MMP7+ Hepatic Stellate Cells as Drivers of Fibrosis in Biliary Atresia - PROJECT SUMMARY Biliary atresia (BA) is the most common indication for pediatric liver transplantation, yet there are no disease- modifying therapies. The current standard of care, Kasai portoenterostomy (KPE), restores bile flow in some patients, but fibrosis inexorably progresses, leading to cirrhosis in nearly 80% of children before adulthood. Fibrosis severity is the key determinant of outcomes in BA, yet its mechanistic drivers remain poorly defined, particularly in patients who achieve bile drainage after KPE. Current paradigms focus on cholangiocyte injury and inflammation, but these insights have not yielded effective antifibrotic strategies. Our preliminary studies identify a unique hepatic stellate cell (HSC) subpopulation in BA marked by matrix metalloproteinase-7 (MMP7) expression, which is released primarily by injured cholangiocytes. MMP7 is a robust diagnostic biomarker and a potential mediator of disease, as its expression correlates with fibrosis severity and persists independent of cholestasis. The role of MMP7 within HSCs has not been studied, and MMP7+ HSCs may represent a disease- specific program driving persistent fibrosis. This project tests the novel hypothesis that MMP7+ HSCs are key effectors of fibrosis progression in BA. We will: (1) define the transcriptomic and spatial identity of MMP7+ HSCs in BA liver explants; (2) determine the role of MMP7 in HSCs in BA progression using conditional knockout murine models; and (3) evaluate the therapeutic potential of MMP7 inhibition in human precision-cut liver slices (hPCLS). By integrating patient tissue, innovative spatial and single cell profiling, targeted mouse models, and translational ex vivo platforms, this work reframes BA pathogenesis around HSC biology and advances MMP7 from biomarker to mechanistic driver. The proposed studies will provide critical insights into fibrosis mechanisms, establish the role MMP7 in HSCs, and lay the foundation for mechanism-based, disease- modifying therapies in BA. I aim to become an independent physician-scientist focused on pediatric cholestatic liver diseases, where drivers of fibrosis progression remains poorly understood. To support this transition, I developed a five-year career development plan with my mentors that includes advanced training in single cell and spatial transcriptomics, hPCLS modeling, in vivo murine studies, and HSC biology. This plan is complemented by structured coursework and mentorship from leaders in hepatology, genomics, and computational biology. My work is embedded within the collaborative and resource-rich environment of the Icahn School of Medicine at Mount Sinai, including the Mindich Child Health and Development Institute (MCHDI), the Division of Liver Diseases, and the Recanati/Miller Transplantation Institute (RMTI), which provide access to cutting-edge technologies, diverse patient populations, and strong institutional support. With 80% protected time for research and a well-integrated training plan, I am well-positioned to establish a distinct and impactful research program in pediatric hepatology.
