Stem Cell Center, Yale: Stem Cells and Tissue Repair | Tissue Specific Stem Cells
Extensive Research Description
The main focus of my laboratory is the pathophysiology and therapy of diseases of the biliary tree (also called cholangiopathies). This is a large group of chronic liver diseases, congenital or acquired, that causes significant morbility and mortality in both the adult and pediatric population. The pathogenesis of biliary tree diseases is still elusive and, contrary to other areas of hepatology, effective treatment is still lacking. Liver transplantation remains the only treatment available for cases progressing to end-stage liver disease. On the other hand, many complications of liver transplantation involve the biliary tree, and biliary cells are intimately involved in liver repair and regeneration. Therefore, the basic scientific interest of the lab nicely complements the clinical interest of the group as it translates into the practice of transplant Hepatology.
Pathophysiology of cholangiopathies.
Previous work from my laboratory has contributed to the understanding of the normal physiology of biliary cells and to the identification of prototypic mechanisms for biliary damage for which a model human cholangiopathy exists (Fig. 1). Among them, the lab is now addressing the pathophysiology and treatment of Cystic Fibrosis cholangiopathy, polycystic liver disease and Alagille syndrome.
Cystic Fibrosis (CF) that alters the ability of the biliary epithelium to secrete Cl - through CFTR, and may leads to sclerosing cholangitis and biliary cirrhosis. We have shown that CFTR loss of function affects bicarbonate transport in biliary duct cells, which in certain circumstances this block can be overcome by purinergic signaling, by aminoglicoside antibiotics and by sulphonylureas. More recent on-going work focuses: a) on the effects of ursodeoxycholic acid (UDCA) on biliary epithelia from CF mice models, and b) the use of cell transplantation strategies to treat genetic diseases of the biliary tree.
Polycystic diseasesof the liver (PLD) are a group of extremely interesting developmental genetic cholangiopathies. In these diseases altered function of ciliary proteins causes dramatic changes in cholangiocyte biology, from altered development resulting in "ductal plate malformations, to altered secretory response to sheer stress, to hyperproliferation, and stimulation of excessive portal fibrogenesis. We have described an increased expression of angiogenic factors in the biliary and cystic epithelium of patients with ADPKD and with Caroli Disease (Fig.2). Angiopoietin-1 and VEGF overexpression may have an autocrine stimulatory effect on cystic cholangiocyte growth. In collaboration with Dr. Somlo and the Yale ADPKD Center and thanks to a novel technique enabling the propagation of primary cholangiocyte cultures from wild-type and PLD transgenic mice, we are planning to explore the intracellular signaling pathways involved in autocrine angiogenic signaling in PLD cystic epithelium and to evaluate the potential inhibitory effect of VEGF signaling blockade on cyst growth in vivo using ADPKD mice.
Alagille Syndrome, a developmental disease of the biliary tree caused by an altered Jaggeded-1/Notch-2 signaling. The patient with Alagille syndrome has severe ductopenia, is jaundiced, and is severely itching, but rarely develops terminal liver diseases and liver fibrosis is negligible. Studies are ongoing to clarify the role of Notch in liver repair and development. In Alagille syndrome there is important cholestasis in the absence of ductular reaction and with an accumulation of intermediate hepatocytes, our hypothesis is that Notch signaling is needed for progenitor cell progression to a biliary phenotype.
Another interest of my group is to understand the role of "activated" biliary cells and liver progenitor cells in liver repair mechanisms. The hypothesis is that, although both mature hepatocytes and biliary cells are able of substantial proliferation, this is restricted to experimental conditions and to rare human conditions, while in most cases of chronic liver diseases, liver repair requires the activation of a population of liver "progenitor cells" closely related to the epithelial cells of the terminal cholangioles. Specific hystochemical markers and a rigorous morphometric approach progenitor cells reaction are used to study with in a number of prototypic diseases.
