Incomplete Differentiation of Engrafted Bone Marrow Endothelial Progenitor Cells Initiates Hepatic Fibrosis in the Rat

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Ana C Maretti-MiraLaurie D DeLeve

Abstract

Normal liver sinusoidal endothelial cells (LSECs) promote quiescence of hepatic stellate cells (HSCs). Prior to fibrosis, LSECs undergo capillarization, which is permissive for HSC activation, the proximate event in hepatic fibrosis. The aims of this study were to elucidate the nature of and mechanisms leading to capillarization and to determine how LSECs promote HSC quiescence and why "capillarized LSECs" lose control of HSC activation. The contribution of bone marrow (BM) endothelial progenitor cells to capillarization was identified using rats transplanted with transgenic enhanced green fluorescent protein-positive BM. Shotgun proteomics and informatics were used to identify the LSEC mediator that maintains HSC quiescence. The study shows that capillarization is due to repair of injured LSECs by BM endothelial progenitors that engraft but fail to fully mature. Lack of maturation of BM-derived LSECs is due to cell autonomous pathways that inhibit the nitric oxide pathway. We identify heparin binding epidermal growth factor-like growth factor (HB-EGF) as the signal that maintains HSC quiescence and show that immature LSECs are unable to shed HB-EGF from the cytosolic membrane. Conclusion: Chronic liver injury can recruit BM pr...Continue Reading

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Citations

Apr 16, 2020·Cells·Erica LafozVirginia Hernández-Gea
Aug 9, 2020·Nature Reviews. Gastroenterology & Hepatology·George K Michalopoulos, Bharat Bhushan
Feb 16, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xiangdong WangLaurie D DeLeve
Nov 1, 2020·Nature Reviews. Gastroenterology & Hepatology·Tatiana Kisseleva, David Brenner
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Mar 18, 2021·Molecular Biology Reports·Heming MaJunqi Niu
Mar 22, 2021·Angiogenesis·Philipp-Sebastian KochHellmut G Augustin
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Aug 28, 2021·Biomedicines·Yufei YanChangyong Li
Aug 31, 2021·Liver International : Official Journal of the International Association for the Study of the Liver·Stefan ThomannKai Breuhahn

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