Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells
Intact function of Lgr5 receptor-expressing intestinal stem cells in the absence of Paneth cells
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DOI：
10.1073/pnas.1113890109
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发表时间：
2012-03-06
影响因子：
11.1
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
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作者：
Kim, Tae-Hee;Escudero, Silvia;Shivdasani, Ramesh A.
成人肠上皮的终身自我更新需要位于粘膜隐窝的干细胞的活性。Lgr5和Bmi1是隐窝细胞群的两个分子标记，随着时间的推移，它们补充了所有谱系，因此具有干细胞的功能。肠道干细胞需要Wnt信号，但对其细胞生态位的了解尚不完整。表达lgr5的隐窝基部柱状细胞（CBCs）存在于隐窝深处，混杂在成熟的Paneth细胞中，这些细胞可以很好地定位于短距离信号传导。部分谱系消融先前暗示Paneth细胞是干细胞生态位的非必需成分，但最近有报道称，Paneth细胞的缺失会干扰Lgr5(+) CBCs，重新提出了一个有吸引力的想法。然而，先前的小鼠模型无法完全或永久地去除Paneth细胞；确定肠道干细胞生态位需要明确潘氏细胞的作用。我们发现，在Paneth细胞发育之前，具有干细胞活性的Lgr5+细胞在生命早期就聚集在未来的隐窝中。我们还将完全缺乏Paneth细胞的条件Atoh1（-/-）小鼠与Lgr5（GFP）小鼠杂交，以观察Lgr5(+) CBCs并追踪其干细胞功能。在持续缺乏Paneth细胞的情况下，Lgr5(+) CBCs占据了整个隐窝基，增殖迅速，并在数月内产生分化的后代。尽管Paneth细胞缺失，但荧光分选的Lgr5(+) CBCs中的基因表达反映了完整的Wnt信号。因此，Paneth细胞对于CBC的存活、增殖和干细胞活性是必不可少的，与不表达lgr5的细胞直接接触对于CBC功能不是必需的。
Lifelong self-renewal of the adult intestinal epithelium requires the activity of stem cells located in mucosal crypts. Lgr5 and Bmi1 are two molecular markers of crypt-cell populations that replenish all lineages over time and hence function as stem cells. Intestinal stem cells require Wnt signaling, but the understanding of their cellular niche is incomplete. Lgr5-expressing crypt base columnar cells (CBCs) reside deep in the crypt, mingled among mature Paneth cells that are well positioned for short-range signaling. Partial lineage ablation previously had implied that Paneth cells are nonessential constituents of the stem-cell niche, but recently their absence was reported to interfere with Lgr5(+) CBCs, resurrecting an appealing idea. However, previous mouse models failed to remove Paneth cells completely or permanently; defining the intestinal stem-cell niche requires clarity with respect to the Paneth cell role. We find that Lgr5+ cells with stem-cell activity cluster in future crypts early in life, before Paneth cells develop. We also crossed conditional Atoh1(-/-) mice, which lack Paneth cells entirely, with Lgr5(GFP) mice to visualize Lgr5(+) CBCs and to track their stem-cell function. In the sustained absence of Paneth cells, Lgr5(+) CBCs occupied the full crypt base, proliferated briskly, and generated differentiated progeny over many months. Gene expression in fluorescence-sorted Lgr5(+) CBCs reflected intact Wnt signaling despite the loss of Paneth cells. Thus, Paneth cells are dispensable for survival, proliferation, and stem-cell activity of CBCs, and direct contact with Lgr5-nonexpressing cells is not essential for CBC function.