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The Tissue Biology of Ductular Reactions in Human Chronic Liver Disease

2007; Elsevier BV; Volume: 133; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2007.05.040

1528-0012

Neil D. Theise, Reichiro Kuwahara,

Pancreatic function and diabetes

See "Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction" by Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, and Clouston AD, on page 80. See "Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction" by Richardson MM, Jonsson JR, Powell EE, Brunt EM, Neuschwander-Tetri BA, Bhathal PS, Dixon JB, Weltman MD, Tilg H, Moschen AR, Purdie DM, Demetris AJ, and Clouston AD, on page 80. Whether there were liver stem cells in animal or human livers was a topic of great debate for decades until their existence was confirmed and their most prominent source identified as the canal of Hering, the meeting point of the hepatocyte canalicular system and the smallest, most proximal branches of the biliary tree.1Theise N.D. Saxena R. Portmann B.P. Thung S.N. Yee H. Chiriboga L Kumar A. Crawford J.M. The canals of Hering and hepatic stem cells in humans.Hepatology. 1999; 30: 1425-1433Google Scholar The debate often centered on whether the rodent variant of hepatic stem/progenitor cells (HSPC), so-called oval cells, were in fact a stem/progenitor population or merely proliferating cholangiocytes. Once data appeared demonstrating that oval cells function as HSPC and arise directly from the biliary tree, it became clear that the functioning of these cells in rodents and humans was somewhat different from other organ systems in which stem cells appeared to have only a repopulating or regenerative function. In the liver they were, indeed, both biliary epithelial cells, part of the conduction system for bile out of the liver, and HSPC, an interestingly complex physiology. In more recent years, it has been recognized that these HSPC are embedded in a network of cellular interactions at the tissue level with at least one specific anatomic location, the so-called stem cell niche.2Theise N.D. Liver stem cells: the fall and rise of tissue biology.Hepatology. 2003; 38: 804-806Google Scholar, 3Theise N.D. Gastrointestinal stem cells III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G189-G193Google Scholar This systems concept of cellular interactions is reflected in the terminology shift proposed by a consensus panel convened under the auspices of the Hans Popper Hepatopathology society, referring to the "ductular reactions" as reactive lesions comprising "intermediate hepatobiliary cells" (functioning at least as HSPC, if not playing other roles) as well as other cell types including, although not limited to, inflammatory, stromal, and endothelial cells.4Roskams T.A. Theise N.D. Balabaud C. Bhagat G. Bhathal P.S. Bioulac-Sage P. Brunt E.M. Crawford J.M. Crosby H.A. Desmet V. Finegold M.J. Geller S.A. Gouw A.S.H. Hytiroglou P. Knisely A.S. Kojiro M. Lefkowitch J.H. Nakanuma Y. Olynyk J.K. Park Y.N. Portmann B. Saxena R. Scheuer P.J. Strain A.J. Thung S.N. Wanless I.R. West A.B. Nomenclature of the finer branches of the biliary tree: canals, ductules and ductular reactions in human livers.Hepatology. 2004; 39: 1739-1745Google Scholar From a variety of sources (summarized in Theise3Theise N.D. Gastrointestinal stem cells III. Emergent themes of liver stem cell biology: niche, quiescence, self-renewal, and plasticity.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G189-G193Google Scholar) we can draw a preliminary diagram of these cell:cell and cell:matrix relationships that comprise the niche (Figure 1). Some of these relationships immediately suggest hypotheses worth investigating. For example, we have previously questioned whether, when acute injury is severe enough to extend all the way from acinus zone 3 into zone 1 (where the Canals of Hering are located), destruction of an hepatocyte linked to an HSPC of the Canals of Hering could disinhibit this HSPC, unlocking its proliferative potential (or, stated conversely, does the hepatocyte keep its proliferation in check)? Is bile not only acted upon by the cholangiocytes lining the canals of Hering, but might it act on them in turn? Perhaps diminished bile flow in massive hepatic necrosis (in which links to the hepatocyte canalicular system are disrupted) promotes hepatocellular differentiation of these cells, whereas increased bile concentration in acute or chronic biliary tract disease leading to interruption of bile excretion might promote cholangiocytic differentiation of these cells. That cholangiocytes in general and HSPC in particular are under some degree of autonomic nervous system control was first demonstrated by the Alpini laboratory5LeSage G. Alvaro D. Benedetti A. Glaser S. Marucci L. Baiocchi L. Eisel W. Caligiuri A. Phinizy J.L. Rodgers R. Francis H. Aplini G. Cholinergic system modulates growth, apoptosis, and secretion of cholangiocytes from bile duct-ligated rats.Gastroenterology. 