Hematopoietic Stem Cell(HSC) response to chronic liver disease and their role in systemic inflammation

About This Grant

Project Summary: Chronic liver disease (CLD) is a major global health burden associated with high morbidity and mortality, primarily due to systemic inflammation (SI) and multiorgan dysfunction and failure (MOF). In advanced stages like as acute-on-chronic liver failure (ACLF), SI drives MOF, yet its underlying mechanisms remain poorly defined. Current immunosuppressive therapies are limited by severe side effects, including infection and malignancy, underscoring the need for safer, targeted approaches. Our preliminary studies in multiple preclinical models (toxin- induced, dietary, genetic) show that chronic liver injury disrupts bone marrow (BM) homeostasis, causing BMHSC expansion and inflammatory cell mobilization. We identified hepatocyte-derived chemokines (C-C motif) ligand 2 (CCL2) as a key mediator of this response, and genetic or pharmacologic blockade of the CCL2– CCL2 binding receptor (CCR2) axis markedly reduces BMHSC activation and SI. Elevated BMHSCs in human NAFLD autopsy samples further support the translational relevance of these findings. The long-term goal of this study is to understand how BM cells respond to stress following chronic liver injury. The overall objective of this application is to identify the underlying mechanisms whereby BMHSCs respond to chronic liver injury stress and how BMHSC activation causes SI in preclinical models of early and advanced stages of CLD. The central hypothesis is that chronic liver injury leads to the extracellular release of CCL2 from hepatocytes, which stimulates BMHSC to proliferate & differentiate, & egression of inflammatory cells from BM to cause SI in CLD. The rationale of this project is that understanding how BMHSC responds to chronic liver injury can provide a scientific framework for developing novel strategies to combat SI in CLD. Guided by strong preliminary data, two specific aims are proposed. Aim 1: Examine the bone marrow hematopoietic stem cell (BMHSC) response to chronic liver injury & its role in SI and Aim 2: Identify the molecular underpinnings of BMHSC “stress-response” & SI in chronic liver injury. Under Aim 1, we will assess BMHSC functional status, kinetics, and persistence during chronic liver injury, as well as resolution after injury withdrawal, and determine whether targeting BMHSC function can correct SI and prevent MOF in advanced CLD. Aim 2 will determine how hepatic CCL2, acting as a damage-associated molecular patterns (DAMPs), drives BMHSC activation and SI in CLD by using hepatocyte-specific CCL2 deletion/overexpression and BMHSC-specific CCR2 deletion, and will define the CCL2–CCR2 signaling pathway underlying BMHSC expansion, with validation in human CLD samples. The proposed research is potentially innovative because it will study a novel mechanism of SI which is mediated by BMHSC response to liver injury using multiple pre-clinical models of CLD and further validate in human tissue samples. The proposed research is potentially significant because it will fill critical gaps in understanding SI in CLD and liver–BM communication. Successful completion of this project will provide a strong foundation for the development of experimental therapeutics targeting CCL2-CCR2 and BMHSC proliferative response as novel strategies to prevent or treat SI of CLD.