Abstract
The precise embryological origin and development of hepatic stellate cells is not established. Animal studies and observations on human fetuses suggest that they derive from posterior mesodermal cells that migrate via the septum transversum and developing diaphragm to form submesothelial cells beneath the liver capsule, which give rise to mesenchymal cells including hepatic stellate cells. However, it is unclear if these are similar to hepatic stellate cells in adults or if this is the only source of stellate cells. We have studied hepatic stellate cells by immunohistochemistry, in developing human liver from autopsies of fetuses with and without malformations and growth restriction, using cellular Retinol Binding Protein-1 (cRBP-1), Glial Fibrillary Acidic Protein (GFAP), and α-Smooth Muscle Actin (αSMA) antibodies, to identify factors that influence their development. We found that hepatic stellate cells expressing cRBP-1 are present from the end of the first trimester of gestation and reduce in density throughout gestation. They appear abnormally formed and variably reduced in number in fetuses with abnormal mesothelial Wilms Tumor 1 (WT1) function, diaphragmatic hernia and in ectopic liver nodules without mesothelium. Stellate cells showed similarities to intravascular cells and their presence in a fetus with diaphragm agenesis suggests they may be derived from circulating stem cells. Our observations suggest circulating stem cells as well as mesothelium can give rise to hepatic stellate cells, and that they require normal mesothelial function for their development.
Highlights
Liver stromal cells influence many biological and pathological processes (Wang et al 2010; Kiyohashi et al 2013)
We describe the development of hepatic stellate cells in these fetuses in more detail and in a much larger cohort of fetuses, including control fetuses and fetuses with other anomalies, using immunohistochemistry for hepatic stellate cell markers, cellular retinol-binding protein-1, glial fibrillary acidic protein (GFAP) and alpha-smooth muscle actin
Hepatic stellate cells from fetal rat liver at E13–14 do not express GFAP in vivo (Kubota et al 2007) unlike adult rodent stellate cells (Zhao and Burt 2007; Yang et al 2008) but GFAP expression can be induced in cultures from E11 mouse stellate cells (Suzuki et al 2008). cellular retinol-binding protein-1 (cRBP-1), claimed to be a relatively specific marker for quiescent human hepatic stellate a 2015 The Authors
Summary
Liver stromal cells influence many biological and pathological processes (Wang et al 2010; Kiyohashi et al 2013). Animal experiments have shown that mesodermal cells delaminate from the mesothelium to form hepatic stellate cells and perivascular mesenchymal cells (Asahina et al 2009, 2011). This process was illustrated in wt1À/À mice (Ijpenberg et al 2007) and in human fetuses (Loo and Wu 2008). We found intravascular cells morphologically similar to hepatic stellate cells in normal and abnormal fetuses, including a fetus with diaphragm agenesis due to failure of development of the pleuroperitoneal folds (as reported Loo et al 2015). We discuss the hypothesis that hepatic stellate cells may be derived from circulating MSC
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