CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation.
CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation.
复制标题
DOI：
10.1038/s41467-022-30851-1
复制
发表时间：
2022-06-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
肠干细胞（ISCs）在隐窝基础上通过自我更新和分化之间的平衡来促进肠道内稳态。然而，调节这种自稳态平衡的分子机制仍然难以捉摸。本研究表明，基质细胞蛋白CCN1/CYR61通过CCN1与整合素αvβ3/αvβ5相互作用产生的不同途径协调调节ISC的增殖和分化。在Lgr5 + ISCs中删除Ccn1或表达无法结合整合素αvβ3/αvβ5的突变Ccn1的小鼠，ISC增殖旺盛，并以小肠吸收性肠细胞为代价，增强向分泌细胞的分化，导致营养吸收不良。对隐窝类器官的分析发现，CCN1通过整合素αvβ3/αvβ5诱导NF-κ b依赖性Jag1表达，调节Notch激活分化，促进src介导的YAP激活和Dkk1表达，控制Wnt信号通路，促进细胞增殖。此外，CCN1和YAP在一个调控回路中相互放大对方的活性。这些发现证实了CCN1是肠隐窝中的一个生态位因子，为了解基质信号传导如何对肠隐窝内稳态施加总体控制提供了见解。肠道干细胞通过自我更新和分化之间的平衡来维持体内平衡。本研究表明，CCN1是一种肠道干细胞生态位因子，可激活整合素αvβ3/αvβ5信号通路，通过不同的下游通路调节增殖和分化。
Intestinal stem cells (ISCs) at the crypt base contribute to intestinal homeostasis through a balance between self-renewal and differentiation. However, the molecular mechanisms regulating this homeostatic balance remain elusive. Here we show that the matricellular protein CCN1/CYR61 coordinately regulates ISC proliferation and differentiation through distinct pathways emanating from CCN1 interaction with integrins αvβ3/αvβ5. Mice that delete Ccn1 in Lgr5 + ISCs or express mutant CCN1 unable to bind integrins αvβ3/αvβ5 exhibited exuberant ISC expansion and enhanced differentiation into secretory cells at the expense of absorptive enterocytes in the small intestine, leading to nutrient malabsorption. Analysis of crypt organoids revealed that through integrins αvβ3/αvβ5, CCN1 induces NF-κB-dependent Jag1 expression to regulate Notch activation for differentiation and promotes Src-mediated YAP activation and Dkk1 expression to control Wnt signaling for proliferation. Moreover, CCN1 and YAP amplify the activities of each other in a regulatory loop. These findings establish CCN1 as a niche factor in the intestinal crypts, providing insights into how matrix signaling exerts overarching control of ISC homeostasis. Intestinal stem cells contribute to homeostasis through a balance between self-renewal and differentiation. Here the authors show that CCN1 is an intestinal stem cell niche factor that activates integrin αvβ3/αvβ5 signaling to regulate proliferation and differentiation through distinct downstream pathways.
登录
查看更多内容
影响因子：
64.8
作者：
通讯作者：
--
肠上皮中β1整联蛋白的条件缺失会导致刺猬表达，肠道增生和早期产后致死性的丧失。
影响因子：
7.8
作者：
Jones, Robert G.;Li, Xiufen;Gray, Phillip D.;Kuang, Jinqiu;Clayton, Frederic;Samowitz, Wade S.;Madison, Blair B.;Gumucio, Deborah L.;Kuwada, Scott K.
通讯作者：
Kuwada, Scott K.
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
64.8
作者：
Hao, Huai-Xiang;Xie, Yang;Cong, Feng
通讯作者：
Cong, Feng
模拟 VGLL4 功能的肽作为 YAP 拮抗剂治疗胃癌
影响因子：
50.3
作者：
Jiao, Shi;Wang, Huizhen;Zhou, Zhaocai
通讯作者：
Zhou, Zhaocai