About

Rebecca G. Wells, MD, is a Professor of Medicine (Gastroenterology) at the University of Pennsylvania School of Medicine. Her research focuses on the mechanisms of hepatic fibrosis, investigating how excess extracellular matrix is deposited by myofibroblasts derived from non-fibrogenic cells that undergo activation during chronic liver injury. She studies the role of liver stiffness and mechanical factors in fibrosis and cirrhosis, examining how mechanical properties influence myofibroblast activation and liver cell behavior. Dr. Wells's work includes exploring the contributions of matrix components such as fibronectin splice variants and proteoglycans to liver fibrosis and angiogenesis. She has demonstrated in rat models that increased liver stiffness precedes matrix deposition and that fibrosis correlates with changes in liver mechanics. Her research extends to understanding the impact of mechanical properties on hepatocellular carcinoma development, as well as studying various cell populations involved in biliary atresia and liver fibrosis. She is involved in developing comprehensive models of liver fibrosis that incorporate cellular, molecular, and mechanical factors, with the goal of advancing understanding and potential therapeutic approaches for liver diseases.

Research topics

• Cancer research
• Biology
• Political Science
• Cell biology
• Chemistry
• Biochemistry
• Internal medicine
• Genetics
• Medicine
• Immunology

Selected publications

• Automated segmentation and quantification of histological liver features for MASH/MASLD scoring

  medRxiv · 2026-02-15 · 1 citations

  articleOpen access

  Abstract Background & Aims The increasing global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) including metabolic dysfunction-associated steatohepatitis (MASH) creates an urgent need for objective methods of histopathological assessment. Conventional histological approaches are time-consuming and rely on interpreter’s experience. Therefore, the results obtained may suffer from high variability and only offer coarse categorisation. In this study, we propose a fully automated, deep-learning-based pipeline for the segmentation and characterisation of histological liver features for MASH/MASLD assessment. Methods Segmentation was applied to H&E sections from 45 mice and 44 humans with MASH/MASLD. The method, which we named qHisto (quantitative histology), utilises the nnU-Net framework and quantifies key histological components of the MASH score, including macro- and microvesicular steatosis, fibrosis, inflammation, hepatocellular ballooning and glycogenated nuclei. Additionally, we characterized the tissue using novel features that are inaccessible through manual histology, such as the distribution of fat droplet sizes, aspect ratio of nuclei and heatmaps. Results qHisto parameters showed strong positive correlations with conventional histology scores (fat area R =0.91, inflammation density R =0.7, ballooning density R =0.49) and also with quantitative magnetic resonance imaging (fat area vs . hepatic fat fraction R =0.87). Our novel scores showed that deformation of nuclei is driven by large fat droplets rather than the overall amount of fat. Conclusions A key advantage of our method is spatially resolved, precise histological quantification. These features provide a finely resolved assessment of disease severity than conventional categorical scoring. By automating time-consuming and repetitive readouts, qHisto improves standardisation and reproducibility of MASH/MASLD feature quantification and provides scalable, slide-wide readouts that can support histopathologists and enhance clinical assessment and therapeutic development. Impact and Implications The proposed method provides an objective, automatic tool for comprehensive, histological liver analysis of MASH/MASLD, which can be extended to other diseases and organs. By offering classic and novel quantitative parameters and scores, our method could support histologists in their daily routines and provide researchers with further insight into steatotic liver diseases.

  PublisherOA PDFDOI

• Cholesterol-containing lipid crystals can directly stiffen the rat steatotic liver before fibrosis

  Proceedings of the National Academy of Sciences · 2026-01-07

  articleOpen accessSenior authorCorresponding

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by liver steatosis with cardiometabolic risk factors like dyslipidemia. Patients may progress from steatosis alone to complications such as fibrosis, end-stage liver disease, and hepatocellular carcinoma. The cause of progression is unclear. We previously showed that liver stiffening can drive fibrosis. However, the mechanical contributions of hepatic lipid and especially cholesterol accumulation are not known. We used rat dietary models to investigate how lipid accumulation affects liver mechanics. Liver stiffness was measured using rheology and magnetic resonance elastography, and associations between stiffness and lipid droplets (LDs) or cholesterol-containing lipid crystals were measured by microindentation-visualization. Polarized light, confocal reflection, and cryo-electron microscopy were employed to assess crystal abundance and structure. LDs and crystals extracted from livers were embedded in fibrous tissue mimics to isolate mechanical effects away from inflammation or fibrosis. Methyl-β-cyclodextrin perfusion was performed to assess whether cholesterol depletion reduced crystal abundance and tissue stiffness. Increased hepatic cholesterol storage led to the formation of cholesterol-containing lipid crystals in the liver. Steatotic livers with crystals stiffened before fibrosis while steatotic livers without crystals did not stiffen or fibrose. Lipid crystals stiffened tissue mimics while LDs did not, suggesting that crystals directly cause stiffening. Cholesterol depletion reduced crystal abundance and reverted tissue stiffness to near controls without changing inflammation, suggesting key roles for cholesterol in tissue stiffening. Lipid crystals cause profibrogenic liver stiffening, connecting high dietary cholesterol to MASLD progression, and may be a target for new diagnostic tools and therapeutics for progressive MASLD.

