Description of Research Expertise

Research Interests

– The role of liver stiffness and other mechanical factors in fibrosis and cirrhosis
- The role of mechanical factors and ECM proteins in myofibroblast differentiation in fibrosis
- The etiology and mechanism of ductal damage and fibrosis in biliary atresia
- The role of fibronectin splice variants, proteoglycans, and other matrix proteins in liver fibrosis and angiogenesis
- Characterization of myofibroblast precursor populations in liver and bile duct
- Hepatic stellate cell and portal fibroblast function in liver fibrosis
- The mechanism of fibrosis in autosomal recessive polycystic kidney disease


Key words: Hepatic stellate cells, liver fibrosis, TGF-ß, portal fibroblasts, biliary atresia, liver mechanics, fibronectin

Description of Research
My research focuses on the mechanism of hepatic fibrosis.

Liver fibrosis results from the deposition of excess, abnormal extracellular matrix by myofibroblasts derived from non-fibrogenic cells that undergo “activation” in the context of chronic liver injury. Fibrosis in the bile duct is a similar matrix-driven process, although the identity of the myofibroblast populations and the chronic vs. acute nature of the injury are not known.

We are investigating the mechanisms of fibrosis in three ways: a) by studying the matrix, mechanical, and soluble factors that influence fibrosis, including the activation of myofibroblast precursor populations; b) by identifying new fibrogenic cell populations and new means of studying previously identified cells; and c) by applying the results of our experiments with isolated cells to whole animal models and to the study of human diseases, including hepatocellular carcinoma and biliary fibrosis.

We have demonstrated in rat models of fibrosis that increased liver stiffness precedes matrix deposition and that fibrosis and liver stiffness are not linearly related. The early increases in liver stiffness are important because hepatic stellate cells and portal fibroblasts, the major myofibroblast precursors of the liver, require increased stiffness to become fibrogenic. Our recent work has examined liver mechanics in more detail, and we have attempted to determine the components of the liver responsible for various mechanical properties. We have found that livers strain soften and compression stiffen, in contrast to biopolymers like collagen. Our work suggests that proteoglycans and other matrix components as well as cell-matrix interactions are the reason for these mechanical properties. Our theory collaborators have developed a new constitutive model for the tissue that is in good agreement with our data.

This work led to an ongoing project examining the mechanics of the cirrhotic liver and their impact on the development of hepatocellular carcinoma (HCC). Using a variety of matrices, animal models, and human and animal cells, we are studying the impact of various mechanical properties on liver cell behavior with the goal of understanding the remarkable propensity of HCC to develop in a highly mechanically abnormal environment.

We have not studied liver mechanics in isolation, but also study various matrix components, including fibronectin splice variants and proteoglycans, and are examining their effects on liver cell function, fibrosis, and liver mechanics.

Human model diseases of interest to our studies of the mechanism of fibrosis include biliary atresia. We are part of an international group that has recently identified a plant toxin that causes biliary atresia. We have developed model mammalian cell systems to study its mechanism of action and are testing structurally similar compounds in an attempt to identify critical structural groups, which may lead us to compounds of relevance to humans. Additionally, as part of a general interest in biliary fibrosis, we are studying potential myofibroblast precursor populations in the extrahepatic bile duct, the impact of acute vs. chronic cholangiocyte injury, mechanisms of liver fibrosis post bile duct obstruction, and differences between intra- and extra-hepatic cholangiocytes.

Summary: Overall, our goal is to develop a unified and comprehensive model of liver fibrosis that incorporates multiple cell types, soluble and secreted factors, matrix proteins, and local and regional mechanical factors.

Selected Publications

Fried S, Har-Zahav A, Hamudi Y, Mahameed S, Mansur R, Dotan M, Cozacov T, Shamir R, Wells RG, Waisbourd-Zinman O: Biliary atresia: insights into mechanisms using a toxic model of the disease including Wnt and Hippo signaling pathways and microtubules. Pediatric Research : 2024.

Chen D, Du Y, Llewellyn J, Bonna A, Zuo B, Janmey PA, Farndale RW, Wells Rg: Versican binds collagen via its G3 domain and regulates the organization and mechanics of collagenous matrices Journal of Biological Chemistry in press : 2024.

Chen D, Du Y, Llewellyn J, Bonna A, Zuo B, Janmey PA, Farndale RW, Wells RG.: Versican binds collagen via its G3 domain and regulates the organization and mechanics of collagenous matrices Journal of Biological Chemistry in press : 2024.

Har-Zahav A, Tobar A, Fried S, Sivan R, Wilkins BJ, Russo P, Shamir R, Wells RG, Gurevich M, Waisbourd-Zinman O: Oral N-acetylcysteine ameliorates liver fibrosis and enhances regenerative responses in Mdr2 knockout mice Scientific Reports 14 : 26513,2024.

Gupta K, Chen D, Wells RG: Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes. JHEP Reports in press : 2024.

Weiguo Fan, Kolade Adebowale, Lóránd Váncza, Yuan Li, Md Foysal Rabbi, Koshi Kunimoto, Dongning Chen, Gergely Mozes, David Kung-Chun Chiu, Yisi Li, Junyan Tao, Yi Wei, Nia Adeniji, Ryan L. Brunsing, Renumathy Dhanasekaran, Aatur Singhi, David Geller, Su Hao Lo, Louis Hodgson, Edgar G. Engleman, Gregory W. Charville, Vivek Charu, Satdarshan P. Monga, Taeyoon Kim, Rebecca G. Wells, Ovijit Chaudhuri & Natalie J. Török: Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver Nature in press : 2024.

Wryebek, R; Fierstein, J; Wells RG; Machry J; Karjoo S: Toxins and Biliary Atresia: Is Karenia Brevis (Red Tide) The Culprit? Harmful Algae in press : 2024.

Gupta K, Llewellyn J, Roberts E, Liu C, Naji A, Assoian RK, Wells RG: The biliary atresia susceptibility gene EFEMP1 regulates extrahepatic bile duct elastic fiber formation and mechanics. JHEP Reports in press : 2024.

Gupta K, XU JP, Diamond T, de Jong IEM, Glass A, Llewellyn J, Theise ND, Waisbourd-Zinman O, Winkler JD, Behrens EM, Mesaros C, Wells RG: Low-dose biliatresone treatment of pregnant mice causes subclinical biliary disease in their offspring: Evidence for a spectrum of neonatal injury. PLOS ONE 19 : e0301824,2024.

Braun J, Bernarding J, Snellings J, Meyer T, Dantas de Moraes PA, Safraou Y, Wells RG, Guo J, Tzschätzsch H, Zappe A, Pagel K, Sauer IM, Hillebrandt KH, Sack I: On the relationship between viscoelasticity and water diffusion in soft biological tissues. Acta Biomaterialia 182 : 42-53,2024.

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Academic Contact Information

421 Curie Boulevard
905 Biomedical Research Building II/III
Philadelphia, PA 19104
Phone: 610-322-2627
Patient appointments: 800-789-7366