Regulation of Stem Cell Self-Renewal and Differentiation

干细胞自我更新和分化的调控

• 批准号: 8465240
• 负责人: MARGARET T FULLER
• 金额: $ 30.32万
• 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/8465240
• 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.

描述（由申请人提供）：干细胞自我更新和分化的调节 NIH 1 R01 GM080501 成体干细胞在整个生命过程中都需要补充分化细胞和修复受损组织。维持和控制成体干细胞群的分子机制是利用成体干细胞的再生医学潜力以及了解癌症的起源和生物学的关键。我们建议研究与干细胞生态位局部环境的相互作用如何维持果蝇睾丸中生殖系干细胞的群体，果蝇睾丸是在其生态位背景下研究体内成体干细胞的强大系统。在之前的资助周期中，我们发现睾丸干细胞生态位中的体细胞支持细胞提供了调节干细胞自我更新和分化的关键微环境，并且生殖系干细胞（GSC）朝向该生态位以建立定型的有丝分裂主轴，确保 GSC 分裂的正常结果不对称。我们发现，来自体细胞中枢的细胞因子样信号会激活 GSC 及其伙伴体细胞囊肿干细胞 (CySC) 中的转录因子 STAT，并且激活的 STAT 对于维持 CySC 身份和 GSC 与中枢的附着至关重要。 CySC 是 GSC 生态位的重要组成部分，可以在远离中心的异位站点中维持 GSC。我们还发现，生殖细胞需要来自体细胞囊肿细胞的“分化”信号才能退出无限的干细胞增殖并进入有限转运放大（TA）分裂然后分化的精原细胞程序。这些发现凸显了来自微环境的信号如何调节干细胞自我更新的新模型，其中从干细胞到TA细胞的及时转变是通过抵消自我更新和分化信号之间的平衡来设计的。我们现在建议利用我们已经建立的强大系统和工具来识别调节干细胞行为以响应来自利基的线索的分子电路。我们将研究 GSC 如何附着并朝向中枢，以及如何通过激活转录因子 STAT 由来自中枢的 Upd 信号控制这种正常行为。我们将研究CySCs是否通过发送“自我更新”信号或阻断“分化”信号来维持GSCs，并测试候选信号传导机制和调节器，以了解生态位如何调节干细胞命运以及两种干细胞类型如何在细胞内发挥作用。相同的利基是协调的。最后，我们将测试该模型，即通过来自囊母细胞的信号激活体细胞囊肿细胞中的 EGFR 下调 CySC 程序，从而允许生殖细胞系和体细胞谱系及时从干细胞状态转变为祖细胞状态。