Mechanisms of fetal intestinal stem cell regulation and maturation

胎儿肠道干细胞调节和成熟的机制

• 批准号: 9334833
• 负责人: Jason Spence
• 金额: $ 34万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9334833
• 关键词: Adult; Affect; Alpha Cell; Animals; Binding; Biological Models; Cells; Chromatin; Competence; Conflict (Psychology); Data; Development; Disease; Distal; Embryo; Epigenetic Process; Epithelial; Event; G-Protein-Coupled Receptors; Gene Expression Profile; Genes; Genetic; Goals; Growth; Human; In Vitro; Intestinal Atresia; Intestines; LGR5 gene; Label; Life; Ligands; Link; Literature; Mesenchymal; Modeling; Molecular; Mus; Neonatal; Organoids; Population; Process; Regulation; Regulator Genes; Role; Short Bowel Syndrome; Signal Transduction; Small Intestines; Stem cells; System; Testing; Time; Tissues; Transgenic Organisms; WNT Signaling Pathway; adult stem cell; base; epigenome; epigenomics; experimental study; fetal; gain of function; human embryonic stem cell; human embryonic stem cell line; human pluripotent stem cell; in vivo; mouse model; novel; progenitor; public health relevance; regenerative; stem; stemness; transcription factor; transcriptome

DESCRIPTION (provided by applicant): Mechanisms of fetal intestinal stem cell regulation and maturation Regulation of embryonic progenitor cells and adult tissue-specific stem cells has been intensely studied. However, these populations (embryonic progenitor vs. adult stem cell) are often considered to be discrete entities existing within time and space. For example, it is uniformly accepted that fetal intestinal progenitor cells give rise to the adult intestinal epithelum, but some literature suggests that adult intestinal stem cells emerge de novo during crypt formation and are molecularly distinct from their embryonic predecessors. However, our preliminary observations suggest that in the fetal/embryonic intestine, adult intestinal stem cell genes are expressed and maintained in a subset of cells throughout development/differentiation. Based on these results, we hypothesize that the "adult stem cell" state is not a discrete event, but part of a developmental continuum. That is, a "stem/progenitor" state is established developmentally in a subset of embryonic intestinal cells that give rise to adult intestinal stem cells. To test our hypothesis we will take advantage of two model systems, the murine model system and human pluripotent stem cell derived intestinal tissue. Combined, these powerful in vivo and in vitro systems will allow us to investigate the genetic and epigenetic ontogeny of intestinal stem cell precursors and adult intestinal stem cells.

描述（由申请人提供）：胎儿肠道干细胞调节和成熟的机制胚胎祖细胞和成体组织特异性干细胞的调节已被深入研究。然而，这些群体（胚胎祖细胞与成体干细胞）通常被认为是存在于时间和空间内的离散实体。例如，人们普遍认为胎儿肠祖细胞产生成体肠上皮，但一些文献表明成体肠干细胞在隐窝形成过程中从头出现，并且在分子上与其胚胎前身不同。然而，我们的初步观察表明，在胎儿/胚胎肠道中，成体肠道干细胞基因在整个发育/分化过程中在细胞子集中表达并维持。基于这些结果，我们假设“成体干细胞”状态不是一个离散事件，而是发育连续体的一部分。也就是说，在产生成体肠干细胞的胚胎肠细胞亚群中发育地建立“干/祖细胞”状态。为了检验我们的假设，我们将利用两个模型系统，即小鼠模型系统和人类多能干细胞衍生的肠道组织。结合起来，这些强大的体内和体外系统将使我们能够研究遗传和表观遗传 肠道干细胞前体和成体肠道干细胞的个体发育。