Mammary basal/stem cell plasticity and regulation

乳腺基底/干细胞可塑性和调节

• 批准号: 9557556
• 负责人: Xing Dai
• 金额: $ 42.73万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9557556
• 关键词: Address; Adopted; Adult; Affect; Animals; Area; Back; Basal Cell; Biological Assay; Biological Models; Biology; Breast Epithelial Cells; Cancer Etiology; Cell Differentiation process; Cell Fate Control; Cell Line; Cells; Characteristics; Colony-Forming Units Assay; Coupled; Data; Development; Disease; Distant Metastasis; Embryonic Development; Epiblast; Epigenetic Process; Epithelial; Epithelial Cells; Equilibrium; Failure; Fibrosis; Genetic; Goals; Heterogeneity; Homeostasis; In Vitro; Individual; Knockout Mice; Knowledge; Learning; Link; Literature; Maintenance; Malignant - descriptor; Mammary gland; Mesenchymal; Mesoderm; Methods; Modeling; Molecular; Molecular Target; Morphogenesis; Multipotent Stem Cells; Mus; Natural regeneration; Organ; Pathologic; Pathologic Processes; Physiological; Play; Pluripotent Stem Cells; Population; Population Heterogeneity; Positioning Attribute; Pregnancy; Process; Property; Puberty; Regenerative Medicine; Regulation; Repression; Research; Role; Self-control as a personality trait; Somatic Cell; Stem cells; Stimulus; Stratum Basale; Subgroup; Technology; Testing; Tissue Engineering; Tissues; Transitional Cell; Transplantation; Work; Wound Healing; adult stem cell; cancer cell; cell type; design; epithelial to mesenchymal transition; experimental study; fluidity; genetic signature; in vivo; in vivo regeneration; inhibitor/antagonist; knock-down; knockout gene; malignant breast neoplasm; mammary epithelium; mammary gland development; mathematical model; novel; overexpression; prevent; prospective; regenerative; self-renewal; single cell analysis; single-cell RNA sequencing; stem; stem cell fate; stem cell therapy; stemness; trait; transcription factor; transcriptomics; tumor progression

PROJECT SUMMARY The ability to reprogram myriad differentiated cells back into a pluripotent stem cell state highlights the remarkable plasticity of somatic cells. Effort is needed to better understand the inherent plasticity of tissue stem cells as well as the underlying regulatory mechanisms, so that we can learn about how to control cell fates in tissue engineering and regenerative medicine. Epithelial cells are long known to possess inherent plasticity, best manifested by their ability to become mesenchymal cells as well as to revert back to an epithelial state, under appropriate stimuli. This plasticity is important for generating mesenchymal cell types during embryogenesis, and is thought to be required for malignant cancer cells to form distant metastases. Recent studies have inspired the hypothesis that the mechanisms that regulate this plasticity are used in committed tissue epithelial cells to control stem cell fates. The mammary epithelia serve an outstanding model system to test this hypothesis, owing to the well-established methods to prospectively isolate and functionally characterize their residential stem cells. The basal layer of the mammary epithelia harbors multipotent stem cells and cells that can turn into such stem cells under conditions such as transplantation and pregnancy. We will organically combine cutting-edge single-cell analysis with state-or-art technology such as tissue-specific gene knockout and inducible overexpression, in vivo and ex vivo stem cell assays, as well as molecular studies to address the following fundamentally important questions: 1) How many cell type subsets or cellular states exist in the mammary basal cell population and do these states correspond to distinct positions in the spectrum of epithelial/EMT plasticity? 2) Are multipotent stem cells or cells with the capacity to become such stem cells defined in part by their high plasticity, namely the potential to adopt both mesenchymal-like and terminal epithelial fates? 3) What is the key molecular circuitry that regulates such plasticity, and whether/how this circuitry dictates the stay of a basal cell in a stem cell state?

项目摘要 将无数分化细胞重新编程为多能干细胞状态的能力突出了 体细胞的显着可塑性。需要努力以更好地了解组织的固有可塑性 干细胞以及潜在的调节机制，因此我们可以了解如何控制细胞 组织工程和再生医学的命运。上皮细胞长期已知具有固有的 可塑性，最好表现为它们成为间充质细胞的能力以及恢复回到一个 上皮状态，在适当的刺激下。这种可塑性对于生成间充质细胞类型很重要 在胚胎发生过程中，被认为是恶性癌细胞形成远处转移所必需的。 最近的研究启发了以下假设：调节这种可塑性的机制 承诺的组织上皮细胞控制干细胞命运。乳腺上皮提供出色的模型 由于建立了良好的方法，可以测试该假设的系统 表征其住宅干细胞。乳腺上皮的基础层藏有多能茎 可以在移植和妊娠等条件下变成干细胞的细胞和细胞。我们 将有机地将尖端单细胞分析与状态或艺术技术（例如组织特异性）结合 基因基因敲除和诱导的过表达，体内和体内干细胞分析以及分子研究 要解决以下重要问题：1）多少个细胞类型子集或细胞状态 存在于乳腺基底细胞种群中，并做这些状态对应于光谱中的不同位置 上皮/EMT可塑性？ 2）是多能干细胞或具有成为这种干细胞的能力的细胞 部分由它们的高可塑性定义，即采用间充质和末端的潜力 上皮命运？ 3）什么是调节这种可塑性的关键分子电路，以及是否/如何 电路决定了基底细胞在干细胞状态下的停留？