The development of hepatic stellate cells in normal and abnormal human fetuses – an immunohistochemical study

• Published in: Physiological reports Vol. 3; no. 8; pp. e12504 - n/a
• Main Authors: Loo, Christine K. C., Pereira, Tamara N., Pozniak, Katarzyna N., Ramsing, Mette, Vogel, Ida, Ramm, Grant A.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2015; John Wiley & Sons, Ltd
• Subjects: Actin; Antigens; Cell adhesion & migration; Cell migration; Circulating stem cells; cRBP‐1; Defects; Diaphragm; Dogs; Esophagus; Fetuses; Gestation; GFAP; Glial fibrillary acidic protein; Hepatocytes; Hernia; Histology; Immunohistochemistry; Laboratories; Liver; Mesenchyme; Mesothelium; Nodules; Original Research; Pathology; Physiology; Plasma; Proteins; Septum; Smooth muscle; Stellate cells; Stem cell transplantation; Stem cells; Studies; Vitamin A; WT1 protein; Circulating stem cells; cRBP‐1; diaphragm; Mesothelium; GFAP
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.12504

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. The embryological development of hepatic mesenchymal cells, especially hepatic stellate cells, is much debated. These cells influence many functions of the liver and their significance is widely recognised. While animal studies support the view that hepatic stellate cells derive from septum transversum, there is also evidence that stellate cells develop from mesenchymal stem cells. We have studied the development of hepatic mesenchymal cells in normal and abnormal human fetuses. Our data suggest that hepatic stellate cells develop from mesothelial cells and mesenchymal stem cells.