Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)
Functional intestinal stem cells after Paneth cell ablation induced by the loss of transcription factor Math1 (Atoh1)
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DOI：
10.1073/pnas.1201652109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Romagnolo, Beatrice
中科院分区：
文献类型：
--
作者：
Durand, Aurelie;Donahue, Bridgitte;Romagnolo, Beatrice
肠上皮具有自我更新和产生分化细胞的能力，通过存在两种类型的上皮干细胞：活跃的隐窝基柱状细胞(CBCs)和静止的+4细胞。这些细胞的行为既受内部程序的调节，也受相邻细胞发出的外部信号的调节，这些信号定义了生态位。显然，β-连环蛋白途径是CBC维持和增殖所必需的内在信号，最近有人提出，Paneth细胞通过分泌Wingless/Int(Wnt)配体提供一个关键的利基环境。在这里，我们研究了通过诱导转录因子Math1(Atoh1)的缺失来扰乱肠道干细胞生态位的效果，Math1(Atoh1)是分泌细胞分化的关键驱动因素。我们发现，由于Math1缺乏而导致的Paneth细胞的完全丧失不会扰乱隐窝的结构，并允许CBCs的维持和增殖。事实上，Math1基因缺陷的隐窝细胞在体内耐受Paneth细胞的丢失，并保持活跃的β-连环蛋白信号，但如果没有外源Wnt，就不能在体外生长，这意味着在体内，潜在的粘膜细胞扮演着潜在的生态位。照射后，Math1缺陷的隐窝细胞再生，CBCs继续循环。最后，缺乏腺瘤性息肉病结肠(APC)和Math1的CBC干细胞能够促进肠道肿瘤的发生。我们得出结论，在体内，Math1缺陷的隐窝可以抵消Paneth细胞来源的WNTs的缺失，防止CBC干细胞耗尽。
Intestinal epithelium has the capacity to self-renew and generate differentiated cells through the existence of two types of epithelial stem cells: active crypt base columnar cells (CBCs) and quiescent +4 cells. The behaviors of these cells are regulated both by intrinsic programs and by extrinsic signals sent by neighboring cells, which define the niche. It is clear that the beta-catenin pathway acts as an essential intrinsic signal for the maintenance and proliferation of CBC, and it was recently proposed that Paneth cells provide a crucial niche by secreting Wingless/Int (Wnt) ligands. Here, we examined the effect of disrupting the intestinal stem cell niche by inducible deletion of the transcription factor Math1 (Atoh1), an essential driver of secretory cell differentiation. We found that complete loss of Paneth cells attributable to Math1 deficiency did not perturb the crypt architecture and allowed the maintenance and proliferation of CBCs. Indeed, Math1-deficient crypt cells tolerated in vivo Paneth cell loss and maintained active beta-catenin signaling but could not grow ex vivo without exogenous Wnt, implying that, in vivo, underlying mucosal cells act as potential niche. Upon irradiation, Math1-deficient crypt cells regenerated and CBCs continued cycling. Finally, CBC stem cells deficient in adenomatous polyposis coli (Apc) and Math1 were able to promote intestinal tumorigenesis. We conclude that in vivo, Math1-deficient crypts counteract the absence of Paneth cell-derived Wnts and prevent CBC stem cell exhaustion.