Understanding the Nature and Regulation of Extramedullary Hematopoiesis in the Liver

About This Grant

Project Summary/Abstract: Hematopoietic stem cells (HSCs) play a vital role in the immune system by generating both innate and adaptive immune cells. My career objective is to lead a laboratory investigating the intrinsic and extrinsic factors that regulate HSC function and the intricate interplay between HSC biology and immunology, with the ultimate aim of improving the treatments for immunity-related diseases. One intriguing aspect of HSCs is their ability to leave the bone marrow (BM) in adult organisms and initiate extramedullary hematopoiesis (EMH) in the liver. While EMH was traditionally considered a compensatory for insufficient BM hematopoiesis, emerging evidence shows that EMH also plays a critical role in the progression of diverse diseases, such as tumorigenesis and heart failure, and is also implicated in trained immunity. However, our knowledge about how the HSCs in the EMH liver are cell-intrinsically and -extrinsically regulated remains limited, which represents a critical knowledge gap for its understanding and manipulation under various pathological processes. In this proposal, I will address this gap by pursuing three specific aims: Aim 1: I will characterize the cellular components of the HSC niche in the EMH liver, focusing on revealing the functional source of two critical cytokines for HSC maintenance, SCF and CXCL12; Aim 2: I will identify whether and which subset of HSC clones initiating liver EMH by utilizing a novel CRISPR/Cas9-mediated barcoding mouse model in combination with multimodal single-cell sequencing; Aim 3: I will investigate the role of HSC-autonomous Rbfox2, an alternative splicing regulator, in regulating liver EMH formation. The gained insights are expected to have broader applications in understanding and manipulating the progression of various pathological processes. During the K99 phase, my research will be conducted in Dr. Lei Ding's laboratory at Columbia University. Dr. Ding is a pioneer in the field of HSC biology and has made significant contributions to revealing the cell-intrinsic and -extrinsic mechanisms regulating HSC function and hematological disorders. To differentiate my research from Dr. Ding's work and enhance my expertise in immunology for my long-term research pursuit, I will receive additional mentorship from my co-mentor Dr. Sankar Ghosh, a distinguished immunologist. I have also assembled an advisory committee consisting of experts in liver biology (Dr. Robert Schwabe), epigenetics (Dr. Chao Lu), CRISPR/Cas9 technology and bioinformatics (Dr. Xuebing Wu), and career development (Dr. Jaime Rubin) to expand and enhance my experimental and professional skills. Furthermore, I will leverage the extensive facilities and resources available at Columbia University. With these supports, I will acquire additional experimental techniques, advance my expertise in bioinformatics, and refine my skills in grantsmanship, mentoring, lab management, and scientific communication, which are instrumental for me in establishing a research niche separate from my mentor's and successfully transitioning from a postdoctoral researcher to an independent investigator.