1999; 117: 191-199Google Scholar; our laboratory has shown at least two possible anatomic relationships between nerves and cholangiocytes, one in which nerves stop at the basement membrane, as they do in the gastrointestinal tract, releasing their neurotransmitters into the subcellular matrix where they can diffuse across to reach the epithelial cells, and a second where they cross the basement membrane and make direct nerve:cholangiocyte contacts.6Zanchi A. Feldman H. Reidy J. Qualter J. Theise N.D. Innervation of an intra-organ hepatic progenitor cell "niche" in normal human liver.Hepatology. 2005; 42: 279AGoogle Scholar In this issue of Gastroenterology, Richardson et al examine the hepatobiliary component of ductular reactions in nonalcoholic fatty liver disease and reach two important conclusions.7Richardson M.M. Jonsson J.R. Powell E.E. Brunt E.M. Neuschwander-Tetri B.A. Bhathal P.S. Dixon J.B. Weltman M.D. Tilg H. Moschen A.R. Purdie D.M. Demetris A.J. Clouston A.D. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction.Gastroenterology. 2007; 133: 80-90Google Scholar The first confirms studies of other chronic liver diseases, by this same group as well as by others, that with hepatocyte replicative senescence in the face of chronic injury, the HSPC compartment is somehow triggered to proliferate.8Falkowski O. An H.J. Ianus I.A. Chiriboga L. Yee H. West A.B. Theise N.D. Regeneration of hepatocyte "buds" in cirrhosis from intrabiliary stem cells.J Hepatology. 2003; 39: 357-364Google Scholar, 9Roskams T. Yang S.Q. Koteish A. Durnez A. DeVos R. Huang X. Achten R. Verslype C. Diehl A.M. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease.Am J Pathol. 2003; 163: 1301-1311Google Scholar, 10Clouston A.D. Powell E.E. Walsh M.J. Richardson M.M. Demetris A.J. Jonsson J.R. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis.Hepatology. 2005; 41: 809-818Google Scholar Given the previous reports, this is not particularly novel, although it is nonetheless important to document it for nonalcoholic fatty liver disease. The second conclusion is of particular interest and adds yet another layer of complexity to our understanding of how diverse cell types in and around the quiescent and the activated stem cell niche of the proximal biliary tree coordinate activities, contributing to the progression of disease in humans. The authors propose the following sequence of events: In NAFLD, when there are features of steatohepatitis (hepatocyte ballooning specifically), there is p21 activation and hepatocyte senescence, resulting in HSPC activation and the development of a ductular reaction, which then incites scar production. Thus, we get a glimpse of the next level of HSPC research and understanding; not only can we describe many anatomic juxtapositions of the cells that comprise the HSPC niche, but we can also begin to speculate about the physiologic interactions between those various elements. The authors state that "findings from the current study suggest that a periportal ductular reaction could be an important intermediary in the development of portal fibrosis, periportal spurs, and linking fibrous septa." Although they acknowledge that the mechanisms of how this step occurs are not known, they raise several intriguing possibilities that represent at least a partial outline of future research for those interested in studying HSPC activation and ductular reactions in human livers. Among those possibilities, discussed both in this paper and elsewhere, are the following:1In experimental and clinical biliary tract injury, the ductular reaction has been shown to participate in signaling that can directly activate hepatic stellate cells and/or periportal fibroblasts through direct signaling pathways. Such cholangiocyte-derived modulators include PDGF, TGF-β1, VEGF, IGF-1, and NGF (reviewed in Alvaro et al11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF Scopus (228) Google Scholar).2Hepatobiliary cells of the ductular reaction can also elaborate factors that up-regulate immunocyte influx and activation which in turn can produce pro-fibrotic effects. Such cholangiocyte-derived immunomodulators and downstream regulators of fibrogenesis include IL-1, IL-6, IL-8, IFN-γ, TGF-β, MCP-1, and endothelin-1 (reviewed in Alvaro et al11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF Scopus (228) Google Scholar).3Hepatic stellate cells are innervated12Bioulac-Sage P. Lafon M.E. Saric J. Balabaud C. Nerves and perisinusoidal cells in human liver.J Hepatol. 1990; 10: 105-112Google Scholar and may be responsive to the same modulation by nerve signaling that stimulate the ductular reaction itself. Cholangiocytes themselves also secrete neuropeptides that might activate stellate cells.11Alvaro D. Mancino M.G. Glaser S. Gaudio E. Marzioni M. Francis H. Alpini G. