WNT-SHH Antagonism Specifies and Expands Stem Cells prior to Niche Formation.
WNT-SHH Antagonism Specifies and Expands Stem Cells prior to Niche Formation.
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DOI：
10.1016/j.cell.2015.11.058
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发表时间：
2016-01-14
期刊：
影响因子：
64.5
通讯作者：
Fuchs E
中科院分区：
文献类型：
--
作者：
Ouspenskaia T;Matos I;Mertz AF;Fiore VF;Fuchs E
已知成体干细胞（SC）的维持和分化依赖于从小生境接收的信号。然而，在这里，我们展示了一种机制，SC规范和监管，是利基独立的。使用免疫荧光，活体成像，遗传学，细胞周期分析，在子宫内慢病毒转导，和谱系追踪，我们表明，在发展中的毛芽，SC出生从不对称分裂，差异显示WNT和SHH信号。移位的WNTlo基底上子体成为响应旁分泌SHH并对称扩张的SC。相比之下，基底子体保持WNThi。它们表达但不响应SHH，因此维持慢循环、不对称分裂。随着时间的推移，它们成为短命的祖细胞，产生分化的子代而不是SC。因此，在一个既定的生态位，其中包含一个固定的SC池，其驱逐后代分化，不对称分裂首先指定和取代早期SC到一个有利于扩张的环境，后来限制他们的数量通过切换不对称的命运。
Adult stem cell (SC) maintenance and differentiation are known to depend on signals received from the niche. Here however, we demonstrate a mechanism for SC specification and regulation that is niche-independent. Using immunofluorescence, live imaging, genetics, cell-cycle analyses, in utero lentiviral transduction, and lineage-tracing, we show that in developing hair buds, SCs are born from asymmetric divisions that differentially display WNT and SHH signaling. Displaced WNTlo suprabasal daughters become SCs that respond to paracrine SHH and symmetrically expand. By contrast, basal daughters remain WNThi. They express but do not respond to SHH, and hence maintain slow-cycling, asymmetric divisions. Over time, they become short-lived progenitors, generating differentiating daughters rather than SCs. Thus, in contrast to an established niche which harbors a fixed SC pool whose expelled progeny differentiate, asymmetric divisions first specify and displace early SCs into an environment conducive to expansion, and later restrict their numbers by switching asymmetric fates.