Hair Follicle Stem Cells Maintain the Differentiation Refractory Niche for Co-Occupant Melanocyte Stem Cells by Regulating Retinoid Metabolic Process

Abstract

Metabolite can regulate stem cell (SC) function in vitro and in vivo. But very little is known about whether or not metabolites function as signaling mediators of SC and niche cross talk during tissue regeneration. The hair follicle stem cells (HFSCs) and melanocyte stem cells (McSC) reside in a shared niche and collaborate in the regeneration of pigmented hair follicles. We show here that deletion of the Notch pathway co-factor RBP-J specifically in mouse HFSCs triggers adjacent McSCs to precociously differentiate in the niche at the beginning of hair regeneration stage. Transcriptome screen revealed elevated expression of retinoic acid (RA) metabolic process genes as a result of RBP-J deletion in HFSCs. The increased level of RA in the niche sensitizes McSCs to differentiation signal KIT-ligand by increasing its c-Kit receptor protein level in vivo. Using genetic approach, we further pinpointed HFSCs as the source of KIT-ligand in the niche, which normally increases at the beginning of hair regeneration cycle. We discovered that RA mediates the cross talk of two different types of SCs in a shared niche. And HFSCs play an essential role of safeguarding the differentiation refractory niche environment for neighboring McSCs by regulating metabolite level in vivo.