Metabolic Control of Hair Follicle Stem Cell Homeostasis and Tumorigenesis

Abstract In the last five years, we discovered a functional role for glycolytic metabolism in HFSC homeostasis. We found that lactate dehydrogenase (Ldh) activity is essential for HFSC activation, and that elevation of Ldh activity through blockade of pyruvate entry into mitochondria can promote HFSC activation. Left unknown from this work is why and how, specifically, HFSCs’ activation is subject to regulation by Ldh activity and/or pyruvate oxidation in the mitochondria. HFSCs are essential for new hair growth, contribute to wound healing, and are cancer cells of origin for squamous cell carcinoma. Therefore, understanding how metabolism can regulate cell fate in HFSCs has important implications. We have several hypotheses to explain how Ldh activity and/or mitochondrial pyruvate oxidation leads to HFSC activation. First, we have found that Ldh inhibition in tumors promotes glutamine anapleurosis, and it has been argued that glutaminolysis is important for HFSC maintenance, so perhaps elevated glutaminolysis prevents HFSC activation in Ldh-null stem cells. Second, lactate has been shown to act as a signaling molecule, sometimes referred to as a lactormone. Third, it is possible that instead of lactate, an alternate product of Ldh activity, L-2-hydroxyglutarate (L2HG), is the key metabolite promoting HFSC activation; L2HG can impact the activity of a diverse class of enzymes, some of which modulate epigenetic state and gene expression. Fourth, we have evidence to suggest that these same regulatory mechanisms are affecting the decision of HFSCs to initiate and drive tumorigenesis, so we will explore these hypotheses in an established cancer paradigm for squamous cell carcinoma.