The balance between Notch/Wnt signaling regulates progenitor cells’ commitment during liver repair: Mystery solved?

COMMENTARY ON: Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ. Nat Med 2012 March 4;18(4):572–579. Copyright (2012). Abstract reprinted by permission from Macmillan Publishers Ltd. http://www.ncbi.nlm.nih.gov/pubmed/22388089 Abstract: During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted. In spite of the impressive regenerative potential of the liver as a result of the mitogenic capabilities of hepatocytes and cholangiocytes, liver repair often involves progenitor cells (HPC). This bipotent cell population, barely identifiable in normal livers, expands following liver injury. Depending on the type of damage including its acute or chronic nature, HPC may differentiate into mature cholangiocytes, hepatocytes or into a population of small cytokeratin 19-positive epithelial cells exhibiting cholangiocyte phenotypic markers that arrange themselves into tubeless structures. These “activated” (or “reactive”) cholangiocytes express an array of inflammatory mediators as well as cytokines and their cognate receptors, and thus are able to orchestrate the functions of several cell types centered around the repair of the epithelial wound. Expansion of activated cholangiocytes is associated with persistent inflammation, mesenchymal cell activation, portal fibrosis and progression of liver disease [1Strazzabosco M. Fabris L. Spirli C. Pathophysiology of cholangiopathies.J Clin Gastroenterol. 2005; 39: S90-S102Crossref PubMed Scopus (135) Google Scholar, 2Fabris L. Strazzabosco M. Epithelial–mesenchymal interactions in biliary diseases.Semin Liver Dis. 2011; 31: 11-32Crossref PubMed Scopus (71) Google Scholar, 3Strazzabosco M. Fabris L. Developments of the bile ducts: essentials for the clinical hepatologist.J Hepatol. 2012; 56: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. While the mechanisms leading to the expansion of the HPC compartment are still unclear, a seminal paper recently published in the April issue of Nature Medicine addresses the mechanisms of HPC specification in chronic liver diseases [[4]Boulter L. Govaere O. Bird T.G. Radulescu S. Ramachandran P. Pellicoro A. et al.Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.Nat Med. 2012; 18: 572-579Crossref PubMed Scopus (595) Google Scholar]. This elegant work demonstrates that HPC specification differs according to which liver epithelial compartment (hepatocellular or biliary) is predominantly damaged and the consequent changes within the progenitor cell niche. It proposes the intriguing hypothesis that the switch is represented by two alternatively acting developmental mechanisms, canonical Wnt/β-catenin signaling or Notch signaling (Fig. 1). Boulter et al. show that hepatocellular specification of HPC is determined by the release of Wnt3a by macrophages after phagocytosis of cellular debris from damaged hepatocytes. Wnt3a then acts on HPC to stimulate the nuclear translocation of β-catenin and its signaling. Wnt/β-catenin/T-cell-specific transcription factor/lymphoid enhancer-binding factor-1 (TCF/LEF-1) signaling is known to participate in several steps of bile duct development. Earlier works by Hu et al. have shown that Wnt3a is able to stimulate the proliferative activity of HPC in vitro, and, different from Boulter et al., activation of canonical Wnt/β-catenin signaling is evident in proliferating HPC in mice in vivo also following the administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), a model of ductular reaction induced by obstructive cholestasis derived from precipitation of protoporphyrins within the intrahepatic bile ducts [[5]Hu M. Kurobe M. Jeong Y.J. Fuerer C. Ghole S. Nusse R. et al.Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells.Gastroenterology. 2007; 133: 1579-1591Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar]. It is important to note that HPC behavior appears to be strongly model- and time-dependent. The choline-deficient, ethionine-supplemented diet (CDE) is a liver carcinogenetic diet that promotes the emergence of a large number of proliferating oval cells, expressing albumin and α-fetoprotein, with little parenchymal necrosis. As originally shown by Guest et al., small ductules are formed by HPC after 10 weeks of CDE treatment [[6]Guest I. Ilic Z. Sell S. Age dependence of oval cell responses and bile duct carcinomas in male fischer 344 rats fed a cyclic choline-deficient, ethionine-supplemented diet.Hepatology. 2010; 52: 1750-1757Crossref PubMed Scopus (16) Google Scholar]. Thus, it remains unclear whether the HPC (or oval cells) that accumulate during a CDE diet are en route to become hepatocytes or “activated” cholangiocytes or both. A major novelty of the recent Nature Medicine paper is the role of Numb. Numb is a target of canonical Wnt signaling and its activation by Wnt3a has several consequences, including Notch receptor inhibition at the level of the intracellular domains [[7]McGill M.A. McGlade C.J. Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain.J Biol Chem. 2003; 278: 23196-23203Crossref PubMed Scopus (379) Google Scholar], and inhibition of Hedgehog signaling [[8]Di Marcotullio L. Ferretti E. Greco A. De Smaele E. Po A. Sico M.A. et al.Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination.Nat Cell Biol. 2006; 8: 1415-1423Crossref PubMed Scopus (240) Google Scholar], another major mechanism of biliary repair [2Fabris L. Strazzabosco M. Epithelial–mesenchymal interactions in biliary diseases.Semin Liver Dis. 2011; 31: 11-32Crossref PubMed Scopus (71) Google Scholar, 3Strazzabosco M. Fabris L. Developments of the bile ducts: essentials for the clinical hepatologist.J Hepatol. 2012; 56: 1159-1170Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. Boulter et al. present circumstantial evidence that specification of HPC is determined by a direct cell–cell interaction between Notch-expressing HPC and Jagged-1-expressing mesenchymal cells and hypothesize that this would be the default specification pathway for HPC in the absence of infiltrating macrophages and Wnt/β-catenin signaling [[4]Boulter L. Govaere O. Bird T.G. Radulescu S. Ramachandran P. Pellicoro A. et al.Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.Nat Med. 2012; 18: 572-579Crossref PubMed Scopus (595) Google Scholar]. Thus, macrophage-derived Wnt inhibits a default-activated Notch signaling via Numb, allowing HPC to escape the biliary cell fate and acquire an hepatocellular specification. By alternatively activating Notch or Wnt/β-catenin signaling, myofibroblasts and macrophages orchestrate the divergent specification of HPC towards the biliary or hepatocellular lineage, respectively [[4]Boulter L. Govaere O. Bird T.G. Radulescu S. Ramachandran P. Pellicoro A. et al.Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.Nat Med. 2012; 18: 572-579Crossref PubMed Scopus (595) Google Scholar]. This seminal work certainly raises a number of open questions, worth being addressed in further studies. For example, the proposed role of macrophages in HPC specification towards the hepatocellular phenotype deserves further investigation. Paracrine factors secreted by macrophages have been previously shown to affect the HPC compartment. For example, the tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor (TNF)-α family and produced by natural killer cells and macrophages, induces a selective expansion of HPC in both DDC and CDE toxicity models [9Jakubowski A. Ambrose C. Parr M. Lincecum J.M. Wang M.Z. Zheng T.S. et al.TWEAK induces liver progenitor cell proliferation.J Clin Invest. 2005; 115: 2330-2340Crossref PubMed Scopus (335) Google Scholar, 10Tirnitz-Parker J.E. Viebahn C.S. Jakubowski A. Klopcic B.R. Olynyk J.K. Yeoh G.C. et al.Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells.Hepatology. 2010; 52: 291-302Crossref PubMed Scopus (140) Google Scholar]. In liver repair, the functions of macrophages strongly depend on their phenotype. Alternatively-activated rather than classically-activated macrophages are key drivers of abnormal liver reparative processes leading to excessive deposition of matrix [[11]Poelstra K. Schuppan D. Targeted therapy of liver fibrosis/cirrhosis and its complications.J Hepatol. 2011; 55: 726-738Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Therefore, phenotypic characterization of macrophages engaged in the crosstalk with the HPC compartment as well as the time frame of these interactions will provide additional insights into their role in HPC commitment. Earlier work in Alagille syndrome (a ductopenic cholangiopathy caused by a genetic defect in Notch signaling) has shown that when Notch signaling is defective, hepatocyte nuclear factor (HNF)-1β, a transcription factor critical for biliary specification, is downregulated and HPC are forced towards the intermediate hepatocyte fate instead of the biliary fate [[12]Fabris L. Cadamuro M. Guido M. Spirli C. Fiorotto R. Colledan M. et al.Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling.Am J Pathol. 2007; 171: 641-653Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar]. Boulter et al. further suggest that Notch is a default inducer of biliary specification that can be activated by interaction with myofibroblasts. These conclusions rely on gene expression studies and on the use of Notch inhibitors that have several off-target effects. Thus, genetic models of Notch loss/gain of function will be needed to prove the relative role of Notch-1/Notch-2 in biliary specification during liver repair. As shown during development, the role of Notch may go well beyond HPC specification and involve branching tubular morphogenesis [[13]Lemaigre F.P. Notch signaling in bile duct development: new insights raise new questions.Hepatology. 2008; 48: 358-360Crossref PubMed Scopus (23) Google Scholar]. Effective biliary repair requires the formation of biliary tubules and regeneration of the branching architecture of the ductal system. If a proper branching structure is not regenerated, the final result will be parenchymal necrosis or vanishing bile duct syndrome and fibrosis, i.e., the final stage of several cholangiopathies. As Boulter’s paper reminds us, liver repair is a complex mechanism that requires the concerted activities of several developmental mechanisms and interactions among multiple cell types. Understanding the role of Notch, Wnt and other morphogens in the regulation of biliary repair is a journey that has just begun, but solving this puzzle will generate significant benefits for liver patients. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. This work was supported by NIH DK079005, NIH Yale Liver Center, P30 DK34989, PSC Partner seeking a cure, Cariplo 2011-0470 and PRIN 2009 ARYX4T_005 to MS, and by Telethon GGP 09189 and Ateneo CPD 113799/11 to LF.

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