1e
19
1
49
2
2
18
1b
1d
18
32
4d
1d
2 29
1d
25
Rebecca G. Wells, MD
78
4d
Professor of Medicine (Gastroenterology)
28
b4
3
5f
Member, NIH/NIDDK Center for Molecular Studies in Digestive and Liver Diseases, University of Pennsylvania School of Medicine
a2
Member, Fred and Suzanne Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia
90
Member, Institute for Translational Medicine and Therapeutics, University of Pennsylvania
b7
Member, Program in Translational Biomechanics, Institute for Translational Medicine and Therapeutics, University of Pennsylvania
70
Member, Penn Muscle Institute, University of Pennsylvania
82
Member and Director of Education, NSF Center for Engineering MechanoBiology
8d
Associate Director, NIDDK Center for Molecular Studies in Digestive and Liver Diseases
84
Co-Director, NSF Science and Technology Center for Engineering MechanoBiology
83
Member, Penn Center for Musculoskeletal Diseases, University of Pennsylvania
11
Department: Medicine
4
1
23
1f
Graduate Group Affiliations
8
b
-
6b
- Cell and Molecular Biology 6a
- Pharmacology 41
- Bioengineering e
1d
46
Contact information
41
4
3
3
1d
41
421 Curie Boulevard
4a 905 Biomedical Research Building II/III
Philadelphia, PA 19104
26
4a 905 Biomedical Research Building II/III
Philadelphia, PA 19104
35
9d
12
18
Publications
23 a
3
2
29
23 a
Links
17d Search PubMed for articles
45 Cell and Molecular Biology graduate group faculty webpage.
c2 University of Pennsylvania Perelman School of Medicine Center for Molecular Studies in Digestive and Liver Diseases
b2 University of Pennsylvania Perelman School of Medicine Institute for Translational Medicine and Therapeutics
94 University of Pennsylvania Center for Engineering Cells and Regeneration
a5 Penn Medicine at Radnor
8f University of Pennsylvania Perelman School of Medicine Muscle Institute
b2 Fred and Suzanne Biesecker Pediatric Liver Center
c
4
b
1f
17d Search PubMed for articles
45 Cell and Molecular Biology graduate group faculty webpage.
c2 University of Pennsylvania Perelman School of Medicine Center for Molecular Studies in Digestive and Liver Diseases
b2 University of Pennsylvania Perelman School of Medicine Institute for Translational Medicine and Therapeutics
94 University of Pennsylvania Center for Engineering Cells and Regeneration
a5 Penn Medicine at Radnor
8f University of Pennsylvania Perelman School of Medicine Muscle Institute
b2 Fred and Suzanne Biesecker Pediatric Liver Center
c
13
Education:
21 9 B.S. 32 (Molecular Biophysics and Biochemistry) c
14 Yale University 16 , 1983.
21 9 M.D. c
1d Johns Hopkins University 16 , 1987.
c
3
3
3
3
8b
Permanent link21 9 B.S. 32 (Molecular Biophysics and Biochemistry) c
14 Yale University 16 , 1983.
21 9 M.D. c
1d Johns Hopkins University 16 , 1987.
c
2 29
21
1e
1d
24
5e
8
5e – The role of liver stiffness and other mechanical factors in fibrosis and cirrhosis
66 - The role of mechanical factors and ECM proteins in myofibroblast differentiation in fibrosis
55 - The etiology and mechanism of ductal damage and fibrosis in biliary atresia
7e - The role of fibronectin splice variants, proteoglycans, and other matrix proteins in liver fibrosis and angiogenesis
58 - Characterization of myofibroblast precursor populations in liver and bile duct
50 - Hepatic stellate cell and portal fibroblast function in liver fibrosis
54 - The mechanism of fibrosis in autosomal recessive polycystic kidney disease
8
9
8c Key words: Hepatic stellate cells, liver fibrosis, TGF-ß, portal fibroblasts, biliary atresia, liver mechanics, fibronectin
8
26 Description of Research
42 My research focuses on the mechanism of hepatic fibrosis.
8
188 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.
8
1fe 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.
8
3a4 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.
8
1b6 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.
8
f4 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.
8
315 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.
8
e4 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.
