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.

非洲爪蟾甲状腺激素依赖性变态过程中肠中干细胞相关基因 LGR5 的时空表达谱。富含亮氨酸重复序列的 G 蛋白偶联受体 5（LGR5 或 Gpr49）是成年小鼠肠隐窝中成熟的干细胞标记物。我们克隆并分析了青蛙变态过程中LGR5基因的时空表达谱。我们发现非洲爪蟾中的两个重复的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。 LGR5 在变态过程中由 TH 诱导在四肢、尾部和肠道中表达。更重要的是，LGR5 mRNA 定位于肠道发育中的成体上皮干细胞。这些结果表明，表达LGR5的细胞是成体肠道的干/祖细胞，并且LGR5在脊椎动物胚胎后发育过程中在成体肠道干细胞的发育和/或维持中发挥作用。 蛋白质精氨酸甲基转移酶 1 在成体肠干细胞胚胎后发育过程中的基本且进化保守的作用。成体干细胞对于成体器官的发育以及组织的修复和再生至关重要。肠道是研究成体干细胞的绝佳器官，因为在脊椎动物的整个成年生命中，肠上皮（负责食物加工和营养吸收的组织）通过干细胞分裂、随后的细胞分化和分化细胞的最终死亡不断更新。 南非青蛙（蟾蜍）非洲爪蟾 TH 依赖性变态过程中的肠道重塑为研究成体干细胞发育和增殖提供了独特的机会。我们已经证明，TH 受体 (TR) 对于介导 TH 对肠道发育的影响是必要且充分的，并且 TR 招募共激活复合物来控制变态。 我们现在已经证明，TR 辅激活因子 PRMT1（蛋白精氨酸甲基转移酶 1）在少数幼虫上皮细胞中上调，并且这些细胞去分化成为成体干细胞。 更重要的是，我们的体内研究表明PRMT1在成体肠道干细胞的发育中发挥着进化保守的作用。 这些发现不仅对于了解器官特异性成体干细胞发育很重要，而且对消化道再生医学也具有重要意义。