DeltaNp63 regulates stem cell dynamics in the mammalian olfactory epithelium.
DeltaNp63 regulates stem cell dynamics in the mammalian olfactory epithelium.
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DOI：
10.1523/jneurosci.0681-11.2011
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发表时间：
2011-06-15
期刊：
影响因子：
--
通讯作者：
Schwob JE
中科院分区：
文献类型：
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作者：
Packard A;Schnittke N;Romano RA;Sinha S;Schwob JE
嗅觉上皮(OE)在损伤后再生的能力至少由两类假定的干细胞--球形基底细胞(GBCS)和水平基底细胞(HBCs)介导。在两者中，GBCs在分子和表型上与胚胎胎盘的嗅觉前体细胞(OPPS)相似。相比之下，HBCs是一种储备干细胞群体，出现在发育后期，需要通过严重的上皮损伤激活，然后才能促进上皮重建。无论是HBC的出现还是损伤后的激活机制都不清楚。在这里，我们发现转录因子p63(Trp63)是HBC分化所必需的，它是由成人HBC选择性表达的。HBC分化的第一个证据是，通过转录因子Sox2、Ascl1和Hes1的形态和表达，与胚胎OPS和成年GBCS非常相似的细胞表达p63。在Ascl1基因敲除OE中，HBC的形成被延迟，而在p63基因缺失的小鼠中，HBC的形成完全被取消。引人注目的是，其他类型的OE细胞在p63基因敲除的OE中正常形成。在再生的OE中，P63在HBC分化中的作用似乎是保守的，其中HbCs消失，然后在组织损伤后重新出现。最后，在损伤激活的HBCs中，p63蛋白下调，成为多潜能的祖细胞。综上所述，我们的数据确定了一种产生储备干细胞群体的新机制，并表明依赖p63的分子开关负责在需要时激活储备干细胞。
The ability of the olfactory epithelium (OE) to regenerate after injury is mediated by at least two populations of presumed stem cells – globose basal cells (GBCs) and horizontal basal cells (HBCs). Of the two, GBCs are molecularly and phenotypically analogous to the olfactory progenitors of the embryonic placode (OPPs). In contrast, HBCs are a reserve stem cell population that appears later in development and requires activation by severe epithelial damage before contributing to epithelial reconstitution. Neither HBC emergence nor the mechanism of activation after injury is understood. Here we show that the transcription factor p63 (Trp63), which is expressed selectively by adult HBCs, is required for HBC differentiation. The first evidence of HBC differentiation is the expression of p63 by cells that closely resemble embryonic OPPs and adult GBCs by morphology and expression of the transcription factors Sox2, Ascl1, and Hes1. HBC formation is delayed in Ascl1 knockout OE and is completely abrogated in p63-null mice. Strikingly, other cell types of the OE form normally in the p63 knockout OE. The role of p63 in HBC differentiation appears to be conserved in the regenerating rat OE, where HBCs disappear and then reappear after tissue lesion. Finally, p63 protein is down-regulated in HBCs activated by lesion to become multipotent progenitor cells. Taken together, our data identify a novel mechanism for the generation of a reserve stem cell population and suggest a p63-dependent molecular switch is responsible for activating reserve stem cells when they are needed.