Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon
Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon
复制标题
DOI：
10.1073/pnas.1607327113
复制
发表时间：
2016-09-13
影响因子：
11.1
通讯作者：
Clevers, Hans
中科院分区：
文献类型：
--
作者：
Sasaki, Nobuo;Sachs, Norman;Clevers, Hans
富含亮氨酸重复序列的G蛋白偶联受体5阳性(Lgr5(+))干细胞位于小肠和大肠的隐窝底部。小肠Paneth细胞向邻近的Lgr5(+)干细胞提供WNT3、EGF和Notch信号。虽然结肠缺乏Paneth细胞，但深隐窝分泌(DC)细胞与隐窝底部的Lgr5(+)干细胞混合在一起。在这里，我们报告再生岛源家族成员4(Reg4)作为DC细胞的标志。为了研究生态位功能，我们用白喉毒素受体基因敲除尿液中的Reg4基因，从而消除了DCs细胞。切除DC细胞会导致结肠隐窝干细胞的丧失，并破坏肠道内环境的稳定和结肠类器官的生长。一致认为，分选的Reg4(+)DC细胞促进单个Lgr5(+)结肠干细胞的类器官形成。Lgr5(+)结肠干细胞可通过Notch抑制和Wnt激活相结合的方法在体外大量产生DC细胞。我们得出结论：Reg4(+)的DCs细胞在结肠隐窝内可作为Paneth细胞的等价物。
Leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5(+)) stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF, and Notch signals to neighboring Lgr5(+) stem cells. Whereas the colon lacks Paneth cells, deep crypt secretory (DCS) cells are intermingled with Lgr5(+) stem cells at crypt bottoms. Here, we report regenerating isletderived family member 4 (Reg4) as a marker of DCS cells. To investigate a niche function, we eliminatedDCS cells by using the diphtheriatoxin receptor gene knocked into themurine Reg4 locus. Ablation of DCS cells results in loss of stem cells from colonic crypts and disrupts gut homeostasis and colon organoid growth. In agreement, sorted Reg4(+) DCS cells promote organoid formation of single Lgr5(+) colon stem cells. DCS cells can be massively produced from Lgr5(+) colon stem cells in vitro by combined Notch inhibition and Wnt activation. We conclude that Reg4(+) DCS cells serve as Paneth cell equivalents in the colon crypt niche.