Activation of Wnt/β‐catenin signalling and HIF1α stabilisation alters pluripotency and differentiation/proliferation properties of human‐induced pluripotent stem cells

Abstract

Background Information Wnt/β‐catenin signalling, in the microenvironment of pluripotent stem cells (PSCs), plays a critical role in their differentiation and proliferation. Contradictory reports on the role of Wnt/β‐catenin signalling in PSCs self‐renewal and differentiation, however, render these mechanisms largely unclear. Results Wnt/β‐catenin signalling pathway in human‐induced pluripotent stem cells (hiPSCs) was activated by inhibiting glycogen synthase kinase 3 (GSK3), driving the cells into a mesodermal/mesenchymal state, exhibiting proliferative, invasive and anchorage‐independent growth properties, where over 70% of cell population became CD 44 (+)/CD133 (+). Wnt/β‐catenin signalling activation also altered the metabolic state of hiPSCs from aerobic glycolysis to oxidative metabolism and changed their drug and oxidative stress sensitivities. These effects of GSK3 inhibition were suppressed in HIF1α‐stabilised cells. Conclusions Persistent activation of Wnt/β‐catenin signalling endows hiPSCs with proliferative/invasive ‘teratoma‐like’ states, shifting their metabolic dependence and allowing HIF1α‐stabilisation to inhibit their proliferative/invasive properties. Significance The hiPSC potential to differentiate into ‘teratoma‐like’ cells suggest that stem cells may exist in two states with differential metabolic and drug dependency.

The role of long non-coding RNAs in angiogenesis and anti-angiogenic therapy resistance in cancer

“…The Wnt/β-catenin signaling pathway participated in the adjustment of various pathophysiological procedure. 80 , 81 , 82 Abnormal Wnt/β-catenin signaling pathway can induce many diseases. 83 , 84 , 85 In western blot analysis, the expression levels of KLK4, Wnt-1, β-catenin, Cyclin D1, and N-cadherin were decreased after the upregulation of LINC01314.…”