Stem Cells Safeguard The Differentiation Refractory Niche Environment

Adult stem cell plays an important role in maintaining homeostasis of tissues and organs in our body.The stem cell niche helps maintain stem cells in undifferentiated state and orchestrates their activation to support long-term tissue regeneration.Increasing efforts are being focused on elucidating the cellular components of the niche and the entailed molecular environment.Yet little is known about the role stem cells play in influencing the very niche space they occupy.The hair follicle stem cells and melanocyte stem cells reside in a shared niche and collaborate in the regeneration of pigmented hair follicles.We found Notch pathway co-factor RBP-J was always expressed in hair follicle stem cell progenitors and hair follicle stem cells themselves,yet no active Notch signal was detected at any time point.Deletion of co-factor RBP-J specifically in mouse hair follicle stem cell progenitors didn' t hamper the formation of hair follicle stem cells.Deletion of RBP-J in hair follicle stem cell in adult didn' t influence anagen entry and showed no obvious defect in short term.However,RBP-J conditional knockout hair follicle stem cells trigger adjacent wild type melanocyte stem cells to precociously differentiate in the niche upon anagen entry.Examining gene expression altered in hair follicle stem cells as a result of RBP-J deletion showed elevated expression of retinoic acid metabolic process genes.We found that inhibitor blocking retinoic acid synthesis enzyme activity prevents precocious melanocyte stem cell differentiation in the RBP-J deficient niche.Mechanistically an increased level of retinoic acid secreted into the niche by hair follicle stem cells sensitizes melanocyte stem cells to KIT-ligand SCF by increasing its receptor c-Kit translation but not transcription level.Inhibitor blocking c-Kit downstream MEK signal transduction rescued precocious differentiation phenotype of melanocyte stem cells in the niche,which proves c-Kit signaling is important in this process.We experimentally pinpointed KIT-ligand originated from hair follicle stem cells as the agent that promotes melanocyte stem cells differentiation,even though the ligand level remains unchanged in the mutant.Genetic deletion of the KIT-ligand concomitant with RBP-J ablation in hair follicle stem cells can rescue the abnormal differentiation of melanocyte stem cells in the niche.Our findings reveal that stem cells function to maintain the differentiation refractory niche environment and illustrate how aberrant hair follicle stem cells can sensitize neighboring melanocyte stem cells to differentiation signals that are normally present in the niche environment.