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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.

项目概要成体干细胞是器官更新、重塑和修复的媒介。他们的标志性能力同时自我更新并产生终末后代，能够终身维持器官形态和功能。在任何给定的时间点，干细胞都会接收到不断变化的局部和全身信号根据需要增强干性、激活分裂或指导细胞命运，以应对组织的进化需要。这些信号跨空间和时间部署，以整理不同的干细胞行为协调的、器官规模的输出，例如组织稳态。这些新出现的特性对于成人组织的生物学特性对人类健康至关重要——然而，我们对其工作原理的了解还很初级。我的实验室致力于揭示成体器官稳健性和灵活性背后的细胞机制维护。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都受到局部和全身信号的引导，以获得器官中细胞平衡的最终结果规模。我们的模型系统是成年果蝇中肠，这是一种基于干细胞的管状上皮器官，功能相当于脊椎动物的胃和小肠。我们的方法利用独特的现场我们实验室首创的成像功能和精密遗传工具可阐明实时细胞动态体内并探索调节这些动态的机制。在这里，我们重点关注三个对基于干细胞的上皮器官具有广泛意义的问题：1）如何干细胞的空间分布——我们发现，由于干细胞的自主运动，它是非随机的—— –影响器官周转的效率和稳健性？ 2）EGF的实时空间动力学是什么平衡干细胞分裂和分化细胞死亡的反馈信号，并且异位这些动力学的操纵支持还是否定器官大小控制的点源模型？ 3）如何做新的，分化细胞诞生于上皮闭塞连接的密封网络之外，整合当它们分化时无缝地进入器官？这些研究建立在并扩展了我们 R01 资助的器官规模干细胞动力学工作的基础上。自从细胞生命周期是自我更新器官的普遍特征，是可调节的群体水平机制我们在果蝇中肠中发现的发现将为思考更复杂的器官提供一个模板，包括那些在人类身上。