Section on Molecular Morphogenesis, Laboratory of Gene Regulation and Development, Program in Cellular Regulation and Metabolism, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2010 Oct 22;5(10):e13605. doi: 10.1371/journal.pone.0013605.
The intestinal epithelium undergoes constant self-renewal throughout adult life across vertebrates. This is accomplished through the proliferation and subsequent differentiation of the adult stem cells. This self-renewal system is established in the so-called postembryonic developmental period in mammals when endogenous thyroid hormone (T3) levels are high.
METHODOLOGY/PRINCIPAL FINDINGS: The T3-dependent metamorphosis in anurans like Xenopus laevis resembles the mammalian postembryonic development and offers a unique opportunity to study how the adult stem cells are developed. The tadpole intestine is predominantly a monolayer of larval epithelial cells. During metamorphosis, the larval epithelial cells undergo apoptosis and, concurrently, adult epithelial stem/progenitor cells develop de novo, rapidly proliferate, and then differentiate to establish a trough-crest axis of the epithelial fold, resembling the crypt-villus axis in the adult mammalian intestine. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) is a well-established stem cell marker in the adult mouse intestinal crypt. Here we have cloned and analyzed the spatiotemporal expression profile of LGR5 gene during frog metamorphosis. We show that the two duplicated LGR5 genes in Xenopus laevis and the LGR5 gene in Xenopus tropicalis are highly homologous to the LGR5 in other vertebrates. The expression of LGR5 is induced in the limb, tail, and intestine by T3 during metamorphosis. More importantly, LGR5 mRNA is localized to the developing adult epithelial stem cells of the intestine.
CONCLUSIONS/SIGNIFICANCE: These results suggest that LGR5-expressing cells are the stem/progenitor cells of the adult intestine and that LGR5 plays a role in the development and/or maintenance of the adult intestinal stem cells during postembryonic development in vertebrates.
在脊椎动物中，成年个体的肠道上皮细胞会不断自我更新。这一过程是通过成年干细胞的增殖和随后的分化来实现的。这种自我更新系统是在哺乳动物所谓的胚胎后发育时期建立的，此时内源性甲状腺激素（T3）水平较高。
方法/主要发现：像非洲爪蟾这样的两栖动物的 T3 依赖性变态与哺乳动物的胚胎后发育相似，为研究成年干细胞的发育提供了独特的机会。蝌蚪的肠道主要由单层幼虫上皮细胞组成。在变态过程中，幼虫上皮细胞发生凋亡，同时，成年上皮干细胞/祖细胞从头发育，迅速增殖，然后分化，形成上皮褶皱的低谷-嵴轴，类似于成年哺乳动物肠道的隐窝-绒毛轴。富含亮氨酸重复的 G 蛋白偶联受体 5（LGR5）是成年小鼠肠道隐窝中一种成熟的干细胞标志物。在这里，我们克隆并分析了 LGR5 基因在青蛙变态过程中的时空表达谱。我们表明，非洲爪蟾和 Xenopus tropicalis 中的两个重复 LGR5 基因与其他脊椎动物的 LGR5 高度同源。在变态过程中，T3 诱导 LGR5 在肢体、尾巴和肠道中表达。更重要的是，LGR5 mRNA 定位于正在发育的成年肠道上皮干细胞。
结论/意义：这些结果表明，表达 LGR5 的细胞是成年肠道的干细胞/祖细胞，并且 LGR5 在脊椎动物胚胎后发育过程中，在成年肠道干细胞的发育和/或维持中发挥作用。
