Organ-scale regulation of stem cell dynamics

干细胞动力学的器官尺度调控

• 批准号: 10399573
• 负责人: Lucy Erin O'brien
• 金额: $ 39.35万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399573
• 关键词: Adult; Biological Models; Biology; Cell Death; Cell Differentiation process; Cells; Complex; Drosophila genus; EGF gene; Epithelial; Equilibrium; Feedback; Funding; Goals; Health; Homeostasis; Human; Imaging Techniques; Individual; Kinetics; Life Cycle Stages; Maintenance; Marshal; Midgut; Organ; Organ Model; Organ Size; Output; Phenotype; Population; Process; Property; Regulation; Resolution; Signal Transduction; Small Intestines; Source; Spatial Distribution; Stomach; Thinking; Tight Junctions; Time; Tissues; Tubular formation; Work; adult stem cell; base; cell behavior; cell motility; flexibility; grasp; imaging capabilities; in vivo; precision genetics; programs; repaired; seal; self-renewal; stem cell division; stem cell model; stem cells; stemness; tool

PROJECT SUMMARY Adult stem cells are the agents of organ renewal, remodeling and repair. Their hallmark ability to concomitantly self-renew and produce terminal progeny enables lifelong maintenance of organ form and function. At any given point in time, stem cells receive an ever-changing panoply of local and systemic signals that reinforce stemness, activate division, or direct cellular fate as needed to respond to the tissue’s evolving needs. These signals are deployed across space and time to marshal diverse stem cell behaviors for coordinated, organ-scale outputs such as tissue homeostasis. Such emergent properties are fundamental to the biology of adult tissues and essential for human health—yet, our grasp of their workings is rudimentary. My lab seeks to uncover the cellular mechanisms that underlie the robustness and flexibility of adult organ maintenance. The goal of our MIRA program is to build a comprehensive framework for understanding how each individual cell is guided by local and systemic signals for a net result of cellular equilibrium at the organ scale. Our model system is the adult Drosophila midgut, a stem cell-based, tubular epithelial organ that is functionally equivalent to the vertebrate stomach and small intestine. Our approach leverages unique live imaging capabilities—pioneered in our lab—and precision genetic tools to illuminate real-time cell dynamics in vivo and to probe the mechanisms that tune these dynamics. Here, we focus on three questions with broad significance to stem cell-based epithelial organs: 1) How does the spatial distribution of stem cells––which we find is non-random, due to autonomous stem cell motility– –impact the efficiency and robustness of organ turnover? 2) What are the real-time spatial kinetics of the EGF feedback signals that equilibrate stem cell divisions and differentiated cell death, and does ectopic manipulation of these kinetics support or negate a point-source model for organ size control? 3) How do new, differentiating cells, which are born outside of the epithelium’s sealed network of occluding junctions, integrate seamlessly into the organ as they differentiate? These studies build upon and expand our R01-funded work on organ-scale stem cell dynamics. Since the cellular life cycle is a universal feature of self-renewing organs, the tunable, population-level mechanisms that we uncover in the Drosophila midgut will provide a template for thinking about more complex organs, including those in humans.

项目摘要 成年干细胞是器官更新，重塑和修复的药物。他们的标志能力 同时自我更新并产生末端后代，可以终身维护器官形式和 功能。在任何给定的时间点，干细胞都会获得局部和全身信号的不断变化 可以根据需要加强茎，激活分裂或直接细胞命运来应对组织的发展 需要。这些信号在空间和时间之间部署到元帅多种干细胞行为的行为 协调的器官规模输出，例如组织稳态。这种紧急特性对于 成人组织的生物学和对人类健康至关重要的生物学 - 但是，我们对它们的工作的掌握是基本的。 我的实验室试图发现成人器官鲁棒性和灵活性的基础的细胞机制 维护。我们MIRA计划的目标是建立一个综合框架，以了解如何 每个单独的细胞都由局部和全身信号引导，以在器官处的细胞平衡结果 规模。我们的模型系统是成年果蝇中肠，一种基于干细胞的管状上皮器官 在功能上等于脊椎动物stallch和小肠。我们的方法利用独特的现场 成像功能 - 在我们的实验室中占有 - 以及精确的遗传工具，以阐明实时细胞动力学 体内并探测调整这些动力学的机制。 在这里，我们专注于三个与基于干细胞的上皮器官具有广泛意义的问题：1） 干细胞的空间分布是否是由于自主干细胞运动 - - 影响器官离职的效率和鲁棒性？ 2）EGF的实时空间动力学是什么 反馈信号表明等效的干细胞分裂和分化细胞死亡，并进行生态 这些动力学的操纵支持或否定了器官尺寸控制的点源模型？ 3）如何新 区分细胞，这些细胞出生在上皮的密封网络以外的遮挡连接处的网络之外 当它们区分时，它们无缝地进入器官？ 这些研究基于和扩展了我们在器官规模的干细胞动力学上的R01资助的工作。自从 蜂窝生命周期是自我更新器官的普遍特征 我们在果蝇中发现的中肠里将提供一个模板，以思考更复杂的器官，包括 那些在人类中。