Finally, the group is interested on hepatocellular carcinoma (HCC) therapy. HCC is one of the most frequent malignant neoplasms worldwide and a leading cause of mortality in the western cirrhotic population. HCC is also an important indication for liver transplantation. Many questions are still open concerning the optimal treatment of HCC. We are studying a prospectively followed up cohort of cirrhotic patients with incident HCC treated according to the BCLC staging system. Studies are planned to implement strategies to reduce recurrence in this population.
- Spirlì C., Fiorotto R., Song L., Santos-Sacchi J., Okolicsanyi L., Masier S., Rocchi L., Vairetti MP., De Bernard M., Melero S., Pozzan T., Strazzabosco M. 2005. Glibenclamide stimulates fluid secretion in rodent cholangiocytes through a CFTR-independent mechanism. Gastroenterology 129:220-233.
- Lazaridis KN, Strazzabosco M, Larusso NF . 2004. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 127(5):1565-77.
- C. Spirlì, L. Fabris, E. Duner, R. Fiorotto, N.F. La Russo, A. Sonzogni, L. Okolicsanyi, Strazzabosco M. 2003. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 124:737-753.
- C. Spirlì, M.H. Nathanson, R. Fiorotto, E. Duner, L.A. Denson, J.M. Sanz, F. Di Virgilio, L. Okolicsanyi, F. Casagrande, Str zzabosco M. . 2001. Proinflammatory Cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology 121:156-169.
- Zsembery A, Jessner W, Sitter G, Spirli C, Strazzabosco M, Graf J . 2002. Correction of CFTR malfunction and stimulation of Ca-activated Cl channels restore HCO3- secretion in cystic fibrosis bile ductular cells. Hepatology 35(1):95-104.
Full List of PubMed Publications
- Kaffe E, Fiorotto R, Pellegrino F, Mariotti V, Amenduni M, Cadamuro M, Fabris L, Strazzabosco M, Spirli C: β-catenin and IL-1β dependent CXCL10 production drives progression of disease in a mouse model of Congenital Hepatic Fibrosis. Hepatology. 2017 Nov 15; 2017 Nov 15. PMID: 29140564
- Morell CM, Fiorotto R, Meroni M, Raizner A, Torsello B, Cadamuro M, Spagnuolo G, Kaffe E, Sutti S, Albano E, Strazzabosco M: Notch signaling and progenitor/ductular reaction in steatohepatitis. PLoS One. 2017; 2017 Nov 15. PMID: 29140985
- Belli LS, Duvoux C, Berenguer M, Berg T, Coilly A, Colle I, Fagiuoli S, Khoo S, Pageaux GP, Puoti M, Samuel D, Strazzabosco M: ELITA consensus statements on the use of DAAs in liver transplant candidates and recipients. J Hepatol. 2017 Sep; 2017 Mar 18. PMID: 28323126
- Carbone M, Cristoferi L, Cortesi PA, Rota M, Ciaccio A, Okolicsanyi S, Gemma M, Scalone L, Cesana G, Fabris L, Colledan M, Fagiuoli S, Ideo G, Belli LS, Munari LM, Mantovani L, Strazzabosco M: Optimising the clinical strategy for autoimmune liver diseases: Principles of value-based medicine. Biochim Biophys Acta. 2017 Aug 24; 2017 Aug 24. PMID: 28844954
- Fabris L, Spirli C, Cadamuro M, Fiorotto R, Strazzabosco M: Emerging concepts in biliary repair and fibrosis. Am J Physiol Gastrointest Liver Physiol. 2017 Aug 1; 2017 May 19. PMID: 28526690
- Cadamuro M, Stecca T, Brivio S, Mariotti V, Fiorotto R, Spirli C, Strazzabosco M, Fabris L: The deleterious interplay between tumor epithelia and stroma in cholangiocarcinoma. Biochim Biophys Acta. 2017 Jul 27; 2017 Jul 27. PMID: 28757170
