Lay Kenneth, Kume Tsutomu, Fuchs Elaine
Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065;
Department of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL 60611.
Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):E1506-15. doi: 10.1073/pnas.1601569113. Epub 2016 Feb 24.
Adult tissue stem cells (SCs) reside in niches, which orchestrate SC behavior. SCs are typically used sparingly and exist in quiescence unless activated for tissue growth. Whether parsimonious SC use is essential to conserve long-term tissue-regenerating potential during normal homeostasis remains poorly understood. Here, we examine this issue by conditionally ablating a key transcription factor Forkhead box C1 (FOXC1) expressed in hair follicle SCs (HFSCs). FOXC1-deficient HFSCs spend less time in quiescence, leading to markedly shortened resting periods between hair cycles. The enhanced hair cycling accelerates HFSC expenditure, and impacts hair regeneration in aging mice. Interestingly, although FOXC1-deficient HFs can still form a new bulge that houses HFSCs for the next hair cycle, the older bulge is left unanchored. As the new hair emerges, the entire old bulge, including its reserve HFSCs and SC-inhibitory inner cell layer, is lost. We trace this mechanism first, to a marked increase in cell cycle-associated transcripts upon Foxc1 ablation, and second, to a downstream reduction in E-cadherin-mediated inter-SC adhesion. Finally, we show that when the old bulge is lost with each hair cycle, overall levels of SC-inhibitory factors are reduced, further lowering the threshold for HFSC activity. Taken together, our findings suggest that HFSCs have restricted potential in vivo, which they conserve by coupling quiescence to adhesion-mediated niche maintenance, thereby achieving long-term tissue homeostasis.
成体组织干细胞（SCs）存在于小生境中，这些小生境调控着干细胞的行为。干细胞通常被少量使用，并处于静止状态，除非被激活以促进组织生长。在正常稳态过程中，干细胞的节俭使用对于保留长期组织再生潜能是否至关重要，目前仍知之甚少。在此，我们通过条件性敲除毛囊干细胞（HFSCs）中表达的关键转录因子叉头框C1（FOXC1）来研究这个问题。缺乏FOXC1的毛囊干细胞处于静止状态的时间减少，导致毛发生长周期之间的休息期明显缩短。毛发生长周期的加速增加了毛囊干细胞的消耗，并影响衰老小鼠的毛发再生。有趣的是，尽管缺乏FOXC1的毛囊仍能形成一个新的隆突，为下一个毛发生长周期容纳毛囊干细胞，但旧的隆突却失去了附着。随着新毛发的出现，整个旧的隆突，包括其储备的毛囊干细胞和抑制干细胞的内细胞层，都丢失了。我们首先将这种机制追溯到Foxc1敲除后细胞周期相关转录本的显著增加，其次追溯到E-钙黏蛋白介导的干细胞间黏附的下游减少。最后，我们表明，当每个毛发生长周期旧的隆突丢失时，干细胞抑制因子的总体水平会降低，进一步降低毛囊干细胞活性的阈值。综上所述，我们的研究结果表明，毛囊干细胞在体内的潜能有限，它们通过将静止状态与黏附介导的小生境维持相耦合来保留这种潜能，从而实现长期的组织稳态。
