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Organ-scale regulation of stem cell dynamics

干细胞动力学的器官尺度调控

基本信息

批准号：
10622498
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
项目类别：
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

项目摘要

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.

项目摘要成体干细胞是器官更新、重塑和修复的媒介。他们标志性的能力，伴随自我更新和产生终末后代使得能够终身维持器官形式，功能在任何给定的时间点，干细胞接收不断变化的局部和系统信号加强干性，激活分裂，或根据需要指导细胞命运，以响应组织的进化需求这些信号在空间和时间上被部署，以组织不同的干细胞行为，协调的、器官规模的输出，如组织内稳态。这些涌现的特性对于成人组织的生物学和对人类健康至关重要，然而，我们对它们的工作原理的理解是初步的。我的实验室致力于揭示成人器官的坚固性和灵活性背后的细胞机制上维护我们的MIRA计划的目标是建立一个全面的框架来了解如何每个单独的细胞由局部和系统信号引导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，在功能上等同于脊椎动物的胃和小肠。我们的方法利用独特的现场成像能力-在我们的实验室开创-和精确的遗传工具，以阐明实时细胞动力学，并探索调节这些动力学的机制。在这里，我们集中在三个问题具有广泛意义的干细胞为基础的上皮器官：1）如何干细胞的空间分布--我们发现是非随机的，这是由于干细胞的自主运动-- - 影响器官周转的效率和稳健性？2)什么是EGF的实时空间动力学反馈信号，平衡干细胞分裂和分化的细胞死亡，操纵这些动力学支持或否定了器官大小控制的点源模型？3)如何做新的，在上皮封闭连接的封闭网络之外产生的分化细胞，在它们分化的过程中无缝地进入器官这些研究建立在并扩展了我们R 01资助的器官规模干细胞动力学工作的基础上。以来细胞生命周期是自我更新器官的一个普遍特征，这种可调节的群体水平机制，我们在果蝇中肠中发现的基因将为思考更复杂的器官提供模板，那些在人类身上。