Abstract
PurposeRetrorsine selectively inhibits hepatocyte proliferation and following liver injury evokes small hepatocyte-like progenitor cells. The aim of this study is to find out whether endogenous extrahepatic cells contribute to small hepatocyte-like progenitor cells after retrorsine treatment.MethodsWild-type Lewis rat liver exposed to retrorsine was transplanted into GFP transgenic Lewis rat. GFP positive, albumin-producing polygonal cells were expected as reciepient-derived hepatocyte-like cells.ResultsFour weeks after transplantation of 50% volume of retrorsine-pretreated liver, the rate of GFP positive hepatocyte-like cells was 0.02365%. Majority of these cells resided as single cells and their cell size was significantly larger than that of normal hepatocytes (mean cell size; 799.4 um2 vs. 451.3 um2, p<0.0001). At eight weeks, clusters of GFP positive small-size albumin-producing cells appeared and occupied 0.00759% of hepatocytes. The morphology of these cells was similar to that of small hepatocyte-like progenitor cells, 12.5% of them were Ki67 positive, majority of them were negative for CYP1A2 staining, and some clusters contained larger cells indicating further maturation.ConclusionEndogenous extrahepatic cells can form a cluster of small cells resembling small hepatocyte-like progenitor cells in a transplanted retrorsine-pretreated liver. The contribution of extrahepatic cells to liver mass maintenance is quite low and its importance is unclear.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-446) contains supplementary material, which is available to authorized users.
Highlights
Under normal condition, liver regeneration is completed through mitosis of mature hepatocytes
When proliferation of hepatocytes is selectively inhibited by retrorsine treatment, albumin-producing small cells termed small hepatocyte-like progenitor cells (SHPCs) arise in response to liver injuries (Gordon et al 2000a, b, Vig et al 2006, Serra et al 2012)
Green fluorescence protein (GFP) positive hepatocyte-like cells contribute to approximately 0.00186% of total hepatocytes at eight weeks after whole liver transplantation (Group 1) (Table 1 and Figure 2A-E)
Summary
Liver regeneration is completed through mitosis of mature hepatocytes. When proliferation of hepatocytes is selectively inhibited by retrorsine treatment, albumin-producing small cells termed small hepatocyte-like progenitor cells (SHPCs) arise in response to liver injuries (Gordon et al 2000a, b, Vig et al 2006, Serra et al 2012). SHPCs form a nodule without a capsule as a result of expansive proliferation, and restore the liver. In order to study the contribution of bone marrow (BM) stem cells to hepatocytes, BM transplantation models have been often used. We used liver transplantation (LT) model (Tomiyama et al 2007) instead of bone marrow transplantation model to study the contribution of extrahepatic cells to hepatocyte in a retrorsine pretreated liver. A cluster of small cells closely resembling SHPCs was identified in the retrorsine-pretreated liver
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