Open AccessGenetic correction of Werner syndrome gene reveals impaired pro‐angiogenic function and HGF insufficiency in mesenchymal stem cells
Author(s) -
Tu Jiajie,
Wan Chao,
Zhang Fengjie,
Cao Lianbao,
Law Patrick Wai Nok,
Tian Yuyao,
Lu Gang,
Rennert Owen M.,
Chan WaiYee,
Cheung HoiHung
Publication year - 2020
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13116
Subject(s) - angiogenesis , biology , mesenchymal stem cell , hepatocyte growth factor , pi3k/akt/mtor pathway , cancer research , protein kinase b , paracrine signalling , stem cell , microbiology and biotechnology , wound healing , immunology , genetics , signal transduction , receptor
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.