Wnt signaling reprograms metabolism in dental pulp stem cells

Human dental pulp stem cells (DPSCs) can differentiate to a wide range of different cell lineages, and share some gene expression and functional similarities with pluripotent stem cells. The stemness of DPSCs can also be pharmacologically enhanced by the activation of canonical Wnt signaling. Here, we examined the metabolic profile of DPSCs during reprogramming linked to Wnt activation, by a short (48hr) exposure to either the GSK3- inhibitor BIO (6-bromoindirubin-3 '-oxine) or human recombinant protein WNT-3A. Both treatments largely increased glucose consumption, and induced a gene overexpression of pyruvate and mitochondrial acetyl-coA producing enzymes, thus activating mitochondrial tricarboxylic acid cycle (TCA) metabolism in DPSCs. This ultimately led to an accumulation of reducing power and a mitochondrial hyperpolarization in DPSCs. Interestingly, Nile Red staining showed that lipid fuel reserves were being stored in Wnt-activated DPSCs. We associate this metabolic reprogramming with an energy-priming state allowing DPSCs to better respond to subsequent high demands of energy and biosynthesis metabolites for cellular growth. These results show that enhancement of the stemness of DPSCs by Wnt activation comes along with a profound metabolic remodeling, which is distinctly characterized by a crucial participation of mitochondrial metabolism.Euskal Herriko Unibertsitatea, Grant/Award Number: GIU16/66; Eusko Jaurlaritza/Basque Covernment, Grant/Award Number: IT-831/13; CHILDREN with CANCER UK, Grant/Award Number: 15-193; Cancer Research UK, Grant/Award Number: C1060/A10334; EPSRC Cancer Imaging Centre in association with the MRC and Department of Health (England), Grant/Award Number: C1060/A1646