The hypothesis for aim 1 is that resident sprocs are the source of liver sinusoidal endothelial cells (LSECs) during normal turnover and that resident sprocs reside in a stem cell niche that promotes their quiescence.
Aim 1 will use lineage-tracing to determine whether LSECs are derived from resident sprocs, will characterize LSECs and resident sprocs in-depth to identify cell differentiation markers and lineage markers to determine whether LSECs share common origins with other liver cells, will identify signaling pathways known to respond to known stem cell niche ligands, and will characterize the various ligands and cellular elements that compose the stem cell niche for sprocs. The hypothesis for aim 2 is that changes particular to the metabolic syndrome suppress the NO pathway in LSECs and induce capillarization.
This aim will characterize the signaling in NAFLD in isolated LSECs in vitro and in LSECs isolated from NAFLD ex vivo. The hypothesis for aim 3 is that the impaired endocytotic function of BM-derived (?capillarized?) LSECs contributes to aberrant clearance of lipids in NAFLD.
Aim 3 will examine uptake of lipids in LSECs taken from rats with NAFLD and will use intravital multiphoton fluorescence confocal microscopy to examine lipid uptake in vivo in rats with NAFLD. Interventions will be used to induce maturation of BM-derived LSECs and studies will examine the effect of this on in vitro and in vivo uptake of lipid. Finally the effect of inducing maturation of BM- derived LSECs on serum lipid level will be compared with the effect of a statin. Collectively, these aims will provide a major advance in our understanding of the role of resident sprocs in liver physiology, which will be critical for future approaches to elicit a greater contribution from resident sprocs to the repair of liver injury and to drive liver regeneration. These studies also have the potential to uncover the mechanisms leading to capillarization in NAFLD as a prelude to providing therapeutic strategies to prevent two consequences of capillarization: the contribution of capillarization to hyperlipidemia and the loss of the ability to suppress hepatic stellate cell activation. Finally, these studies should uncover an important mechanism that contributes to elevated lipid levels in NAFLD with its attendant increased risk of cardiovascular mortality and that may lead to novel approaches to treat this aspect of hyperlipidemia.

Public Health Relevance

This application has three goals: first, to determine whether liver sinusoidal endothelial cells (LSECs) in healthy liver originate from stem cells or are self-renewing, and to characterize the intrahepatic niche for intrahepatic LSEC stem cells. Second, to characterize the signaling pathways that alter the LSEC phenotype in fatty liver. Third, to examine whether changes in how specific serum lipids are cleared from the blood stream by LSECs in fatty liver disease might contribute to a potentially treatable risk factor for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK100580-06
Application #
10075906
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Burgess-Beusse, Bonnie L
Project Start
2014-08-01
Project End
2023-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
6
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Maretti-Mira, Ana C; Wang, Xiangdong; Wang, Lei et al. (2018) Incomplete differentiation of engrafted bone marrow endothelial progenitor cells initiates hepatic fibrosis in the rat. Hepatology :
DeLeve, Laurie D; Maretti-Mira, Ana C (2017) Liver Sinusoidal Endothelial Cell: An Update. Semin Liver Dis 37:377-387
DeLeve, Laurie D (2015) Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61:1740-6