Mrp1 is not required for hepatocyte- and hepatic progenitor cell-dependent liver
regeneration in mice.
Axel van Steenpaal, Mariska Geuken, Han Moshage and Klaas Nico Faber.
Department of Gastroenterology and Hepatology, University Medical Center Groningen,
University of Groningen, Groningen, The Netherlands.
Abstract
Hepatic progenitor cells (HPCs) and bone marrow stem cells contribute to liver regeneration
when hepatocyte proliferation is compromised, e.g. during severe liver injury. The multidrug
resistance-associated protein 1 (MRP1) is expressed in HPCs as well as in bone marrow
mononuclear cells. Recently, we found that MRP1 provides cellular protection against
cytokine-induced apoptosis. Induced expression of MRP1 was observed in the regenerative
compartment of the intestinal epithelium of patients with inflammatory bowel disease and the
liver of patients with hepatitis. Thus, MRP1 may protect stem cells to allow tissue
regeneration in pathophysiological conditions. The aim of this study was to determine whether
Mrp1 is required for stem cell-dependent liver regeneration in mice.
Mrp1-/- mice and wild type control mice were subjected to 70% partial hepatectomy (pHx) in
the presence or absence of 2-acetylaminofluorene (2-AAF) to block hepatocyte proliferation.
Liver regeneration was monitored by liver weight recovery. Hepatic expression of genes
encoding Mrp’s and stem cell markers (alpha-fetoprotein; AFP) was determined by
quantitative PCR. Cell proliferation was analyzed by immunohistochemical microscopy after
Ki-67 staining.
Three days after 70% pHx, liver weight in wild type and Mrp1-/- mice was 85% of the preoperative liver mass, independent of the 2-AAF treatment. 2-AAF treatment lead to strongly
increased AFP expression in PHx-treated wild type mice, which was not observed in Mrp1-/mice. 2-AAF treatment increased the number of Ki-67 positive cells to a similar level in the
livers of pHx-treated wild type and Mrp1-/- mice. Mrp3 expression was significantly increased
in untreated Mrp1-/- mice compared to wild type controls., but was comparable in the 2AAF/pHx-treated groups.
Stem cell activation is compromised in Mrp1-/- mice, but does not affect liver regeneration in
2-AAF-treated animals.