A novel group of secretory cells regulates development of the immature intestinal stem cell niche through repression of the main signaling pathways driving proliferation.
A novel group of secretory cells regulates development of the immature intestinal stem cell niche through repression of the main signaling pathways driving proliferation.
复制标题
一组新的分泌细胞通过抑制驱动增殖的主要信号通路来调节未成熟肠道干细胞生态位的发育。
DOI：
10.1016/j.ydbio.2019.08.005
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发表时间：
2019
影响因子：
2.7
通讯作者：
Wallace,KennethN
中科院分区：
文献类型：
--
作者：
Li,Jianlong;Dedloff,MargaretR;Stevens,Katrina;Maney,Lea;Prochaska,Morgan;Hongay,CintiaF;Wallace,KennethN
肠上皮在器官的整个生命周期中不断更新，褶皱或绒毛末端的细胞凋亡将细胞释放到管腔中。由于不断更新，上皮细胞需要不断更换。上皮细胞由干细胞龛提供，干细胞龛形成于褶皱间空间（斑马鱼）和隐窝（鸟类和哺乳动物）的基部。在哺乳动物的成体干细胞生态位内，分泌细胞如潘氏细胞和杯状细胞在调节增殖和干细胞活性中发挥作用，产生不对称分裂。不对称分裂的后代沿着褶皱或绒毛向上移动，产生所有的上皮细胞类型。虽然对成体肠干细胞龛的功能和组织了解很多，但对未成熟干细胞隔室内的调节了解较少。平滑肌形成后，肠上皮折叠，增殖仅限于折叠间基底。对称分裂在发育中的褶皱间小生境中继续，直到干细胞后代开始不对称分裂，产生沿着发育中的褶皱向上迁移的后代。在胚胎发生后第三周（斑马鱼）或出生后期间（哺乳动物），来自发育中的干细胞生态位的繁殖后代开始迁移出生态位。未成熟干细胞龛中上皮细胞增殖的调节和组织可能受到与成人龛相当的信号的调节。在这里，我们确定了一个新的分泌细胞的子集与发展中的干细胞龛接收Notch信号（称为NRSC）。在74 hpf至120 hpf之间抑制胚胎NRSC增加上皮增殖以及EGF和IGF信号传导。胚胎后NRSC（6 hpf至12 dpf）的抑制也增加上皮增殖和Wnt靶基因的表达水平。我们的结论是，NRSC发挥作用，通过抑制信号通路，驱动增殖在胚胎发生和胚胎后期上皮细胞增殖的调制。
The intestinal epithelium has constant turnover throughout the life of the organ, with apoptosis of cells at the tips of folds or villi releasing cells into the lumen. Due to constant turnover, epithelial cells need to be constantly replaced. Epithelial cells are supplied by stem cell niches that form at the base of the interfold space (zebrafish) and crypts (birds and mammals). Within the adult stem cell niche of mammals, secretory cells such as Paneth and goblet cells play a role in modulation of proliferation and stem cell activity, producing asymmetric divisions. Progeny of asymmetric divisions move up the fold or villi, giving rise to all of the epithelial cell types. Although much is known about function and organization of the adult intestinal stem cell niche, less is understood about regulation within the immature stem cell compartment. Following smooth muscle formation, the intestinal epithelium folds and proliferation becomes restricted to the interfold base. Symmetric divisions continue in the developing interfold niche until stem cell progeny begin asymmetric divisions, producing progeny that migrate up the developing folds. Proliferative progeny from the developing stem cell niche begin migrating out of the niche during the third week post-embryogenesis (zebrafish) or during the postnatal period (mammals). Regulation and organization of epithelial proliferation in the immature stem cell niche may be regulated by signals comparable to the adult niche. Here we identify a novel subset of secretory cells associated with the developing stem cell niche that receive Notch signaling (referred to as NRSCs). Inhibition of the embryonic NRSCs between 74 hpf to 120 hpf increases epithelial proliferation as well as EGF and IGF signaling. Inhibition of post-embryonic NRSCs (6 hpf to 12 dpf) also increases epithelial proliferation and expression level of Wnt target genes. We conclude that NRSCs play a role in modulation of epithelial proliferation through repression of signaling pathways that drive proliferation during both embryogenesis and the post embryonic period.