Wnt/BMP Mediated Metabolic Reprogramming Preserves Multipotency of Neural Crest-Like Stem Cells

Neural crest-like stem cells resembling embryonic neural crest cells (NCs) can be derived from adult human tissues such as the epidermis. However, these cells lose their multipotency rapidly in culture limiting their expansion for clinical use. Here, we show that the multipotency of keratinocyte-derived NCs (KC-NCs) can be preserved by activating the Wnt and BMP signaling axis, promoting expression of key NC-specifier genes and ultimately enhancing their differentiation potential. We also show that transcriptional changes leading to multipotency are linked to metabolic reprogramming of KC-NCs to a highly glycolytic state. Specifically, KC-NCs treated with CHIR and BMP2 rely almost exclusively on glycolysis for their energy needs, as seen by increased lactate production, glucose uptake, and glycolytic enzyme activities. This was accompanied by mitochondrial depolarization and decreased mitochondrial ATP production. Interestingly, the glycolytic end-product lactate stabilized β-catenin and further augmented NC-gene expression. Taken together, our study shows that activation of the Wnt/BMP signaling coordinates the metabolic demands of neural crest-like stem cells governing decisions regarding multipotency and differentiation, with possible implications for regenerative medicine.