The liver is a peculiar organ when it comes to stem cells

Abstract

Tissue biology has emerged as an interesting field of study. Differentiation of cells in different tissues follows similar rules, although it involves different tissue-specific genes, proteins, and extracellular matrix components. In tissues such as skin, hematopoietic cells, intestinal mucosa, and the glands of prostate and bronchus, cell renewal is dependent on the presence and continual proliferation of tissue-specific stem cells, which reside in specific histological locations, clearly visible under microscopic examination. Bone marrow hematopoietic stem cells, although not easily identifiable in tissue sections, can be easily separated and studied using cell-sorting methods. The sole role of tissue-specific stem cells is the maintenance of the needed numbers of the fully differentiated epithelial cells, which are the hallmark of the organ’s identity and function. Cells derived from such tissue-specific stem cells, or progenitor cells, are not yet fully differentiated but continue to proliferate toward the terminal differentiated phenotype. Studies in liver growth biology have been tackling such issues, and much new knowledge has emerged. The article by Sekiya and Suzuki1Sekiya S. Suzuki A. Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver.Am J Pathol. 2014; 184: 1468-1478Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar in this issue of The American Journal of Pathology highlights the complexity of hepatic biology in the context of liver growth. Despite several discussions concerning the existence and nature of liver-specific stem cells2Sell S. Is there a liver stem cell?.Cancer Res. 1990; 50: 3811-3815PubMed Google Scholar and identification of isolated candidate cells with aberrant biomarkers by electron microscopy or immunohistochemistry,3Novikoff P.M. Yam A. Stem cells and rat liver carcinogenesis: contributions of confocal and electron microscopy.J Histochem Cytochem. 1998; 46: 613-626Crossref PubMed Scopus (22) Google Scholar there is no concrete evidence of a histologically demonstrable location for stem cells in hepatic lobules. Moreover, studies have shown that all mature and fully differentiated liver cell types participate in liver regeneration after partial hepatectomy, without the intervention of stem cells,4Stöcker E. Wullstein H.K. Bräu G. Capacity of regeneration in liver epithelia of juvenile, repeated partially hepatectomized rats: autoradiographic studies after continous infusion of 3H-thymidine (author’s transl) [German].Virchows Arch B Cell Pathol. 1973; 14: 93-103PubMed Google Scholar, 5Michalopoulos G.K. Principles of liver regeneration and growth homeostasis.Compr Physiol. 2013; 3: 485-513Crossref PubMed Scopus (176) Google Scholar raising questions about their existence. In view of the failure of classic histological approaches to identify a specific and easily demonstrable lobular location for hepatic stem cells, other molecular approaches have been used. For example, tissue-specific stem cells typically proliferate by generating another tissue-specific stem cell and a progenitor cell, which continue to proliferate and derive the finally differentiated epithelial cells of the organ. Thus, administration of the DNA-labeling agent, bromodeoxyuridine (BrdU), results in long-term labeling of the tissue-specific stem cells, whereas the label is diluted from the multiple sequential proliferation cycles of the progenitor cells. By using this approach, Theise and colleagues6Kuwahara R. Kofman A.V. Landis C.S. Swenson E.S. Barendswaard E. Theise N.D. The hepatic stem cell niche: identification by label-retaining cell assay.Hepatology. 2008; 47: 1994-2002Crossref PubMed Scopus (223) Google Scholar demonstrated BrdU-retaining cells in biliary ductules and the immediate proximate periportal hepatocytes. Although these cells retain BrdU for a long period, they cannot be viewed as tissue-specific stem cells because they perform routine differentiated functions for the organ (eg, proteins specific to hepatocyte differentiation and lining of mature bile ductules). Hepatocytes play an essential role in liver regeneration after partial hepatectomy. Hepatocytes undergo the necessary number of proliferation cycles, as well as produce paracrine signals, which stimulate proliferation of other liver cells, which, in turn, use growth factors and cytokines to further enhance hepatocyte proliferation.5Michalopoulos G.K. Principles of liver regeneration and growth homeostasis.Compr Physiol. 2013; 3: 485-513Crossref PubMed Scopus (176) Google Scholar, 7Michalopoulos G.K. Liver regeneration.J Cell Physiol. 2007; 213: 286-300Crossref PubMed Scopus (1177) Google Scholar Inhibition of hepatocyte proliferation after partial hepatectomy results in the appearance of a new population of cells, called oval cells because of the shape of their nucleus.8Tatematsu M. Ho R.H. Kaku T. Ekem J.K. Farber E. Studies on the prolifer