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Rebecca G. Wells, M.D.

Rebecca G. Wells, M.D.

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Associate Professor of Medicine
Department: Medicine
Graduate Group Affiliations

Contact information
421 Curie Boulevard
905 Biomedical Research Building
Philadelphia, PA 19104
Office: 215 573-1860
Fax: 215 573-2024
Lab: 215 573-1881
B.S. (Molecular Biophysics and Biochemistry)
Yale University , 1983.
Johns Hopkins University , 1987.
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Perelman School of Medicine > Faculty > Search

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.

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

Lab personnel:

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

Description of Clinical Expertise

Dr. Wells's clinical interests include the care of patients with a variety of GI and liver disorders. Additionally, she carries out screening upper and lower endoscopies at Penn Medicine at Radnor.

Selected Publications

Lorent K, Gong W, Koo KA, Waisbourd-Zinman O, Karjoo S, Zhao X, Sealy I, Kettleborough RN, Stemple DL, Windsor PA, Whittaker SJ, Porter JR, Wells RG*, Pack M* (co-corresponding author): Identification of a plant isoflavonoid that causes biliary atresia. Science Translational Medicine 7: 286ra67, 2015 Notes: Featured research highlight in Nature Reviews Gastroenterology & Hepatology.

Brisson BK, Mauldin EA, Lei W, Vogel LK, Power AM, Lo A, Dopkin D, Khanna C, Wells RG, Puré E, Volk SW: Type III collagen directs stromal organization and limits metastasis in a murine model of breast cancer. American Journal of Pathology 185: 1471-1486, 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: A role of Prx1-dependent extracellular matrix properties in vascular smooth muscle development in the embryonic lung. Pulmonary Circulation 5: 382-397, 2015.

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: 1519-1521, 2015.

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 1751-6161(13): 395-0, December 2014.

Wang H, Nair A, Chen CS, Wells RG, Shenoy VB.: Long Range Force Transmission in Fibrous Matrices Enabled by Tension-Driven Alignment of Fibers Biophysical Journal in press, 2014.

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

Pogoda K, Chin L, Georges PC, Byfield FJ, Bucki R, Kim R, Weaver M, Wells RG, Marcinkiewicz C, Janmey PA: Compression stiffening of brain and its effect on mechanosensing by glioma cells. New J Physics 16: 075002, 2014.

Saums MK, Wang W, Han B, Madhavan L, Han L, Lee D, Wells RG. : Mechanically and chemically tunable cell culture system for studying the myofibroblast phenotype. Langmuir 30(19): 5481-7, 2014.

Muir AB, Dods K, Noah Y, Toltzis S, Chandramouleeswaran PM, Lee A, Benitez A, Bedenbaugh A, Falk GW, Wells RG, Nakagawa H, Wang ML: Esophageal epithelial cells acquire functional characteristics, of activated myofibroblasts after undergoing an epithelial to mesenchymal transition. \{Esophageal epithelial cells acquire functional characteristics, of activated myofibroblasts after undergoing an epithelial to mesenchymal transition. Exp Cell Res.} in press, 2014 Notes: 2014 Aug 27 [Epub ahead of print].

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Last updated: 10/26/2015
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