Bmi1 Overexpression in Mesenchymal Stem Cells Exerts Antiaging and Antiosteoporosis Effects by Inactivating p16/p19 Signaling and Inhibiting Oxidative Stress

Abstract

We previously demonstrated that Bmi1 deficiency leads to osteoporosis phenotype by inhibiting the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells (MSCs), but it is unclear whether overexpression of Bmi1 in MSCs stimulates skeletal development and rescues Bmi1 deficiency-induced osteoporosis. To answer this question, we constructed transgenic mice (Bmi1^Tg ) that overexpressed Bmi1 driven by the Prx1 gene and analyzed their skeletal phenotype differences with that of wild-type littermates. We then hybridized Bmi1^Tg to Bmi1^-/- mice to generate Bmi1^-/- mice overexpressing Bmi1 in MSCs and compared their skeletal phenotypes with those of Bmi1^-/- and wild-type mice using imaging, histopathological, immunohistochemical, histomorphometric, cellular, and molecular methods. Bmi1^Tg mice exhibited enhanced bone growth and osteoblast formation, including the augmentation of bone size, cortical and trabecular volume, number of osteoblasts, alkaline phosphatase (ALP)-positive and type I collagen-positive areas, number of total colony forming unit fibroblasts (CFU-f) and ALP⁺ CFU-f, and osteogenic gene expression levels. Consistently, MSC overexpressing Bmi1 in the Bmi1^-/- background not only largely reversed Bmi1 systemic deficiency-induced skeletal growth retardation and osteoporosis, but also partially reversed Bmi1 deficiency-induced systemic growth retardation and premature aging. To further explore the mechanism of action of MSCs overexpressing Bmi1 in antiosteoporosis and antiaging, we examined changes in oxidative stress and expression levels of p16 and p19. Our results showed that overexpression of Bmi1 in MSCs inhibited oxidative stress and downregulated p16 and p19. Taken together, the results of this study indicate that overexpression of Bmi1 in MSCs exerts antiaging and antiosteoporosis effects by inactivating p16/p19 signaling and inhibiting oxidative stress. Stem Cells 2019;37:1200-1211.

Keywords: Bmi1; Mesenchymal stem cells; Osteoporosis; Oxidative stress; Transgenic mouse model.