Oral Presentation 6th Annual Meeting for Australasian Society for Stem Cell Research 2013

Growth hormone (GH) induction of the immunotolerance protein H2-Bl/HLA-G is essential for survival and liver regeneration after partial hepatectomy. (#31)

Andrew J Brooks 1 , Mayumi Ishikawa 2 , Manuel A Fernández-Rojo 3 , Yash Chhabra 1 , Shiro Minami 2 , Robert G Parton 1 , Mike J Waters 1
  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
  2. Center for Endocrinology, Diabetes and Arteriosclerosis, Nippon Medical School, Kawasaki, Japan
  3. Department of Biochemistry and Molecular Biology School of Biomedical Sciences, Monash University, Melbourne, VIC, Australia
Normal liver regeneration after partial hepatectomy is a growth hormone (GH) dependent process in animal models. In transgenic mice expressing excess GH antagonist, not only is hepatocyte proliferation markedly decreased and delayed, but there is a pronounced early mortality of over 40%. We sought to explain the molecular basis for this using a panel of C57BL/6 mice harbouring different GH receptor mutants which delete key signalling domains. We found virtually complete mortality in the absence of GH receptor (ghr-/-), while mice disabled for all JAK2 signalling (box1-/-), and mice disabled for JAK2 dependent STAT5 signalling (ghr391-/-) showed no mortality. Ghr-/- mortality was associated with increased apoptosis and expression of NK and NKT and macrophage cell markers, together with decreased phospho-jun level. Through microarray transcript profiling, we had identified a set of GH-regulated genes triggered by a novel Src/ERK pathway independent of JAK2, and within this restricted set we found H2-Bl (in humans, HLA-G), a key immunotolerance molecule protecting the foetal allograft from NK/NKT and macrophage cell attack. Since these cells are instrumental in failure of liver regeneration, we replaced the absent H2-Bl by administration of a H2-Bl adenoviral expression vector, and found that this (but not GFP-adenovirus) recovered liver regeneration, decreased apoptosis and largely prevented mouse mortality in ghr-/- mice. This study demonstrates that the key immunotolerance protein H2-Bl/HLA-G is essential for survival after partial hepatectomy in C57BL/6 mice, and its induction by GH explains the requirement for GH in survival after liver resection.