Role of BMP Signaling in Intestine Stem Cell Development

BMP 信号传导在肠干细胞发育中的作用

• 批准号: 7121488
• 负责人: LINHENG LI
• 金额: $ 31.83万
• 依托单位: STOWERS INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121488
• 关键词: apoptosis; biological signal transduction; bone morphogenetic proteins; cadherins; cell differentiation; cell proliferation; flow cytometry; gene targeting; genetically modified animals; immunocytochemistry; intestines; laboratory mouse; monoclonal antibody; mutant; stem cells

DESCRIPTION (provided by applicant): The intestinal architecture is composed of a sequential array of zones along the villus-crypt axis in which cellular self-renewal, proliferation, differentiation, and apoptosis is ongoing. Postnatal regeneration of the intestines is driven by intestinal stem cells (ISCs), which have the ability to regenerate by self-renewal and are multipotent, giving rise to four different types of epithelial lineages. Thus far, regulation of this sequential developmental process remains largely unknown. Although ISCs have been reported to be located at the 4th or 5th position from the crypt base, no biological marker is available for recognition and mapping the fate of ISCs. Nor has the cellular component of the ISC niche been identified. We have generated a BMPRIA knockout mutant mouse line to explore the roles of the BMP signal in regulating ISC development. This mutant mouse model develops profuse polyps in the gastrointestinal tract resembling human juvenile polyposis, and with it an increased number of ISCs and progenitor cells. In these mice we have found compartmentalized BMP activity which ties in with the zones of ISCs self-renewal, proliferation, differentiation, and apoptosis. This research proposal is to test our theories that 1) the compartmentalized BMP activity determines the zones in which ISCs undergo sequential development, 2) to isolate and characterize intestinal stem cells using ISC-SM1 which we identified recently through analysis of the Bmprla mutant mice, and 3) to isolate and characterize ISC candidate niche cells using N-cadherin as the surface marker. We believe that the results derived from these studies will provide important insight into understanding the properties of intestinal stem cells and intestinal regeneration. Identification and isolation of both ISCs and their niche cells will not only open a new avenue for studying stem cell behavior in vitro, but will also have clinical implications in the areas of stem cell transplantation and stem cell-based replacement therapy for gastrointestinal diseases.

描述（由申请人提供）：肠结构由沿着绒毛-隐窝轴的连续区域阵列组成，其中细胞自我更新、增殖、分化和凋亡正在进行中。出生后肠道的再生是由肠道干细胞（ISCs）驱动的，ISCs具有自我更新的能力，并且是多能的，产生四种不同类型的上皮谱系。到目前为止，这一连续发育过程的调控仍在很大程度上未知。虽然已经报道了ISC位于从隐窝基部开始的第4或第5位置，但是没有生物标记可用于识别和绘制ISC的命运。ISC生态位的细胞成分也没有被确定。我们已经产生了一个BMPRIA基因敲除突变小鼠系，以探讨BMP信号在调节ISC发展中的作用。这种突变小鼠模型在胃肠道中产生大量息肉，类似于人类青少年息肉病，并伴随着ISC和祖细胞数量的增加。在这些小鼠中，我们发现了与ISCs自我更新、增殖、分化和凋亡区域相关的区室化BMP活性。本研究的目的是验证我们的理论：1）区室化的BMP活性决定了ISC经历顺序发育的区域，2）使用我们最近通过分析Bmprla突变小鼠鉴定的ISC-SM 1分离和表征肠干细胞，3）使用N-cadherin作为表面标记分离和表征ISC候选小生境细胞。我们相信，这些研究的结果将为理解肠道干细胞和肠道再生的特性提供重要的见解。ISCs及其小生境细胞的鉴定和分离不仅为研究干细胞的体外行为开辟了新的途径，而且在干细胞移植和基于干细胞的胃肠道疾病替代治疗领域也具有临床意义。