Understanding haematopoietic stem cell fate choices by comparing distinct cellular states

造血是一个复杂的、微调的过程，每天产生数万亿个新的血细胞。成人造血干细胞(HSCs)负责这一系统的终生维护，因此了解它们的生物学特性是至关重要的。成熟细胞的产生和HSC的维持之间的平衡主要由细胞因子与HSC上的受体结合并激活下游信号通路来控制。最近发现，细胞因子受体的激活比先前认为的更复杂和多样化，导致了命运选择概率的显著更大的灵活性和多样性，这可能解释了一些细胞因子(如SCF、TPO)如何同时支持HSC维持和驱动成熟血细胞的产生。该项目重点研究细胞因子的生物学机制：HSCs中的受体相互作用，为调节血细胞生产和在体外产生大量HSCs提供信息。这个项目是高度跨学科的，研究单个小鼠和人类造血干细胞中的单分子，并利用定量和生物物理生物学中的新技术/方法。它建立在东道主实验室最近的跨学科项目的基础上，这些项目应用新技术来解决HSC生物学(《自然》，2018)和细胞因子受体信号传递(《科学》，2020)中的基本生物学问题。

Haematopoiesis is a complex, finely-tuned process that produces trillions of new blood cells daily. Adult haematopoietic stem cells (HSCs) are responsible for the lifelong maintenance of this system, making it essential to understand their biology. The balance between mature cell production and HSC maintenance is primarily controlled by cytokines binding to receptors on HSCs and activating downstream signaling pathways. The recent discovery that cytokine receptor activation is more complex and diverse than previously thought leads to significantly more flexibility and diversity in fate choice probabilities, potentially explaining how some cytokines (e.g., SCF, TPO) can simultaneously support HSC maintenance and drive mature blood cell production. This project focuses on the biological mechanism of cytokine: receptor interaction in HSCs, informing efforts to modulate blood cell production and to produce vast quantities of HSCs outside the body. This project is highly interdisciplinary, studying single molecules in single mouse and human HSCs and leveraging new technologies/approaches in quantitative and biophysical biology. It builds on recent interdisciplinary projects in the host labs which apply new technologies to address fundamental biological questions in HSC biology (Nature, 2018) and cytokine receptor signaling (Science, 2020).