Papel de la Interacción Colangiocito-Matriz Extracelular en la cistogénesis de las enfermedades hepáticas poliquísticas

Resum

ROLE OF CHOLANGIOCYTE-EXTRACELLULAR MATRIX INTERACTION IN THE CYSTOGENESIS OF POLYCYSTIC LIVER DISEASE Aura Daniela Urribarri Marín, Laboratory of Molecular Genetics, Division of Gene Therapy and Hepatology, School of Medicine and CIMA of the University of Navarra (Spain) 2012. Polycystic Liver Diseases (PCLDs) are genetic disorders characterized by progressive bile-duct dilatation and/or cyst development, representing the major cause of morbidity and mortality. We have recently reported that cystogenesis in PCLDs is consequence of hyper-proliferation, hyper-secretion, and alterations in the miRNA expression pattern of cholangiocytes. Here we tested the potential role of cholangiocyte-extracelular matrix interaction in the hepatic cystogenesis of PCLDs. Microfluorimetric assays revealed that polycystic human cholangiocytes in culture present increased metalloprotease (MMP)-activity compared to normal human cholangiocytes, an event associated with increased mRNA levels of different MMPs by real-time qPCR. Interleukins 6 and 8 (IL6, IL8) and estrogens, which are upregulated in the cystic fluid of PCLD patients, were found to stimulate the MMP-activity of both normal and polycystic human cholangiocytes in culture. The presence of antibodies against IL6 and/or IL8 receptor/s inhibited the basal MMP-hyperactivity of polycystic human cholangiocytes and did not affect the basal MMP-activity of normal human cholangiocytes. Immunohistochemical staining showed MMP3 overexpression in cystic cholangiocytes from PCLD tissues compared to normal human livers, as well as in cystic cholangiocytes from PCK rat (animal model of PCLDs) livers compared to normal rat livers. Marimastat, a synthetic pseudopeptide that inhibit MMP-activity, reduced the MMP-hyperactivity of polycystic human cholangiocytes and inhibited the cystic expansion of PCK cholangiocytes grown in a 3-dimentional collagen matrix. Finally, chronic treatment of PCK rats with Marimastat inhibited hepatic cystogenesis. Conclusion: PCLDs are associated with cholangiocyte MMP-hyperactivity stimulated by IL6, IL8, and estrogens. Inhibition of this MMP-hyperactivity with Marimastat decreased the hepatic cystogenesis in vitro and in an animal model of PCLD, representing a potential therapeutic tool for these diseases.