Organ-scale regulation of stem cell dynamics

项目总结 成体干细胞是器官更新、重塑和修复的媒介。他们标志性的能力是 伴随着自我更新和产生末端后代，使器官形态和 功能。在任何给定的时间点，干细胞都会收到一系列不断变化的局部和全身信号。 这加强了茎，激活分裂，或根据需要直接细胞命运，以响应组织的进化 需要。这些信号被部署在空间和时间上，以整合不同的干细胞行为 协调的器官规模的输出，如组织动态平衡。这些新出现的特性是 成人组织的生物学，对人类健康是必不可少的--然而，我们对它们的工作原理的了解还很初级。 我的实验室试图揭开成年器官坚固和灵活的细胞机制。 维修。我们Mira计划的目标是建立一个全面的框架，以便了解如何 每个单独的细胞都受到局部和系统信号的引导，以获得器官细胞平衡的净结果 比例。我们的模型系统是成年果蝇中肠，一个基于干细胞的管状上皮器官，它是 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LIVE 成像功能-在我们的实验室中首创-和精确的基因工具，以照亮实时细胞动力学 并探索调节这些动力学的机制。 在这里，我们聚焦于三个对干细胞为基础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--我们发现这是非随机的，由于干细胞的自主运动-- -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，以及异位 操纵这些动力学支持或否定器官大小控制的点源模型？3)新的， 分化细胞出生在上皮封闭的闭塞连接网络之外，整合 随着它们的分化而无缝地进入器官？ 这些研究建立在我们R01资助的器官规模干细胞动力学工作的基础上，并对其进行了扩展。自.以来 细胞生命周期是自我更新器官的普遍特征，这种可调节的、种群水平的机制 我们在果蝇中肠中发现的将为思考更复杂的器官提供一个模板，包括 这些在人类身上。

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.