ABSTRACT FINAL ID: 1699
TITLE: Functional analysis of a novel regeneration factor, Opioid growth factor receptor-like 1, that regulates both hepatic development and regeneration of injured/fibrotic liver
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Background & Aims: We have previously identified opioid growth factor receptor like-1 (OGFRL1) as a novel G-CSF-induced factor that not only suppresses fibrogenesis but also accelerates regeneration of fibrotic liver. Intrasplenic administration of OGFRL1-expressing cells into CCl4-treated fibrotic mice remarkably increased gene expression of a-fetoprotein and cell cycle-related factors such as cyclins after partial hepatectomy. Since OGFRL1 is also expressed in the fetal liver, it may influence the development of fetal liver and regeneration of injured/fibrotic liver through mobilization of hepatic progenitor cells (HPCs). To elucidate the molecular mechanism responsible for the action of OGFRL1, we examined in the present study, localization of OGFRL1 expression in normal and fibrotic liver tissues as well as its changes during the regeneration process. We also characterized its functions in the growth and differentiation of fetal HPCs.
Methods: Acute liver injury and fibrosis was induced by a single and repeated CCl4 administration, respectively. OGFRL1 expression was detected by immunohistochemistry with its specific antibodies we had prepared. Intracellular localization of OGFRL1 was examined by co-staining with antibodies recognizing a Golgi marker MG130 or autophagy-related proteins (p62 and LC3). Fetal HPCs (Ter119-CD45-Dlk+) were isolated from fetal liver at dpc 13.5. After infection with a recombinant retroviral vector overexpressing OGFRL1, proliferation and phenotypical changes of HPCs were examined by a colony forming assay and microarray analysis, respectively.
Results: OGFRL1 was not detected in normal adult liver before or after partial hepatectomy. After a single CCl4 injection, OGFRL1 expression was detected transiently as characteristic dots in the perinuclear cytoplasm of zone 2 hepatocytes that surround the damaged hepatocytes in zone 3. On the other hand, OGFRL1-expressing hepatocytes appeared along the fibrous septa following repeated CCL4 injections, and expanded towards the center of parenchyma after hepatectomy. OGFRL1 was co-localized with a Golgi marker MG130, but not with autophagy-related proteins. During embryonic development, strong OGFRL1 expression was detected in the fetal liver tissue at dpc 13.5. When OGFRL1 was overexpressed in fetal HPCs dpc 13.5, it accelerated the pathways of inflammation, immune response and wound healing, while it had no effect on the colony-forming ability of HPCs.
Conclusions: OGFRL1 is considered as a common regulator in the fetal liver development and regeneration of injured/fibrotic liver through HPC mobilization. It may be modified in the Golgi body or act as a component of Golgi apparatus.