There are two populations of liver sinusoidal endothelial cell (LSEC) progenitor cells. The LSEC progenitor cells in the bone marrow play an important role in repair of liver injury and promoting liver regeneration, but play no role in norml turnover. The LSEC progenitor cells in the liver (resident LSEC progenitor cells) contribute much less to repair of liver injury and promoting liver regeneration, but are the progenitors for normal LSEC turnover. The overarching objective of this proposal is to elucidate mechanisms underlying dysfunction of LSEC progenitor cells and of progenitor cell repair with the goal of identifying therapeutic targets.
Specific aim 1 is based on the hypothesis that regulation of recruitment of bone marrow LSEC progenitor cells (i.e. proliferation of LSEC progenitors in the bone marrow, mobilization of progenitors from bone marrow to the circulation, and engraftment in the liver) is impaired in chronic liver disease and that this impairment of a repair process increases the damage of acute liver injury and impairs liver regeneration in chronic liver disease. Studies will examine the effect of acute injury in chronic liver disease on bone marrow LSEC progenitor cell recruitment to the liver, establish predictors for the risk of inadequate progenitor cell recruitment, and determine whether acute injury is attenuated with progenitor cell therapy. The hypothesis for specific aim 2 is that acute liver injury alters the signaling pathways for bone marrow LSEC progenitor cell engraftment in the liver. Studies will examine the effect of altered signaling on bone marrow LSEC progenitor cell engraftment and on liver regeneration, elucidate the mechanisms that lead to the impairment of signaling, and will determine whether strategies to restore normal signaling ameliorate acute injury. The hypothesis for the third aim is that phenotypic changes in LSEC with aging are due to changes in resident progenitor cells. Studies will determine whether the changes in the LSEC are indeed due to changes in the progenitor cell and will examine the signaling pathways that lead to the changes in the resident progenitor cells.

Public Health Relevance

Stem cells maintain normal tissue function and repair tissue injury. This proposal examines whether a change in the aging liver is due to changes in liver stem cells and what interventions might reverse this. Studies will also examine processes in liver injury and liver disease that impede stem cell repair of tissue injury and will identify approaches to improve stem cell repair.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
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University of Southern California
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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McDonald, George B; Freston, James W; Boyer, James L et al. (2018) Liver complications following treatment of hematologic malignancy with anti-cd22-calicheamicin (Inotuzumab Ozogamicin). Hepatology :
Wang, Xiangdong; Maretti-Mira, Ana C; Wang, Lei et al. (2018) Liver-selective mmp-9 inhibition in the rat eliminates ischemia-reperfusion injury and accelerates liver regeneration. Hepatology :
DeLeve, Laurie D; Maretti-Mira, Ana C (2017) Liver Sinusoidal Endothelial Cell: An Update. Semin Liver Dis 37:377-387
DeLeve, Laurie D; Wang, Xiangdong; Wang, Lei (2016) VEGF-sdf1 recruitment of CXCR7+ bone marrow progenitors of liver sinusoidal endothelial cells promotes rat liver regeneration. Am J Physiol Gastrointest Liver Physiol 310:G739-46
DeLeve, Laurie D (2013) Liver sinusoidal endothelial cells and liver regeneration. J Clin Invest 123:1861-6
Wang, Lin; Wang, Xiangdong; Xie, Guanhua et al. (2012) Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest 122:1567-73
Wang, Lin; Wang, Xiangdong; Wang, Lei et al. (2012) Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells. Gastroenterology 143:1555-1563.e2
Warren, Alessandra; Cogger, Victoria C; Fraser, Robin et al. (2011) The effects of old age on hepatic stellate cells. Curr Gerontol Geriatr Res 2011:439835
Xie, Guanhua; Wang, Lin; Wang, Xiangdong et al. (2010) Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 299:G1204-10
Harb, Rula; Xie, Guanhua; Lutzko, Carolyn et al. (2009) Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology 137:704-12