Control of Stem Cell Dynamics by a Niche at Steady-State and During Aging

稳态和衰老过程中微环境对干细胞动力学的控制

• 批准号: 10600108
• 负责人: STEPHEN Francis DINARDO
• 金额: $ 41.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600108
• 关键词: Ablation; Actomyosin; Address; Aging; Architecture; Biological; Biological Assay; Biological Process; Cell physiology; Cells; Centrosome; Communication; Cytoskeleton; Defect; Excision; Funding; Genetic; Genetic Transcription; Homeostasis; Image; Knowledge; Lasers; Maintenance; Mechanics; Morphogenesis; Normal Cell; Property; Regenerative Medicine; Signal Transduction; Specific qualifier value; Stress; Tissues; Work; cancer cell; cell behavior; interest; stem cells; virtual

Stem cells are necessary for tissue homeostasis, and are often localized to specialized niches that control their function. In this manner, niches control virtually all aspects of stem cell dynamics, and these properties of stem cells are essential to tissue maintenance. Recent work has shown that precise cellular architecture is important in order for a niche to communicate with fidelity to the stem cells it controls. A major issue is that the field does not understand how niches are initially formed in a tissue, nor the key cell biological steps that constitute stem cell dynamics., and how these are regulated by niche signals. Our lab made significant advances on these questions over the past five years of GM funding. First, after identifying key signals and transcriptional regulators of niche cell specification, we revealed the dynamics of niche formation by live-imaging. This enabled us to suggest mechanisms underlying niche morphogenesis that are so central to its function. We pursue the underlying mechanisms in this proposal, capitalizing on our knowledge of cytoskeletal control over cell-cell organization, and in particular the involvement of actomyosin contractility and RhoA signaling. Second, we discovered that the niche imposes precise control over fundamental cellular processes such as abscission and midbody inheritance in order to regulate stem cell dynamics during tissue homeostasis and upon stresses, such as aging. We found that dysregulations of either of these fundamental cell biological processes compromises tissue function. Furthermore, the control of midbody inheritance as detailed in the proposal should have an impact generally on our understanding of how normal and cancer cells deal with defects in centrosome number. To address our hyptheses, we combine the powerful genetic and molecalur approaches available in using Drosohila, with state-of-the-art assays in cellualr mechanics, which include high spatial and temporal live-imaging, FRAP and laser ablation. Collectively, our approaches should reveal the undelying mechnics that establish a niche properly, and reveal important cellular features that allow stem cells to maintain tissues. !

干细胞对于组织稳态是必需的，并且通常位于专门的生态位中， 控制它们的功能。通过这种方式，生态位几乎控制干细胞动力学的所有方面，并且 干细胞的这些特性对于组织维持至关重要。最近的工作表明 精确的细胞结构对于生态位与茎的保真度沟通非常重要 它控制的细胞。一个主要问题是该领域不了解利基市场最初是如何形成的。 组织，也不是构成干细胞动力学的关键细胞生物学步骤，以及它们是如何发生的 受利基信号调节。我们的实验室在过去五年中在这些问题上取得了重大进展 多年的通用汽车资助。 首先，在确定了生态位细胞规范的关键信号和转录调节因子后，我们揭示了 通过实时成像研究生态位形成的动态。这使我们能够提出潜在的机制 生态位形态发生对其功能至关重要。我们追求这方面的根本机制 提案，利用我们对细胞骨架控制细胞组织的知识，并在 特别是肌动球蛋白收缩性和 RhoA 信号传导的参与。 其次，我们发现利基对基本细胞过程进行精确控制 例如脱落和中体遗传，以调节组织过程中的干细胞动力学 体内平衡和压力（例如衰老）。我们发现其中任何一个的失调 基本的细胞生物过程会损害组织功能。此外，控制 提案中详细说明的中体继承应该对我们的总体产生影响 了解正常细胞和癌细胞如何处理中心体数量缺陷。 为了解决我们的假设，我们结合了强大的遗传和分子计算方法 使用 Drosohila 进行细胞力学方面最先进的检测，其中包括高空间和 时间实时成像、FRAP 和激光消融。 总的来说，我们的方法应该揭示正确建立利基市场的根本机制， 并揭示使干细胞维持组织的重要细胞特征。 ！