- Strazzabosco M, Fiorotto R, Cadamuro M, Spirli C, Mariotti V, Kaffe E, Scirpo R, Fabris L: Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim Biophys Acta. 2017 Jul 25; 2017 Jul 25. PMID: 28754453
- Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M: Src kinase inhibition reduces inflammatory and cytoskeletal changes in ΔF508 human cholangiocytes and improves CFTR correctors efficacy. Hepatology. 2017 Jul 24; 2017 Jul 24. PMID: 28836688
- Mariotti V, Strazzabosco M, Fabris L, Calvisi DF: Animal models of biliary injury and altered bile acid metabolism. Biochim Biophys Acta. 2017 Jul 11; 2017 Jul 11. PMID: 28709963
- Ciaccio A, Cortesi PA, Bellelli G, Rota M, Conti S, Okolicsanyi S, Rota M, Cesana G, Mantovani LG, Annoni G, Strazzabosco M: Direct-acting antivirals combination for elderly patients with chronic hepatitis C: A cost-effectiveness analysis. Liver Int. 2017 Jul; 2017 Mar 2. PMID: 27943549
- Ippolito D, Querques G, Okolicsanyi S, Franzesi CT, Strazzabosco M, Sironi S: Diagnostic value of dynamic contrast-enhanced CT with perfusion imaging in the quantitative assessment of tumor response to sorafenib in patients with advanced hepatocellular carcinoma: A feasibility study. Eur J Radiol. 2017 May; 2017 Feb 20. PMID: 28583645
- Strazzabosco M, Allen JI, Teisberg EO: Value-based care in hepatology. Hepatology. 2017 May. PMID: 28073146
- Spirli C, Mariotti V, Villani A, Fabris L, Fiorotto R, Strazzabosco M: Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease. J Hepatol. 2017 Mar; 2016 Nov 5. PMID: 27826057
- Cadamuro M, Brivio S, Spirli C, Joplin RE, Strazzabosco M, Fabris L: Autocrine and Paracrine Mechanisms Promoting Chemoresistance in Cholangiocarcinoma. Int J Mol Sci. 2017 Jan 13; 2017 Jan 13. PMID: 28098760
- De Carlis L, Di Sandro S, Centonze L, Lauterio A, Buscemi V, De Carlis R, Ferla F, Sguinzi R, Okolicsanyi S, Belli L, Strazzabosco M: Liver-allocation policies for patients affected by HCC in Europe. Curr Transplant Rep. 2016 Dec; 2016 Oct 7. PMID: 28473952
- Fiorotto R, Villani A, Kourtidis A, Scirpo R, Amenduni M, Geibel PJ, Cadamuro M, Spirli C, Anastasiadis PZ, Strazzabosco M: The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology. 2016 Dec; 2016 Oct 27. PMID: 27629435
- Mantovani LG, Cortesi PA, Strazzabosco M: Effective but costly: How to tackle difficult trade-offs in evaluating health improving technologies in liver diseases. Hepatology. 2016 Oct; 2016 Apr 4. PMID: 26926906
- Belli LS, Berenguer M, Cortesi PA, Strazzabosco M, Rockenschaub SR, Martini S, Morelli C, Donato F, Volpes R, Pageaux GP, Coilly A, Fagiuoli S, Amaddeo G, Perricone G, Vinaixa C, Berlakovich G, Facchetti R, Polak W, Muiesan P, Duvoux C, European Liver and Intestine Association (ELITA).: Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study. J Hepatol. 2016 Sep; 2016 May 17. PMID: 27212241
- Cadamuro M, Spagnuolo G, Sambado L, Indraccolo S, Nardo G, Rosato A, Brivio S, Caslini C, Stecca T, Massani M, Bassi N, Novelli E, Spirli C, Fabris L, Strazzabosco M: Low-Dose Paclitaxel Reduces S100A4 Nuclear Import to Inhibit Invasion and Hematogenous Metastasis of Cholangiocarcinoma. Cancer Res. 2016 Aug 15; 2016 Jun 21. PMID: 27328733
- Locatelli L, Cadamuro M, Spirlì C, Fiorotto R, Lecchi S, Morell CM, Popov Y, Scirpo R, De Matteis M, Amenduni M, Pietrobattista A, Torre G, Schuppan D, Fabris L, Strazzabosco M: Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology. 2016 Mar; 2016 Jan 16. PMID: 26645994
