Rebecca G. Wells, MD

faculty photo
Professor of Medicine (Gastroenterology)
Department: Medicine

Contact information
421 Curie Boulevard
905 Biomedical Research Building II/III
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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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

Selected Publications

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.

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 Notes: Epub Jan 31, 2024.

de Jong IEM, Hunt ML, Chen D, Yu D, Llewellyn J, Gupta K, Li D, Erxleben D, Rivas F, Hall AR, Furth EE, Naji A, Liu C, Dhand A, Burdick JA, Davey MG, Flake AW, Porte RJ, Russo PA, Gaynor JW, Wells RG: A fetal wound healing program after intrauterine bile duct injury may contribute to biliary atresia. J Hepatology Page: S0168-8278(23)05060-2, Aug 2023.

de Jong IEM, Bodewas SB, van Leeuwen OB, Oosterhuis D, Lantinga VA, Thorne AM, Lascaris B, van den Heuvel MC, Wells RG, Olinga P, de Meijer VE, Porte RE: Restoration of Bile Duct Injury of Donor Livers During Ex Situ Normothermic Machine Perfusion. Transplantation 107(6): e161-e172, Jun 2023.

Loneker AE, Alisafaei F, Kant A, Li D, Janmey PA, Shenoy VB, Wells RG.: Lipid droplets are intracellular mechanical stressors that impair hepatocyte function. PNAS 120(16): e2216811120, Apr 2023.

Li D, Janmey PA, Wells RG: Local fat content determines local and global stiffness in livers with simple steatosis. FASEB Bioadvances 5(6): 251-261, Apr 2023.

Lewellyn J, Fede C, Loneker AE, Friday CS, Hast MW, Theise ND, Furth EE, Guido M, Stecco C, Wells RG: Glisson's capsule matrix structure and function is altered in patients with cirrhosis irrespective of etiology. JHEP Reports 5(9): 100760, Apr 2023.

Wu B, Lu D-A, Guan L, Myint PK, Chin L, Dang H, Xu Y, Ren J, Li T, Yu Z, Jabban S, Mills GF, Nukpezah, Chen YH, Furth EE, Gimotty PA, Wells RG, Weaver VM, Radhakrishnan R, Wang X-W, Guo W. : Stiff Matrix Induces Exosome Secretion to Promote Tumor Growth. Nature Cell Biology 25(3): 415-424, Mar 2023.

Du Y, de Jong IEM, Gupta K, Waisbourd-Zinman O, Har-Zahav A, Soroka CJ, Boyer JL, Llewellyn J, Liu C, Naji A, Polacheck WJ, Wells RG: Human vascularized bile duct-on-a chip: a multi-cellular micro-physiological system for studying cholestatic liver disease. Biofabrication 16(1): 015004, 2023.

Filliol A, Saito Y, Nair A, Dapito DH, Yu LX, Ravichandra A, Bhattacharjee S, Affo S, Fujiwara N, Su H, Sun Q, Savage TM, Wilson-Kanamori JR, Caviglia JM, Chin L, Chen D, Wang X, Caruso S, Kang JK, Amin AD, Wallace S, Dobie R, Yin D, Rodriguez-Fiallos OM, Yin C, Mehal A, Izar B, Friedman RA, Wells RG, Pajvani UB, Hoshida Y, Remotti HE, Arpaia N, Zucman-Rossi J, Karin M, Henderson NC, Tabas I, Schwabe RF.: Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610(7931): 356-365, October 2022.

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Last updated: 01/31/2024
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