Regulation of Stem Cell Self-Renewal and Differentiation

干细胞自我更新和分化的调控

• 批准号: 8241038
• 负责人: MARGARET T FULLER
• 金额: $ 31.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241038
• 关键词: Address; Adherens Junction; Anatomy; Apical; Behavior; Binding; Cancer Biology; Cell Lineage; Cell Maintenance; Cell Proliferation; Cell-Matrix Junction; Cells; Centrosome; ChIP-seq; Communication; Cues; Cyst; Defect; Drosophila genus; Ensure; Environment; Epidermal Growth Factor Receptor; Epigenetic Process; Equilibrium; Event; Funding; Gene Targeting; Genetic; Germ Cells; Germ Lines; Goals; Homologous Gene; Human body; Lead; Life; Maintenance; Malignant Neoplasms; Mitotic Spindle Apparatus; Mitotic spindle; Modeling; Molecular; Mutation; Natural regeneration; Nuclear; Outcome; Phosphotransferases; Population; Proliferating; Protein Tyrosine Phosphatase; Regenerative Medicine; Regulation; Role; Signal Transduction; Signal Transduction Pathway; Site; Somatic Cell; Specific qualifier value; Spermatogonia; Stem cells; Stereotyping; Supporting Cell; System; Testing; Testis; Time; Tissues; United States National Institutes of Health; activating transcription factor; adult stem cell; cancer stem cell; cell behavior; cell type; cytokine; in vivo; in vivo regeneration; male; profilin; progenitor; programs; public health relevance; receptor; repaired; reproductive; response; self-renewal; stem; stem cell division; stem cell fate; stem cell niche; stem cell population; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): Regulation of Stem Cell Self-renewal and Differentiation NIH 1 R01 GM080501 Adult stem cells are required throughout life to replenish differentiated cells and repair damaged tissue. The molecular mechanisms that maintain and keep in check adult stem cell populations are key for harnessing the potential of adult stem cells for regenerative medicine as well as understanding the genesis and biology of cancer. We propose to investigate how interactions with the local environment of the stem cell niche maintain populations of germ line stem cells in the Drosophila testis, a powerful system for study of adult stem cells in vivo in the context of their niche. In previous funding cycles, we discovered that somatic support cells in the testis stem cell niche provide a crucial microenvironment that regulates both stem cell self renewal and differentiation, and that germ line stem cells (GSCs) orient toward this niche to set up a stereotyped mitotic spindle, ensuring the normally asymmetric outcome of GSC divisions. We showed that a cytokine like signal from the somatic hub activates the transcription factor STAT in GSCs and their partner somatic cyst stem cells (CySCs) and that activated STAT is critical for maintenance of CySC identity and GSC attachment to the hub. CySCs are an important component of the GSC niche and can maintain GSCs in ectopic sites away from the hub. We also found that germ cells require a "go differentiate" signal from somatic cyst cells to exit limitless stem cell proliferation and enter the spermatogonial program of limited transit amplifying (TA) divisions then differentiation. These findings highlight a new model for how signals from the niche regulate stem cell self- renewal, in which timely transition from stem to TA cell is choreographed by a balance between counteracting self-renewal and differentiation signals. We now propose to utilize the powerful system and tools we have established to identify the molecular circuitry that regulates stem cell behavior in response to cues from the niche. We will investigate how GSCs attach to and orient toward the hub and how this normal behavior is controlled by the Upd signal from the hub through activation of the transcription factor STAT. We will investigate whether CySCs maintain GSCs by sending a "self renew" signal or blocking a "go differentiate" signal and test candidate signaling mechanisms and regulators to understand how the niche regulates stem cell fate and how the actions of two stem cell types within the same niche are coordinated. Finally, we will test the model that activation of the EGFR in somatic cyst cells by a signal from cystoblasts downregulates the CySC program, allowing a timely switch from stem cell to progenitor state in both the germ line and somatic lineages. PUBLIC HEALTH RELEVANCE: The results of the proposed studies will establish paradigms for how the tissue microenvironment regulates self-renewal and differentiation of adult stem cells, which are centrally important for tissue maintenance and repair for many cell types in the human body. Understanding how support cell niches regulate adult stem cell behavior may illuminate how tumor stroma support cancer stem cells and how stem cells maintained in their normal environment may be restrained from uncontrolled proliferation by signals from support cells that trigger differentiation.

描述（由申请人提供）：干细胞自我更新和分化NIH 1 R01 GM080501成年干细胞的调节，以补充分化的细胞并修复受损的组织。维持和保持检查成年干细胞种群的分子机制是利用成年干细胞再生医学潜力的关键，以及了解癌症的生物学和生物学。我们建议研究如何与干细胞生态裂市场的局部环境相互作用在果蝇睾丸中维持生殖系干细胞的种群，果蝇睾丸是一个强大的系统，用于研究其在其小裂的背景下体内对成年干细胞的研究。在先前的资金周期中，我们发现睾丸干细胞壁the中的躯体支撑细胞提供了一种至关重要的微环境，可以调节干细胞的自我更新和分化，以及该生殖系干细胞（GSCS）方向朝向该小裂，以建立一个定型的线粒体观点，主轴，确保GSC划分的通常不对称结果。我们表明，来自体细胞枢纽的细胞因子类似的信号激活了GSC中的转录因子统计数据及其伴侣体细胞干细胞（CYSC）和活化的统计数据对于维持CYSC身份和GSC附着在集线器上至关重要。 CYSC是GSC利基市场的重要组成部分，可以在远离轮毂的异位部位维持GSC。我们还发现，生殖细胞需要“分化”与体细胞细胞的信号，以退出无限的干细胞增殖，并输入有限的传输放大（TA）分裂的精子型程序，然后分化。这些发现突出了一个新模型，该模型是从利基市场调节干细胞自我更新的信号，其中及时从茎到TA细胞的过渡是通过反对自我更新和分化信号之间的平衡来编排的。现在，我们建议利用我们已经建立的强大系统和工具来确定根据利基线索的响应来调节干细胞行为的分子电路。我们将研究GSC如何通过转录因子STAT的激活从HUB中的UPD信号来控制和方向。我们将调查CYSC是否通过发送“自我续订”信号或阻止“ GO区分”信号和测试候选信号传导机制和调节器来了解利基市场如何调节干细胞命运以及如何调节两种干细胞类型的作用如何来维护GSC。同一利基是协调的。最后，我们将测试模型，即通过囊写细胞的信号在体细胞细胞中激活EGFR会下调CYSC程序，从而允许在生殖线和躯体谱系中及时从干细胞转换为祖细胞状态。 公共卫生相关性：拟议研究的结果将建立组织微环境如何调节成年干细胞的自我更新和分化的范例，这对于人体许多细胞类型的组织维护和修复非常重要。了解支持细胞壁细胞如何调节成年干细胞行为可能会阐明肿瘤基质如何支撑癌症干细胞以及在其正常环境中维持的干细胞如何通过触发分化的支持细胞的信号限制在不受控制的增殖中。