Description of Research Expertise:
– 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.
There are several; please speak with Dr. Wells.
Shannon Tsai - Research Specialist
Orith Waisbourd-Zinman, MD - Fellow
Lucas Smith, PhD - Postdoctoral Researcher
Alyssa Kriegermeier, MD - Fellow
Bridget Sackey - CAMB PhD Student
Hani Nagi- Undergraduate
Dongning Chen - BE Masters student
Amy Lee - BE Masters student
Gi Yun Lee - Undergraduate
Muir AB, Dods K, Henry SJ, Benitez AJ, Lee D, Whelan KA, DeMarshall M, Hammer DA, Falk G, Wells RG, Spergel J, Nakagawa H, Wang ML: Eosinophilic esophagitis associated chemical and mechanical microenvironment shapes esophageal fibroblast behavior J Pediatr Gastroenterol Nutr 63(2) : 200-9,2016.
Waisbourd-Zinman O, Koh H, Tsai S, Lavrut P-M, Dang C, Zhao X, Pack M, Cave J, Hawes M, Koo KA, Porter JR, Wells RG: The toxin biliatresone causes mouse extrahepatic cholangiocyte damage and fibrosis via decreased glutathione and SOX17 Hepatology 64(3) : 880-93,2016.
Koo K, Waisbourd-Zinman O, Wells R, Pack M, Porter JR: Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine and Amino Acids Chemical Research in Toxicology 29 (2): 142-9,2016.
Maryna Perepelyuk, LiKang Chin, Xuan Cao, Anne van Oosten, Vivek B. Shenoy, Paul A. Janmey, Rebecca G. Wells: Normal and Fibrotic Rat Livers Demonstrate Shear Strain Softening and Compression Stiffening: a Model for Soft Tissue Mechanics PLOS One 11 (1): e0146588,2016.
Steven Caliari, Maryna Perepelyuk, Brian Cosgrove, Shannon Tsai, Gi Yun Lee, Robert Mauck, Rebecca Wells, and Jason Burdick: Stiffening hydrogels for investigating the dynamics of hepatic stellate cell mechanotransduction during myofibroblast activation Scientific Reports 6 : 21387,2016.
Zhao X, Lorent K, Wilkins B, Marchione DM, Gillespie K, Waisbourd-Zinman O, So J, Koo KA, Shin D, Porter JR, Wells RG, Blair I, Pack M: Glutathione antioxidant pathway activity and reserve determine toxicity and specificity of the biliary toxin biliatresone in zebrafish Hepatology : 2016.
Bridget Sackey-Aboagye, Abby L. Olsen, Sarmistha M. Mukherjee, Alexander Ventriglia, Yasuyuki Yokosaki, Linda E. Greenbaum, Gi Yun Lee, Hani Naga and Rebecca G. Wells: Fibronectin extra domain A promotes liver sinusoid repair following hepatectomy PLOS One in press : 2016.
Caliari SR, Perepelyuk M, Soulas EM, Lee GY, Wells RG, Burdick JA: Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression Integrative Biology : 2016.
Koo K, Lorent K, Gong W, Windsor P, Whittaker S, Pack M, Wells RG, Porter J: Biliatresone, A Reactive Natural Toxin from Dysphania glomulifera and D. littoralis: Discovery of the Toxic Moiety 1,2-Diaryl-2-Propenone Chemical Research in Toxicology 28(8) : 1519-1521,2015.
Iheda-Stansbury K, Ames J, Chokshi M, Aiad N, Sanyal S, Kawabata KC, Levental I, Sundararaghavan HG, Burdick JA, Janmey P, Miyazono K, Wells RG, Jones PL: Role played by Prx1-dependent extracellular matrix properties in vascular smooth muscle development in the embryonic lungs Pulmonary Circulation 5(2) : 382-397,2015.
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