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.

中文翻译：

---

Gremlin1对人尿诱导的多能干细胞向内皮祖细胞分化和扩增的阶段特异性调节。

由尿液中脱落的肾上皮细胞产生的人尿诱导的多能干细胞（hUiPSC）可能为治疗缺血性疾病提供了非侵入性的内皮祖细胞来源。然而，它们的分化效率不能令人满意，并且分化的潜在机理仍是未知的。Gremlin1（GREM1）是参与细胞分化的重要基因。因此，我们试图阐明GREM1在内皮祖细胞分化和扩增过程中的作用。HUiPSCs通过三个阶段被诱导为内皮祖细胞。分化后，在hUiPSC诱导的内皮祖细胞（hUiPSC-EPs）中GREM1明显增加。RNA干扰（RNAi）分别在三个阶段沉默GREM1表达。我们证明了GREM1在中胚层诱导阶段（阶段1）减少hUiPSC-EP分化，同时在内皮祖细胞诱导阶段（阶段2）和扩增阶段（阶段3）增加分化的阶段性作用。尽管VEGFR2 / Akt或VEGFR2 / p42 / 44MAPK途径被激活，但在内皮祖细胞的扩增阶段（阶段3）外源添加GREM1重组蛋白促进了hUiPSC-EPs的扩增。我们的研究为内皮祖细胞提供了新的非侵入性来源，证明了GREM1在hUiPSC-EP中的关键作用，并为改善基于干细胞的缺血性疾病治疗提供了新的策略。诱导阶段（阶段2）和扩展阶段（阶段3）。尽管VEGFR2 / Akt或VEGFR2 / p42 / 44MAPK途径被激活，但在内皮祖细胞的扩增阶段（阶段3）外源添加GREM1重组蛋白促进了hUiPSC-EPs的扩增。我们的研究为内皮祖细胞提供了新的非侵入性来源，证明了GREM1在hUiPSC-EP中的关键作用，并为改善基于干细胞的缺血性疾病治疗提供了新的策略。诱导阶段（阶段2）和扩展阶段（阶段3）。尽管VEGFR2 / Akt或VEGFR2 / p42 / 44MAPK途径被激活，但在内皮祖细胞的扩增阶段（阶段3）外源添加GREM1重组蛋白促进了hUiPSC-EPs的扩增。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GREM1在hUiPSC-EP中的关键作用，并为改善基于干细胞的缺血性疾病治疗提供了新的策略。