Genetic correction of Werner syndrome gene reveals impaired pro-angiogenic function and HGF insufficiency in mesenchymal stem cells.,Aging Cell

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Genetic correction of Werner syndrome gene reveals impaired pro-angiogenic function and HGF insufficiency in mesenchymal stem cells.
Aging Cell ( IF 8.0 ) Pub Date : 2020-04-22 , DOI: 10.1111/acel.13116
Jiajie Tu _{1,

2,

3} , Chao Wan _{1,

4,

5} , Fengjie Zhang _{1,

5} , Lianbao Cao ₃ , Patrick Wai Nok Law ₁ , Yuyao Tian ₁ , Gang Lu _{1,

3} , Owen M Rennert ₆ , Wai-Yee Chan _{1,

3,

5} , Hoi-Hung Cheung _{1,

3,

4,

5}

Affiliation

WRN mutation causes a premature aging disease called Werner syndrome (WS). However, the mechanism by which WRN loss leads to progeroid features evident with impaired tissue repair and regeneration remains unclear. To determine this mechanism, we performed gene editing in reprogrammed induced pluripotent stem cells (iPSCs) derived from WS fibroblasts. Gene correction restored the expression of WRN. WRN^+/+ mesenchymal stem cells (MSCs) exhibited improved pro‐angiogenesis. An analysis of paracrine factors revealed that hepatocyte growth factor (HGF) was downregulated in WRN^−/− MSCs. HGF insufficiency resulted in poor angiogenesis and cutaneous wound healing. Furthermore, HGF was partially regulated by PI3K/AKT signaling, which was desensitized in WRN^−/− MSCs. Consistently, the inhibition of the PI3K/AKT pathway in WRN^+/+ MSC resulted in reduced angiogenesis and poor wound healing. Our findings indicate that the impairment in the pro‐angiogenic function of WS‐MSCs is due to HGF insufficiency and PI3K/AKT dysregulation, suggesting trophic disruption between stromal and epithelial cells as a mechanism for WS pathogenesis.

中文翻译：

Werner综合征基因的遗传校正显示间充质干细胞中促血管生成功能受损和HGF功能不足。

WRN突变会导致一种称为Werner综合征（WS）的过早衰老疾病。然而，WRN丢失导致早衰特征的机制明显，受损的组织修复和再生能力尚不清楚。为了确定该机制，我们在源自WS成纤维细胞的重编程诱导多能干细胞（iPSC）中进行了基因编辑。基因校正恢复了WRN的表达。WRN ^{+ / +}间充质干细胞（MSC）表现出改善的促血管生成作用。对旁分泌因子的分析显示，在WRN ^-/- MSC中肝细胞生长因子（HGF）被下调。HGF功能不全导致血管生成不良和皮肤伤口愈合。此外，HGF受PI3K / AKT信号传导部分调节，而PI3K / AKT信号传导在WRN ^-/- MSC。一致地，WRN ^{+ / +} MSC中PI3K / AKT途径的抑制导致血管生成减少和伤口愈合不良。我们的发现表明，WS-MSCs促血管生成功能的损害是由于HGF功能不全和PI3K / AKT失调所致，提示间质和上皮细胞之间的营养性破坏是WS发病机理的一种机制。

更新日期：2020-04-22

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