Development and vascularity of intestinal mesenchyme

肠间质的发育和血管分布

• 批准号: 10735493
• 负责人: Ramesh A Shivdasani
• 金额: $ 44.81万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735493
• 关键词: Abbreviations; Acceleration; Actins; Address; Adult; Anatomy; BMP6 gene; Basic Science; Biological Assay; Blood Vessels; Blood capillaries; Bone Morphogenetic Proteins; CD34 gene; CD81 gene; Cell Differentiation Induction; Cell Differentiation process; Cell Line; Cell Maturation; Cell Nucleus; Cell Proliferation; Cells; Censuses; Chromatin; Collection; Colon; Colorectal Cancer; Complement; Consensus; Data; Development; Developmental Biology; Digestive Physiology; Dimensions; Disease; Elements; Embryo; Endoderm; Endothelial Cells; Enterobacteria phage P1 Cre recombinase; Epidermal Growth Factor; Epithelial Cells; Epithelium; Erinaceidae; Estrogen Receptors; FOXL1 gene; Fibroblasts; Foundations; Funding; Future; Gastrointestinal tract structure; Genetic; Genetic Transcription; Growth; Health; Human; Inflammatory Bowel Diseases; Injury; Interleukin-6; Intestines; Investigation; Knowledge; LGR5 gene; Laboratories; Life; Ligands; Maps; Mesenchymal; Mesenchyme; Mesoderm; Mitotic; Modeling; Modernization; Molecular; Motivation; Mus; Muscularis Mucosa; Myofibroblast; PDGFRA gene; Pericytes; Population; Process; Recombinants; Regulatory Element; Reporter; Reporting; Rest; SHH gene; Signal Induction; Signal Transduction; Signaling Protein; Small Intestines; Smooth Muscle; Smooth Muscle Myocytes; Solid; Source; Specific qualifier value; Stereotyping; Stromal Cells; Submucosa; Tamoxifen; Testing; Tissues; Transposase; Villus; Work; XCL1 gene; base; cell assembly; cell type; cofactor; design; developmental plasticity; experimental study; fetal; fetus cell culture; improved; inhibitor; injured; insight; intestinal crypt; intestinal injury; novel; postnatal; prevent; progenitor; reconstitution; repaired; restraint; segregation; self organization; self-renewal; stem cell niche; stem cells; success; tissue repair; transcription factor; transcriptome sequencing; vasculogenesis

Project Summary Adult digestive epithelia depend on adjacent mesenchyme to sustain intestinal stem cells (ISCs) at the crypt base and drive cell maturation at the villus base. Precisely layered cells that provide redundant and partially overlapping “trophic” factors execute these essential polarized functions. Our lab’s contributions to this emerging understanding include deep characterization of small intestine (SI) and colonic mesenchyme, discovery of potent “trophocytes,” a cellular explanation for the crypt BMP signaling gradient, identification of the authentic source of canonical Wnt ligands, and discovery of niche self-organization. Importantly, work from several groups converges on nearly identical consensus cell populations in mouse and human intestines. Strategically localized fractions of the most abundant cells (which express low PDGFRA), including distinct CD81+ trophocytes, represent notable functional niche elements. In the developing gut mesoderm, PDGFRAlo cells seem to give rise to key structural elements, such as different smooth muscle (SM) compartments and unique intestinal capillaries, before the remaining PDGFRAlo cells generate the ISC niche. Against the backdrop of a complete census of adult mesenchymal cells, these findings pave the way to understand their embryonic origins in modern mechanistic terms. This simple but crucial tissue thus offers opportunities to address a broad, fundamental question in developmental biology: How does an embryonic anlage with limited external cell input achieve and retain its adult form? Because injured intestines must reconstitute the mesenchymal compartment, the answers have important implications for understanding and treating ulcerative and other forms of intestinal damage. Prior investigation of signaling in intestinal development elegantly implicates Hedgehog (Hh, from endoderm) and BMP (from mesoderm) in specifying at least SM and endothelial cells (EC), and possibly other compartments, but how these signals elicit distinct cell fates in ostensibly similar progenitors remains unclear. Discrete cell identities reflect opening and closing of thousands of different cis-regulatory elements (CREs); to deconstruct steps that lie between a mesodermal anlage and the functional tissue into which it develops, we propose to study the chromatin basis of SM (Aim 1) and EC (Aim 2) differentiation. We will map mesenchymal ontogeny rigorously with respect to signature CREs for each resident cell type (Aims 1A and 1B), then investigate in primary fetal cell cultures how Hh activity and BMP inhibition together induce the CRE complement necessary for naïve precursors to undergo SM differentiation (Aim 1C). We then ask how the same signals (albeit likely in different forms or concentrations) induce ECs in similar progenitors (Aim 2A). Finally, we propose studies for mechanistic insight into processes designed for intestinal capillary growth to match, but not exceed, resting tissue demands (Aim 2B). Together, this basic science effort aims for fundamental knowledge about a tissue that is critical for intestinal function in resting and injured states.

项目摘要 成年消化性上皮依赖于相邻的间质以维持肠道干细胞（ISC） 地穴底座和驱动绒毛基部的细胞成熟。精确的分层单元，可提供冗余和 部分重叠的“营养”因素执行这些基本的极化函数。我们实验室对 这种新兴的理解包括对小肠（SI）和结肠间充质的深刻表征， 发现潜在的“滋养细胞”，这是隐窝BMP信号梯度的细胞解释，识别 典型的Wnt配体的真实来源以及发现利基自组织的发现。重要的是， 来自几个小组的工作在小鼠和人类中几乎相同的共有细胞种群收敛 肠。最丰富的细胞（表达较低的PDGFRA）的策略性局部分数， 包括不同的CD81+滋养细胞，代表着值得注意的功能小众元素。在发育中的肠道 中胚层，PDGFRALO细胞似乎会产生关键的结构元素，例如不同的平滑肌 （SM）隔室和独特的肠毛细血管，在其余的PDGFRALO细胞生成 ISC利基。在成年间充质细胞的完整普查的背景下，这些发现铺平了 在现代机械术语中理解其胚胎起源的方法。因此，这种简单但至关重要的组织 提供了解决发展生物学中广泛的基本问题的机会： 外部细胞输入有限的胚胎动物实现并保留其成人形式？因为受伤 肠必须重建间充质隔室，答案对 理解和治疗溃疡性和其他形式的肠道损伤。先前对信号的调查 在肠发展中，实质上实现了刺猬（HH，来自内胚层）和BMP（来自中胚层） 在指定至少SM和内皮细胞（EC）以及可能的其他隔室时，但是如何 信号在表面上相似的祖细胞中引起不同的细胞命运尚不清楚。离散的细胞身份 反映成千上万种不同顺式调节元件（CRE）的开放和关闭；解构步骤 那是在中胚层的动力和发展成的功能组织之间，我们建议研究 SM（AIM 1）和EC（AIM 2）分化的染色质基础。我们将绘制间充质的个体发育 关于每种居民单元类型的签名CRE（目标1A和1B）的严格性，然后在 原代胎儿细胞培养HH活性和BMP抑制如何诱导CRE完成 天真的前体进行SM分化所必需的（AIM 1C）。然后我们问相同的信号如何 （尽管可能以不同的形式或浓度）在相似的祖细胞中诱导EC（AIM 2A）。最后，我们 提出的研究，以洞悉用于肠道毛细血管生长的过程的机械洞察力，但 不超过，静止组织的需求（AIM 2B）。这项基础科学努力共同旨在实现基本 关于在静止和受伤状态中肠道功能至关重要的组织的知识。