Rebecca G. Wells, M.D.

faculty photo
Associate Professor of Medicine
Department: Medicine
Graduate Group Affiliations

Contact information
421 Curie Boulevard
9th Floor Biomedical Research Building
Philadelphia, PA 19104
Office: 215 573-1860
Fax: 215 573-2024
Lab: 215 573-1881
Education:
B.S. (Molecular Biophysics and Biochemistry)
Yale University , 1983.
M.D.
Johns Hopkins University , 1987.
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Description of Research Expertise

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

Key words: Hepatic stellate cells, liver fibrosis, TGF-ß, portal fibroblasts, biliary atresia, liver mechanics, autosomal recessive polycystic kidney disease

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. We are investigating the mechanism of fibrosis in three ways: a) by studying the matrix, mechanical, and soluble factors that influence activation of known 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.

We are studying the matrix, mechanical, and soluble factors that influence activation of two known myofibroblast precursor populations, hepatic stellate cells (HSC) and portal fibroblasts (PF). HSC have for many years been regarded as the most important myofibroblast precursor population and have been studied extensively in a cell culture model of activation. PF have only recently been identified and isolated but are now appreciated to be as important in some liver diseases as HSC. We have successfully developed and characterized an in vitro activation assay for PF. We have used a novel cell culture system to study the role of mechanical and chemical factors in activation of both PF and HSC and have demonstrated for the first time that activation of both PF and HSC is determined by matrix stiffness. Additionally, we have shown that PF absolutely require TGF-β for activation, while HSC require TGF-β, signaling specifically via the downstream mediator Smad3, only in late stages of activation. We have proposed different models of in vitro activation for each cell type.

We are also applying our findings about the role of mechanical stiffness in liver myofibroblast activation to whole animal models. 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. Current work is focused on determining the cause of early increases in liver stiffness, in particular the role of collagen cross-linking enzymes, the relevance of in vivo liver stiffness to myofibroblast activation, the role of early matrix synthesis, and the role of TGF-β in the mechanical changes of the liver in fibrosis. We are also interested in the role of mechanical changes in driving the architectural changes of late fibrosis and cirrhosis.

We have recently begun studying other mechanical factors (including compressive pressure) which drive myofibroblast activation and fibrosis in the liver. Additionally, we are actively studying the role of fibronectin splice variants in fibrosis and angiogenesis, and the role of small proteoglycans (including lumican) in collagen mechanics and myofibroblast differentiation.

Human model diseases of interest to our studies of the mechanism of fibrosis include biliary atresia and autosomal recessive polycystic kidney disease (ARPKD). We are part of an international group which has recently identified a plant toxin that causes biliary atresia and are actively studying its effects on cholangiocytes. We area also studying the mechanism of fibrosis in ARPKD, in particular the role of portal fibroblasts and mechanisms of portal hypertension in this disease.

Summary: Overall, my 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.

Rotation Projects
There are several; please speak with Dr. Wells.

Lab personnel:

Shannon Tsai - Research Specialist
Orith Waisbourd-Zinman, MD - Fellow
Marina Perepelyuk, PhD - Postdoctoral Researcher
Bridget Sackey - PhD Student
Alexander Ventriglia- Undergraduate
Jessica Bermudez - Masters student
Jennifer Smith - Masters student
Jude Dong Hun Han - Masters student
Bhavana Vidyashankar - Undergraduate
Christine Dang - Undergraduate
Robert Kent- Undergraduate

Selected Publications

Guvendiren M, Perepelyuk M, Wells RG, Burdick JA: Hydrogels with differential and patterned mechanics to study stiffness-mediated myofibroblastic differentiation of hepatic stellate cells. J Mech Behav Biomed Mater in press, 2014 Notes: 2013 Dec 4. pii: S1751-6161(13)00395-0. doi: 10.1016/j.jmbbm.2013.11.008. [Epub ahead of print]

Karjoo, S; Wells, RG: Isolation of Neonatal Extrahepatic Cholangiocytes. Journal of Visualized Experiments in press, 2014.

Fickert P, Krones E, Pollheimer MJ, Thueringer A, Moustafa T, Silbert D, Halilbasic E, Yang M, Jaeschke H, Stokman G, Wells RG, Eller K, Rosenkranz AR, Eggertsen G, Wagner CA, Langner C, Denk H, Trauner M: Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice. Hepatology 58(6): 2056-69, Dec. 2013.

Karjoo S, Hand NJ, Loarca L, Russo PA, Friedman JR, Wells RG: Extrahepatic cholangiocyte cilia are abnormal in biliary atresia. J Pediatr Gastroenterol Nutr 57(1): 96-101, Jul 2013.

Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, Thung SN, Wells RG, Greenbaum LE, Stanger BZ: Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27(7): 719-24, Apr 2013.

Perepelyuk M, Terajima M, Wang AY, Georges PC, Janmey PA, Yamauchi M, Wells RG: Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 304(6): G605-14, Mar 2013.

Wen J, Olsen AL Perepelyuk M, Wells RG.: Isolation of Rat Portal Fibroblasts by in situ Liver Perfusion. Journal of Visualized Experiments Page: pii: 3669, June 2012.

Chu AS, Russo PA, Wells RG: Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Modern Pathology 25(5): 751-7, May 2012.

Olsen AL, Sackey BK, Marcinkiewicz C, Boettiger D, Wells RG: Fibronectin extra domain-A promotes hepatic stellate cell motility but not differentiation into myofibroblasts. Gastroenterology 142(4): 928-937, April 2012.

Chu AS, Diaz R, Hui J-J, Yanger K, Zong Y, Alpini F, Stanger BZ, Wells RG: Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis Hepatology in press, 2011.

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Last updated: 04/12/2014
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