分化的重要基因。因此，我们试图阐明GREM 1在内皮祖细胞分化和扩增过程中的作用。HUiPSC通过三个阶段诱导为内皮祖细胞。在hUiPSC诱导的内皮祖细胞（hUiPSC-EPs）中，分化后GREM 1明显增加。RNA干扰（RNAi）分别在三个阶段沉默GREM 1的表达。我们证明了GREM 1在中胚层诱导阶段（第1阶段）中降低hUiPSC-EP分化，而在内皮祖细胞诱导阶段（第2阶段）和扩增阶段（第3阶段）中增加分化的阶段特异性作用。在内皮祖细胞扩增阶段（第3阶段）外源性添加GREM 1重组蛋白促进hUiPSC-EPs的扩增，尽管激活了VEGFR 2/Akt或VEGFR 2/p42/44 MAPK通路。我们的研究为内皮祖细胞提供了一种新的非侵入性来源，证明了GREM 1在hUiPSC-EP中的关键作用，并为改善缺血性疾病的干细胞治疗提供了一种新的策略。
Human urinary induced pluripotent stem cells (hUiPSCs) produced from exfoliated renal epithelial cells present in urine may provide a non-invasive source of endothelial progenitors for the treatment of ischaemic diseases. However, their differentiation efficiency is unsatisfactory and the underlying mechanism of differentiation is still unknown. Gremlin1 (GREM1) is an important gene involved in cell differentiation. Therefore, we tried to elucidate the roles of GREM1 during the differentiation and expansion of endothelial progenitors. HUiPSCs were induced into endothelial progenitors by three stages. After differentiation, GREM1 was obviously increased in hUiPSC-induced endothelial progenitors (hUiPSC-EPs). RNA interference (RNAi) was used to silence GREM1 expression in three stages, respectively. We demonstrated a stage-specific effect of GREM1 in decreasing hUiPSC-EP differentiation in the mesoderm induction stage (Stage 1), while increasing differentiation in the endothelial progenitors' induction stage (Stage 2) and expansion stage (Stage 3). Exogenous addition of GREM1 recombinant protein in the endothelial progenitors' expansion stage (Stage 3) promoted the expansion of hUiPSC-EPs although the activation of VEGFR2/Akt or VEGFR2/p42/44MAPK pathway. Our study provided a new non-invasive source for endothelial progenitors, demonstrated critical roles of GREM1 in hUiPSC-EP and afforded a novel strategy to improve stem cell-based therapy for the ischaemic diseases.