Novel GSK-3β Inhibitors and CBM-1078 Guide hATSCs' Deaging Via Oct4 and β-Catenin Activation

Abstract

Abstract Aims: The fate decision of adult stem cells is determined by the activation of specific intracellular signaling pathways after exposure to specific stimuli. In this study, we demonstrated specific functions of a novel small molecule, CBM-1078, that induced cell self-renewal via Oct4- and canonical Wnt/β-catenin-mediated deaging in cultured human adipose tissue-derived stem cells (hATSCs). As a potential glycogen synthase kinase-3β (GSK-3β) inhibitor, CBM-1078 primarily activated β-catenin and Oct4 expression after inhibition of GSK-3β. Treatment of hATSCs with CBM-1078 led to transdifferentiation toward a neural precursor cell fate after transient self-renewal, and the cells were capable of differentiation into gamma-Aminobutyric acid (GABA)-secreting neuronal cells with pain-modulating functions in an animal model of neuropathic pain. During cell self-renewal, CBM-1078 directs the translocalization of β-catenin and Oct4 into the nucleus, an event that is crucial for the cooperative activation of hATSC neurogenesis via Oct4 and Wnt/β-catenin. Nuclear-localized β-catenin and Oct4 act together to regulate the expression of Oct4, Nanog, Sox2, β-catenin, c-Myc, and STAT3 after binding to the regulatory regions of these genes. Nuclear Oct4 and Wnt3a/β-catenin also control cell growth by binding to the promoters of STAT3, Gli3, and c-Myc after complex formation and direct interaction. CBM-1078 actively enhanced the DNA-binding affinity of Oct4 and β-catenin to functional genes and activated the Wnt/β-catenin pathway to promote hATSC reprogramming. This study revealed the value of a single small molecule, CBM-1078, showing a definitive cell reprogramming mechanism. Finally, we confirmed the therapeutic potential of GABA-hATSCs for treatment of neuropathic pain, which could be used for therapeutic purposes in humans. Antioxid. Redox Signal. 00, 000-000.