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver.Gastroenterology. 2007; 132: 415-431Abstract Full Text Full Text PDF Scopus (228) Google Scholar4Perhaps the strangest possibility is that of the epithelial–mesenchymal transition (EMT). Immunohistochemical staining in cholangiocytes for markers of EMT such as S100A4 and vimentin indicate that cholangiocytes may very well undergo such direct differentiative events13Robertson H. Kirby J.A. Yip W.W. Jones D.E.J. Burt A.D. Biliary epithelial-mesenchymal cell transition in posttransplantation recurrence of primary biliary cirrhosis.Hepatology. 2007; 45: 977-981Google Scholar and there is little reason to think that the cholangiocytes cannot themselves become collagen producing myofibroblasts.14Theise N.D. Implications of "post-modern biology" for pathology: the cell doctrine.Lab Invest. 2006; 86: 335-344Google Scholar Much of the relevant research in humans regarding these topics has been published by academic, diagnostic pathologists. This is surprising only if one assumes that the pinnacle of contemporary biological investigations is to be found in cell and molecular biology. The reductionist approach, reducing histology to isolated cellular components and then examining these cells in light of the biomolecules that comprise them, has been and continues to be phenomenally productive. But new and recent efforts by the likes of Clouston et al,10Clouston A.D. Powell E.E. Walsh M.J. Richardson M.M. Demetris A.J. Jonsson J.R. Fibrosis correlates with a ductular reaction in hepatitis C: roles of impaired replication, progenitor cells and steatosis.Hepatology. 2005; 41: 809-818Google Scholar and others listed in the references below, represent a reintegration of these reductionist bits and pieces into a tissue level perspective which is much closer to the actual moment to moment physiologic events in health and disease. Indeed, decades long controversy regarding the existence of HSPC was settled largely by pathologists examining whole tissues, sometimes in 3 dimensions, not by cell and molecular biologists. We have previously described this as a resurgence of a neglected field of tissue biology.2Theise N.D. Liver stem cells: the fall and rise of tissue biology.Hepatology. 2003; 38: 804-806Google Scholar This field implicitly represents a systems approach to scientific hypothesis formation and is carried out by the only individuals academically and professionally trained to recognize interactions at the tissue level of observation, namely, diagnostic pathologists. The functioning of stem cells can be investigated to some extent with isolated cells, ex vivo, but their full participation in tissue maintenance, repair, and perhaps in disease, as described in this current paper, can only be fully appreciated by examining the intact tissues, reassembling the knowledge gained by examination of tissue components at lower levels of scale. Such a systems approach also opens up the possibilities for mathematical/computational modeling of tissue behaviors—a promising approach to understanding how our bodies function and how interventions at the tissue level should be planned and assessed.15D'Inverno M. Theise N.D. Prophet J. Mathematical modeling of stem cells: a complexity primer for the stem cell biologist.in: Potten C. Wilson J. Clarke R. Renahan A. Tissue stem cells: Biology and applications. 2nd ed. Marcel Dekker, New York2006Google Scholar Hepatopathology, a subspecialty of the scientific field of tissue biology, is primed to make contributions of great value to our understanding of hepatic pathophysiology and to the development of possible therapeutic interventions. Reductionism will certainly continue in a profitable way, but the bias that reductionism is the only scientific approach to understanding biological systems is most certainly coming to an end. It behooves scientists and clinicians of various stripes to pay close attention to what histopathologists are doing as they weave molecular and cell biologic discoveries into the complex tapestry of tissue-level interactions. As demonstrated in this current paper from Richardson et al,7Richardson M.M. Jonsson J.R. Powell E.E. Brunt E.M. Neuschwander-Tetri B.A. Bhathal P.S. Dixon J.B. Weltman M.D. Tilg H. Moschen A.R. Purdie D.M. Demetris A.J. Clouston A.D. Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction.Gastroenterology. 2007; 133: 80-90Google Scholar this process will most certainly contribute key insights that will benefit all who are interested in hepatology. Progressive Fibrosis in Nonalcoholic Steatohepatitis: Association With Altered Regeneration and a Ductular ReactionGastroenterologyVol. 133Issue 1PreviewBackground & Aims: Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus. Full-Text PDF