Regulation of stem cell development during tissue remodeling

组织重塑过程中干细胞发育的调节

• 批准号: 8149374
• 负责人: Yun-Bo Shi
• 金额: $ 55.24万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149374
• 关键词: Regulation; Stem Cell Development; Tissues

SPATIO-TEMPORAL EXPRESSION PROFILE OF STEM CELL-ASSOCIATED GENE LGR5 IN THE INTESTINE DURING THYROID HORMONE-DEPENDENT METAMORPHOSIS IN XENOPUS LAEVIS. The leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5 or Gpr49) is a well-established stem cell marker in the adult mouse intestinal crypt. We have cloned and analyzed the spatiotemporal expression profile of LGR5 gene during frog metamorphosis. We showed 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 TH during metamorphosis. More importantly, LGR5 mRNA is localized to the developing adult epithelial stem cells of the intestine. 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. AN ESSENTIAL AND EVOLUTIONARILY CONSERVED ROLE OF PROTEIN ARGININE METHYLTRANSFERASE 1 FOR ADULT INTESTINAL STEM CELLS DURING POSTEMBRYONIC DEVELOPMENT. Adult stem cells are essential for the development of adult organs and tissue repair and regeneration. The intestine is an excellent organ for studying adult stem cells as the intestinal epithelium, the tissue responsible for the food processing and nutrient absorption, is continuously renewed through stem cell division followed by cell differentiation and eventual death of the differentiated cells throughout adult life in vertebrate. Intestinal remodeling during TH-dependent metamorphosis of the South African frog (toad) Xenopus laevis offers a unique opportunity to study adult stem cell development and proliferation. We have shown that TH receptor (TR) is both necessary and sufficient for mediating the effects of TH on intestinal development and that TR recruits coactivator complexes to control metamorphosis. We have now shown that the TR-coactivator PRMT1 (protein arginine methyltransferase 1) is upregulated in a small number of larval epithelial cells and that these cells dedifferentiate to become the adult stem cells. More importantly, our in vivo studies showed that PRMT1 plays an evolutionally conserved role in the development of adult intestinal stem cells. These findings are not only important for the understanding of organ-specific adult stem cell development but also have important implications in regenerative medicine of the digestive tract.

甲状腺激素依赖性变态中Xenopus laevis中肠道中与干细胞相关基因LGR5的时空表达谱。富含亮氨酸重复的G蛋白偶联受体5（LGR5或GPR49）是成年小鼠肠道隐窝中的完善的干细胞标记。我们已经克隆并分析了青蛙变态过程中LGR5基因的时空表达谱。我们表明，在Xenopus laevis中的两个重复的LGR5基因和热带爪蟾中的LGR5基因与其他脊椎动物中的LGR5高度同源。在变形过程中，TH在肢体，尾巴和肠中诱导LGR5的表达。更重要的是，LGR5 mRNA位于肠中发育中的成年上皮干细胞中。这些结果表明，表达LGR5的细胞是成年肠的茎/祖细胞，而LGR5在脊椎动物的胚胎后发育过程中在成年肠干细胞的发育和/或维持中起作用。 在胚胎后发育过程中，蛋白精氨酸甲基转移酶1对成年肠干细胞的必不可少的和进化保守的作用。成年干细胞对于发展成人器官以及组织修复和再生至关重要。肠道是研究成年干细胞的绝佳器官，因为肠上皮（负责食物加工和营养吸收的组织）通过干细胞分裂不断更新，然后在整个椎骨中成人生命中分化细胞的细胞分化和最终死亡。 南非青蛙（蟾蜍）爪诺司氏菌的TH依赖性变态过程中的肠道重塑为研究成人干细胞发育和增殖提供了独特的机会。我们已经表明，TH受体（TR）对于介导TH对肠发育的影响既需要且足够，并且TR募集了共激活因子复合物以控制变形。 现在，我们已经表明，在少数幼虫上皮细胞中，TR氧化激活剂PRMT1（蛋白精氨酸甲基转移酶1）被上调，并且这些细胞被去分化成为成年干细胞。 更重要的是，我们的体内研究表明，PRMT1在成年肠干细胞的发展中起进化保守的作用。 这些发现不仅对于理解特定器官的成年干细胞发育很重要，而且对消化道的再生医学具有重要意义。