- Fabris L, Brivio S, Cadamuro M, Strazzabosco M: Revisiting Epithelial-to-Mesenchymal Transition in Liver Fibrosis: Clues for a Better Understanding of the "Reactive" Biliary Epithelial Phenotype. Stem Cells Int. 2016; 2016 Jan 6. PMID: 26880950
- Brivio S, Cadamuro M, Fabris L, Strazzabosco M: Epithelial-to-Mesenchymal Transition and Cancer Invasiveness: What Can We Learn from Cholangiocarcinoma? J Clin Med. 2015 Dec 19; 2015 Dec 19. PMID: 26703747
- Spirli C, Villani A, Mariotti V, Fabris L, Fiorotto R, Strazzabosco M: Posttranslational regulation of polycystin-2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage. Hepatology. 2015 Dec; 2015 Oct 10. PMID: 26313562
- Scirpo R, Fiorotto R, Villani A, Amenduni M, Spirli C, Strazzabosco M: Stimulation of nuclear receptor peroxisome proliferator-activated receptor-γ limits NF-κB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology. 2015 Nov; 2015 Aug 28. PMID: 26199136
- Morton SD, Cadamuro M, Brivio S, Vismara M, Stecca T, Massani M, Bassi N, Furlanetto A, Joplin RE, Floreani A, Fabris L, Strazzabosco M: Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation. Oncotarget. 2015 Sep 22. PMID: 26296968
- Belli LS, Romagnoli R, Nardi A, Marianelli T, Donato F, Corradini SG, Iemmolo RM, Morelli C, Pasulo L, Rendina M, De Martin E, Ponziani FR, Volpes R, Strazzabosco M, Angelico M, Liver Match Investigators.: Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort. Dig Liver Dis. 2015 Aug; 2015 Apr 16. PMID: 26055490
- Strazzabosco M, Fabris L, Albano E: Osteopontin: a new player in regulating hepatic ductular reaction and hepatic progenitor cell responses during chronic liver injury. Gut. 2014 Nov; 2014 Jul 23. PMID: 25056656
- Strazzabosco M, Fabris L: Neural cell adhesion molecule and polysialic acid in ductular reaction: the puzzle is far from completed, but the picture is becoming more clear. Hepatology. 2014 Nov; 2014 Oct 1. PMID: 24995463
- Fickert P, Pollheimer MJ, Beuers U, Lackner C, Hirschfield G, Housset C, Keitel V, Schramm C, Marschall HU, Karlsen TH, Melum E, Kaser A, Eksteen B, Strazzabosco M, Manns M, Trauner M, International PSC Study Group (IPSCSG).: Characterization of animal models for primary sclerosing cholangitis (PSC). J Hepatol. 2014 Jun; 2014 Feb 19. PMID: 24560657
- Angelico M, Nardi A, Romagnoli R, Marianelli T, Corradini SG, Tandoi F, Gavrila C, Salizzoni M, Pinna AD, Cillo U, Gridelli B, De Carlis LG, Colledan M, Gerunda GE, Costa AN, Strazzabosco M, Liver Match Study Investigators.: A Bayesian methodology to improve prediction of early graft loss after liver transplantation derived from the liver match study. Dig Liver Dis. 2014 Apr; 2014 Jan 9. PMID: 24411484
- Morell CM, Strazzabosco M: Notch signaling and new therapeutic options in liver disease. J Hepatol. 2014 Apr; 2013 Dec 3. PMID: 24308992
- Spirli C, Locatelli L, Morell CM, Fiorotto R, Morton SD, Cadamuro M, Fabris L, Strazzabosco M: Protein kinase A-dependent pSer(675) -β-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology. 2013 Nov; 2013 Sep 30. PMID: 23744610
- Kim AK, Dziura J, Strazzabosco M: Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma: the egg of columbus or another illusion? Hepatology. 2013 Aug. PMID: 23703812
