Intrinsic and extrinsic control of epithelial tissue stem cell activity

上皮组织干细胞活性的内在和外在控制

• 批准号: 10406792
• 负责人: Xing Dai
• 金额: $ 44.8万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406792
• 关键词: Address; Basal Cell; Biological Models; Cancer Etiology; Cell Compartmentation; Cells; Characteristics; Chromatin; Colony-Forming Units Assay; Disease; Epithelial; Event; Failure; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genomics; Heterogeneity; Homeostasis; Knowledge; Lead; Mammary gland; Mesenchymal; Molecular; Molecular Target; Morphogenesis; Natural regeneration; Proliferating; Prostate; Regenerative Medicine; Regulation; Research; Signal Pathway; Signal Transduction; Skin; Technology; Testing; Tissue Engineering; Tissues; Undifferentiated; beta catenin; cancer cell; cell type; clinically relevant; in vivo; innovation; insight; interdisciplinary approach; knockout gene; macrophage; malignant breast neoplasm; mammary; mammary epithelium; novel; prevent; programs; regenerative; self-renewal; single cell sequencing; stem; stem cell biology; stem cell genes; stem cells; tissue regeneration; tissue stem cells

PROJECT SUMMARY Tissue stem cells are rare, undifferentiated cells that are capable of self-renewal and are essential for fueling the homeostasis and regeneration of the tissue in which they reside. They are often quiescent, and when activated, they proliferate and differentiate to produce mature cell types with specialized functions. Stem cell activities are jointly controlled by the intrinsic gene expression program and the signals from the surrounding tissue microenvironment. Dissecting the intrinsic and extrinsic mechanisms that govern stem cell quiescence and activation is important not only for gaining fundamental knowledge of tissue and stem cell biology, but also for understanding how to manipulate cell fates in tissue engineering and regenerative medicine. Myriad regenerative epithelial tissues, such as mammary gland, skin, and prostate, house stem cells in their basal cell compartment. We use two mammalian tissues, mammary gland and skin, each with its unique advantages and clinical relevance, as complimentary model systems to study both general and tissue- specific mechanisms underlying the regulation of basal cell fate and stem cell activities. Our research has elucidated the function of key transcription and chromatin factors in mammary and skin basal/stem cell gene regulation, and how these factors interface with major signaling pathways to control the activation, proliferation, differentiation, and epithelial-mesenchymal plasticity of basal stem cells. The recent advent of single-cell sequencing technology has enabled us to systematically probe the cellular and molecular heterogeneities of mammary and skin basal cells, allowing a deeper and more comprehensive understanding of their compositions and characteristics as well as providing novel insights into the sequence of events in stem cell activation and differentiation. In the next five years, we will continue to employ a multi-disciplinary approach combining single-cell genomics and spatial gene expression mapping with tissue-specific gene knockout and lineage tracing, in vivo and ex vivo stem cell assays, as well as molecular studies to address two major knowledge gaps regarding mammary basal stem cells: how their quiescence is maintained and active expansion is achieved. Specifically, we will test the innovative hypothesis that a low level of Wnt/b-catenin signaling and molecular cross-talks between basal cells and specific macrophage subsets are critical for maintaining basal stem cell quiescence. We will also characterize the novel function and regulation of a newly discovered subset of basal cells as transit amplifying progenitor cells that serve as workhorses to drive basal cell expansion during mammary epithelial morphogenesis, homeostasis, and regeneration. When and where applicable, we will perform parallel analysis on skin in order to identify potentially general principles and strategies underlying basal cell-macrophage cross-talks. Our findings will expose novel intrinsic and extrinsic regulators of basal stem cell quiescence and active expansion. This knowledge is fundamental to preventing stem cell depletion and regenerative diseases as well as to understanding cancer cell dormancy.

项目概要 组织干细胞是罕见的未分化细胞，具有自我更新能力，对于维持生命至关重要 促进它们所在组织的稳态和再生。它们常常处于静止状态，并且 当被激活时，它们会增殖和分化，产生具有特殊功能的成熟细胞类型。干 细胞活动由内在基因表达程序和来自外源的信号共同控制。 周围组织微环境。剖析控制干细胞的内在和外在机制 静止和激活不仅对于获得组织和干细胞的基础知识很重要 生物学，还可以了解如何在组织工程和再生中操纵细胞命运 药品。无数的再生上皮组织，如乳腺、皮肤和前列腺，都含有干细胞 在它们的基底细胞室中。我们使用两种哺乳动物组织，乳腺和皮肤，每种组织都有其 独特的优势和临床相关性，作为研究一般和组织的补充模型系统 基底细胞命运和干细胞活性调节的具体机制。我们的研究有 阐明了乳腺和皮肤基底/干细胞基因中关键转录和染色质因子的功能 调节，以及这些因子如何与主要信号通路相互作用以控制激活、增殖、 基底干细胞的分化和上皮间质可塑性。最近单细胞的出现 测序技术使我们能够系统地探究细胞和分子的异质性 乳腺和皮肤基底细胞，可以更深入、更全面地了解它们 组成和特征，并提供对干细胞事件顺序的新见解 激活和分化。未来五年，我们将继续采用多学科的方法 将单细胞基因组学和空间基因表达图谱与组织特异性基因敲除相结合 谱系追踪、体内和离体干细胞测定以及解决两个主要问题的分子研究 关于乳腺基底干细胞的知识差距：它们如何保持静止和活跃 实现了扩展。具体来说，我们将测试低水平的 Wnt/b-连环蛋白这一创新假设 基底细胞和特定巨噬细胞亚群之间的信号传导和分子串扰对于 维持基底干细胞静止。我们还将描述新的功能和调节 发现基底细胞的子集作为转运放大祖细胞，作为驱动基底细胞的主力 乳腺上皮形态发生、稳态和再生过程中的细胞扩张。何时何地 适用时，我们将对皮肤进行并行分析，以确定潜在的一般原则和 基底细胞-巨噬细胞相互作用的策略。我们的发现将揭示新颖的内在和外在 基底干细胞静止和活跃扩张的调节因子。这些知识对于预防 干细胞耗竭和再生疾病以及了解癌细胞休眠。