Stem cells reside in specialized niches that are critical for their function. Upon activation, hair follicle stem cells (HFSCs) exit their niche to generate the outer root sheath (ORS), but a subset of ORS progeny returns to the niche to resume an SC state. Mechanisms of this fate reversibility are unclear. We show that the ability of ORS cells to return to the SC state requires suppression of a metabolic switch from glycolysis to oxidative phosphorylation and glutamine metabolism that occurs during early HFSC lineage progression. HFSC fate reversibility and glutamine metabolism are regulated by the mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling axis within the niche. Deletion of mTORC2 results in a failure to re-establish the HFSC niche, defective hair follicle regeneration, and compromised long-term maintenance of HFSCs. These findings highlight the importance of spatiotemporal control of SC metabolic states in organ homeostasis.

干细胞位于对其功能至关重要的特殊壁龛中。激活后，毛囊干细胞 (HFSC) 退出其生态位以生成外根鞘 (ORS)，但一部分 ORS 后代返回生态位以恢复 SC 状态。这种命运可逆性的机制尚不清楚。我们表明 ORS 细胞返回 SC 状态的能力需要抑制在早期 HFSC 谱系进展期间发生的从糖酵解到氧化磷酸化和谷氨酰胺代谢的代谢转换。HFSC 命运可逆性和谷氨酰胺代谢受哺乳动物雷帕霉素复合物 2 (mTORC2)-Akt 信号轴靶标在生态位内的调节。删除 mTORC2 会导致无法重新建立 HFSC 生态位、毛囊再生缺陷和 HFSC 的长期维护。