- Fiorotto R, Raizner A, Morell CM, Torsello B, Scirpo R, Fabris L, Spirli C, Strazzabosco M: Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol. 2013 Jul; 2013 Mar 7. PMID: 23500150
- Cadamuro M, Morton SD, Strazzabosco M, Fabris L: Unveiling the role of tumor reactive stroma in cholangiocarcinoma: an opportunity for new therapeutic strategies. Transl Gastrointest Cancer. 2013 Jul. PMID: 28989865
- Spirli C, Strazzabosco M: Vascular endothelial growth factors in progenitor cells mediated liver repair. Hepatobiliary Surg Nutr. 2013 Apr. PMID: 24570918
- Strazzabosco M, Fabris L: The balance between Notch/Wnt signaling regulates progenitor cells' commitment during liver repair: mystery solved? J Hepatol. 2013 Jan; 2012 Aug 15. PMID: 22902547
- Spirli C, Morell CM, Locatelli L, Okolicsanyi S, Ferrero C, Kim AK, Fabris L, Fiorotto R, Strazzabosco M: Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib. Hepatology. 2012 Dec; 2012 Aug 27. PMID: 22653837
- Strazzabosco M, Fabris L: Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol. 2012 May; 2012 Jan 13. PMID: 22245898
- Spirli C, Locatelli L, Fiorotto R, Morell CM, Fabris L, Pozzan T, Strazzabosco M: Altered store operated calcium entry increases cyclic 3',5'-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology. 2012 Mar. PMID: 21987453
- Fiorotto R, Scirpo R, Trauner M, Fabris L, Hoque R, Spirli C, Strazzabosco M: Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-κB-mediated inflammatory response in mice. Gastroenterology. 2011 Oct; 2011 Jun 26. PMID: 21712022
- Strazzabosco M, Somlo S: Polycystic liver diseases: congenital disorders of cholangiocyte signaling. Gastroenterology. 2011 Jun; 2011 Apr 22. PMID: 21515270
- Wrzesinski SH, Taddei TH, Strazzabosco M: Systemic therapy in hepatocellular carcinoma. Clin Liver Dis. 2011 May. PMID: 21689622
- Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M: Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology. 2010 May. PMID: 20131403
- Strazzabosco M: Foxa1 and Foxa2 regulate bile duct development in mice. J Hepatol. 2010 May; 2010 Feb 18. PMID: 20347503
- Spirli C, Okolicsanyi S, Fiorotto R, Fabris L, Cadamuro M, Lecchi S, Tian X, Somlo S, Strazzabosco M: ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology. 2010 Jan; 2009 Sep 18. PMID: 19766642
- Strazzabosco M, Fiorotto R, Melero S, Glaser S, Francis H, Spirli C, Alpini G: Differentially expressed adenylyl cyclase isoforms mediate secretory functions in cholangiocyte subpopulation. Hepatology. 2009 Jul. PMID: 19444869
- Nishihori T, Strazzabosco M, Saif MW: Incidence and management of colorectal cancer in liver transplant recipients. Clin Colorectal Cancer. 2008 Jul. PMID: 18650194
- Rogart JN, Iyer A, Robert ME, Levy G, Strazzabosco M: Type I autoimmune hepatitis presenting with acute liver failure in the setting of wild mushroom ingestion. J Clin Gastroenterol. 2008 Jul. PMID: 18496396
- Strazzabosco M, Fabris L: Functional anatomy of normal bile ducts. Anat Rec (Hoboken). 2008 Jun. PMID: 18484611
- Fiorotto R, Spirlì C, Fabris L, Cadamuro M, Okolicsanyi L, Strazzabosco M: Ursodeoxycholic acid stimulates cholangiocyte fluid secretion in mice via CFTR-dependent ATP secretion. Gastroenterology. 2007 Nov; 2007 Sep 2. PMID: 17983806