26 29
27
Description of Research Expertise
2b Research Interests8
5e – The role of liver stiffness and other mechanical factors in fibrosis and cirrhosis
66 - The role of mechanical factors and ECM proteins in myofibroblast differentiation in fibrosis
55 - The etiology and mechanism of ductal damage and fibrosis in biliary atresia
7e - The role of fibronectin splice variants, proteoglycans, and other matrix proteins in liver fibrosis and angiogenesis
58 - Characterization of myofibroblast precursor populations in liver and bile duct
50 - Hepatic stellate cell and portal fibroblast function in liver fibrosis
54 - The mechanism of fibrosis in autosomal recessive polycystic kidney disease
8
9
8c Key words: Hepatic stellate cells, liver fibrosis, TGF-ß, portal fibroblasts, biliary atresia, liver mechanics, fibronectin
8
26 Description of Research
42 My research focuses on the mechanism of hepatic fibrosis.
8
188 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.
8
1fe 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.
8
3a4 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.
8
1b6 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.
8
f4 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.
8
315 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.
8
e4 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.
26 29
23
149 Ordner J, Narula N, Chiriboga L, Zeck B, Majd M, Gupta K, Gaglia R, Zhou F, Moreira A, Iman R, Ko JP, Le L, Wells RG, Theise ND.: Continuity of interstitial spaces within and outside the human lung. Journal of Anatomy May 2025 Notes: online ahead of print.
1bc Ma S, Habash NW, Dehankar MK, Jalan-Sakrikar N, Cooper SA, Anwar AA, Jerez S, Sutthirat P, Gao J, Diamond T, Jiao J, Qiu C, Yang J, Ilyas SI, Lee M, Yaqoob U, Cao S, Wells RG, Shah VH, Hilscher MB: Congestion enriches intra-hepatic macrophages through reverse zonation of CXCL9 in liver sinusoidal endothelial cells. Cell Mol Gastroenterol Hepatol Page: 101475, Feb 2025.
155 Byfield FJ, Eftekhari B, Kaymak-Loveless K, Mandal K, Li D, Wells RG, Chen W, Brujic J, Bergamaschi G, Wuite GJL, Patteson AE, Janmey PA: Metabolically intact nuclei are fluidized by the activity of the chromatin remodeling motor BRG1. Biophys J 124(3): 494-507, 2025.
19b 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 Notes: Online ahead of print: doi: 10.1038/s41390-024-03335-9.
13d 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 300(12): 107968, 2024.
149 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.
da Gupta K, Chen D, Wells RG: Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes. JHEP Reports 7(1): 101218, 2024.
184 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.
16b 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.
2c
7
1d
1f
Selected Publications
120 Theise ND, Kohnehshahri MN, Chiriboga LA, Fyfe B, Cao W, Zee S, Imam R, Pichler-Sekulic S, Wells RG.: Evidence of interstitial continuity within and beyond the human pancreas. Human Pathology 161: 105855, June 2025.149 Ordner J, Narula N, Chiriboga L, Zeck B, Majd M, Gupta K, Gaglia R, Zhou F, Moreira A, Iman R, Ko JP, Le L, Wells RG, Theise ND.: Continuity of interstitial spaces within and outside the human lung. Journal of Anatomy May 2025 Notes: online ahead of print.
1bc Ma S, Habash NW, Dehankar MK, Jalan-Sakrikar N, Cooper SA, Anwar AA, Jerez S, Sutthirat P, Gao J, Diamond T, Jiao J, Qiu C, Yang J, Ilyas SI, Lee M, Yaqoob U, Cao S, Wells RG, Shah VH, Hilscher MB: Congestion enriches intra-hepatic macrophages through reverse zonation of CXCL9 in liver sinusoidal endothelial cells. Cell Mol Gastroenterol Hepatol Page: 101475, Feb 2025.
155 Byfield FJ, Eftekhari B, Kaymak-Loveless K, Mandal K, Li D, Wells RG, Chen W, Brujic J, Bergamaschi G, Wuite GJL, Patteson AE, Janmey PA: Metabolically intact nuclei are fluidized by the activity of the chromatin remodeling motor BRG1. Biophys J 124(3): 494-507, 2025.
19b 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 Notes: Online ahead of print: doi: 10.1038/s41390-024-03335-9.
13d 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 300(12): 107968, 2024.
149 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.
da Gupta K, Chen D, Wells RG: Microcystin-RR is a biliary toxin selective for neonatal extrahepatic cholangiocytes. JHEP Reports 7(1): 101218, 2024.
184 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.
16b 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.
2c