Tissue development and regeneration involve the coordinated efforts of many individual stem and progenitor cells. The coordination between individual cells is critical to maintaining tissue size and function. However, it remains poorly understood particularly at the single cell level and quantitatively. Using mouse blood and immune cell development and regeneration as a primary model, our research program is motivated by two fundamental questions: how do individual hematopoietic stem and progenitor cells (HSPCs) differ from one another, and how are they coordinated as a network in sustaining a balanced supply of blood and immune cells? With cutting-edge technologies including single-cell analyses, quantitative biology, synthetic biology, omics, large-scale data mining, and machine learning, our research delves into the regulation of hematopoietic development and regeneration from a systems biology perspective, encompassing organismal, tissue, cellular, and molecular levels of investigation. Our findings can invigorate broad areas of basic and biomedical research including developmental biology, stem cell biology, regenerative medicine, tissue engineering, immunology, hematology, aging, cancer and other diseases. Our research primarily focuses on the following four areas:
1. Tracking the temporal dynamics of the HSPC network during its formation, homeostasis, and decline
Tissue formation, regeneration, and repair unfold over time. Understanding the temporal dynamics of these processes is crucial as it reveals the orchestrated sequences of cellular events, signaling pathways, and regulatory mechanisms that control tissue size and function. The temporal order also provides insights into the precise interactions and dependencies of the cellular and molecular elements within the network. By investigating the temporal dynamics of a stem cell network, our research aims to shed light on a fundamental question in development and regeneration: how is cell fate determined by the complex convergence of intrinsic and extrinsic factors.
2. Deciphering spatial dynamics and intercellular communication of HSPCs in the bone marrow
While cell identity, spatial organization and interactions are well understood in most tissues, hardly anything is known about the spatial organization and dynamic interactions between individual cells in the bone marrow. Spatial interactions among cells define their exposure to external signals, thus playing a pivotal role in shaping cell fate decisions. To addresses the key knowledge gaps in the field, we will explore the mechanisms and impacts of cell-cell interactions in the bone marrow.
3. Uncovering the regulatory mechanisms that govern the robustness of the HSPC network
Given the critical importance of blood and immune cells, the HSPC network has evolved remarkable robustness, allowing it to sustain essential functions of the blood and immune systems upon perturbation. Understanding the mechanisms regulating the robustness can revolutionize regenerative medicine, tissue engineering, and disease study. Earlier research has alluded to the presence of mechanisms such as redundancy and feedback loops, but a systematic and quantitative investigation remains lacking. We will comprehensively study the regulation of the HSPC network using cutting-edge single cell analyses and clonal tracking techniques.
4. Monitoring and engineering the HSPC network
Redundancy and adaptability in the HSPC network create tremendous challenges for disease diagnosis and treatment. When hematopoietic diseases are detected in patients, the HSPC network has often already evolved beyond its resilience, obscuring the disease source and the ability to eliminate all diseased cells. Through close collaborations with clinicians, our research group has investigated both normal and disordered hematopoiesis using primary human samples. Building upon our strong basic science research on the HSPC network, our engineering and translational projects strive to engineer innovative approaches in diagnosis, treatment, and preventative care.
