FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential
FOXC1 maintains the hair follicle stem cell niche and governs stem cell quiescence to preserve long-term tissue-regenerating potential
复制标题
DOI：
10.1073/pnas.1601569113
复制
发表时间：
2016-03-15
影响因子：
11.1
通讯作者：
Fuchs, Elaine
中科院分区：
文献类型：
--
作者：
Lay, Kenneth;Kume, Tsutomu;Fuchs, Elaine
成体组织干细胞（SCs）存在于调控其行为的生态位中。SCs通常很少使用，除非被激活用于组织生长，否则它们处于静止状态。在正常的体内平衡过程中，是否吝啬的SC使用对于保存长期的组织再生潜能是必要的，目前还不清楚。在这里，我们通过有条件地消融毛囊SCs （HFSCs）中表达的关键转录因子叉头盒C1 （FOXC1）来研究这个问题。缺乏foxc1的HFSCs处于静止状态的时间更短，导致毛发周期之间的休息时间明显缩短。毛发循环的增强加速了HFSC的消耗，并影响了衰老小鼠的毛发再生。有趣的是，尽管缺乏foxc1的HFs仍然可以形成一个新的凸起，为下一个毛发周期容纳HFSCs，但旧的凸起是不固定的。随着新头发的出现，整个旧的凸起，包括其储备的HFSCs和sc抑制内细胞层，都消失了。我们首先追踪了这一机制，Foxc1消融后细胞周期相关转录物的显著增加，其次，e-钙粘蛋白介导的sc间粘附的下游减少。最后，我们表明，当每个头发周期的旧凸起消失时，sc抑制因子的总体水平降低，进一步降低了HFSC活性的阈值。综上所述，我们的研究结果表明，HFSCs在体内具有有限的潜力，它们通过将静止与粘附介导的生态位维持相结合来保存这种潜力，从而实现长期的组织稳态。
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.