  PublisherOA PDFDOI

• Matrix Stiffness Governs Fibroblasts’ Regulation of Gingival Immune Homeostasis

  Advanced Materials · 2026-02-08

  articleOpen access

  Periodontal disease is characterized by inflamed gingival tissues and degradation of the gingival extracellular matrix (ECM), yet the role of mechanical cues remains poorly understood. Gingival ECM in periodontal disease showed reduced fibrillar collagen compared to healthy samples. We hypothesized that ECM softening in periodontal disease contributes to inflammation by dysregulating gingival fibroblasts (GFs). A mechanically tunable hydrogel model of the gingival ECM was developed to investigate the mechano-immune crosstalk. Stiff and soft collagen-alginate hydrogels matched the rheological properties of healthy and diseased gingival biopsies respectively. Human donor GFs encapsulated in these stiff hydrogels showed significantly suppressed toll-like receptor-mediated inflammatory responses compared to those in soft hydrogels. The non-canonical NFκB pathway and epigenetic nuclear organization directed stiffness-dependent inflammatory responses of GFs. The direct impact of mechanical cues on immune responses was investigated ex vivo by co-culture of donor-derived human GFs with myeloid cells and in human gingival explants. Myeloid progenitors co-cultured with GFs in stiff hydrogels differentiated into immunomodulatory dendritic cells. Ex vivo crosslinking of human gingival tissue increased stiffness and reduced the production of inflammatory cytokines. Gingival mechano-immune regulation offers a novel approach to biomaterial-based treatments for periodontitis.

  PublisherOA PDFDOI

• Understanding sub-cellular mechanochemical correlations of the neonatal extrahepatic bile duct extracellular matrix by atomic force microscope-Infrared spectroscopy

  Analytica Chimica Acta · 2026-01-31

  articleOpen access
  PublisherOA PDFDOI

• Data from: Matrix stiffness governs fibroblasts' regulation of gingival immune homeostasis

  DRYAD · 2026-02-12

  datasetOpen access

  Periodontal disease is characterized by inflamed gingival tissues and degradation of the gingival extracellular matrix (ECM), yet the role of mechanical cues remains poorly understood. Gingival ECM in periodontal disease showed reduced fibrillar collagen compared to healthy samples. We hypothesized that ECM softening in periodontal disease contributes to inflammation by dysregulating gingival fibroblasts (GFs). A mechanically tunable hydrogel model of the gingival ECM was developed to investigate the mechano-immune crosstalk. Stiff and soft collagen-alginate hydrogels matched the rheological properties of healthy and diseased gingival biopsies, respectively. Human donor GFs encapsulated in these stiff hydrogels showed significantly suppressed toll-like receptor-mediated inflammatory responses compared to those in soft hydrogels. The non-canonical NFκB pathway and epigenetic nuclear organization directed stiffness-dependent inflammatory responses of GFs. The direct impact of mechanical cues on immune responses was investigated ex vivo by co-culture of donor-derived human GFs with myeloid cells and in human gingival explants. Myeloid progenitors co-cultured with GFs in stiff hydrogels differentiated into immunomodulatory dendritic cells. Ex vivo crosslinking of human gingival tissue increased stiffness and reduced the production of inflammatory cytokines. Gingival mechano-immune regulation offers a novel approach to biomaterial-based treatments for periodontitis.

  PublisherDOI

• Reduction in Hepatic Phosphatidylcholine Biosynthesis Promotes MASH Through Copper Deficiency

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-14

  articleOpen access

  Abstract Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease for which the mechanisms linking lipid dysregulation to fibrosis remain poorly defined. Hepatic phosphatidylcholine (PC) content is reduced in MASH, but how this alteration drives disease progression is unclear. Here, we identify a role for copper (Cu) homeostasis as a downstream effector of impaired PC biosynthesis. Using single-nucleus RNA sequencing in complementary genetic and dietary mouse models, we found that reduced hepatic PC is associated with marked depletion of hepatic Cu and a concomitant increase in circulating Cu, indicating disrupted Cu distribution. Mechanistically, PC depletion impaired plasma membrane localization of the high-affinity Cu transporter CTR1 ( SLC31A1 ) in hepatocytes, limiting Cu uptake. In human hepatic stellate cells, Cu promoted fibrogenic activation, whereas suppression of Cu import or pharmacologic inhibition of MAPK signaling attenuated fibronectin deposition. In vivo , liver-directed Cu supplementation restored hepatic Cu levels and reduced steatosis but failed to improve fibrosis. In contrast, pharmacologic Cu chelation with bathocuproinedisulfonic acid (BCS) reduced fibrosis without affecting inflammation. Together, these findings identify Cu redistribution as a consequence of impaired PC biosynthesis and implicate Cu-dependent signaling in stellate cell activation, fibrogenesis and MASH pathogenesis. Graphical Abstract

  PublisherDOI

• Continuity of interstitial spaces within and outside the human lung

  Journal of Anatomy · 2025-05-29 · 3 citations

  articleOpen access

  There is a body-wide network of interstitial spaces that includes three components: a large-scale fascial network made up of fluid-filled spaces containing collagens and other extracellular matrix components like hyaluronic acid (HA), the peri-vascular/capillary interstitium, and intercellular interstitial spaces. Staining for HA within the colon, skin, and liver has demonstrated spatial continuity of the fascial interstitium across tissue layers and between organs, while continuity of HA staining between perineurial and adventitial sheathes beyond organ boundaries confirmed that they also participate in this body-wide network. We asked whether the pulmonary interstitium comprises a continuous organ-wide network that also connects to the body-wide interstitium via routes along nerves and the vasculature. We studied archival lung lobectomy specimens containing normal tissues inclusive of all lung anatomical units from six females and three males (mean age 53+/- 16.5 years). For comparison, we also studied normal mouse lung. Multiplex immunohistochemical cocktails were used to identify: (1) HA, CD34, and vimentin - highlighting interstitium; (2) HA, CD34, and podoplanin (D2-40) - highlighting relationships between the interstitium, vasculature, and lymphatics. Sizes of extracellular APP were measured. Tissues from nine patients (six females, three males, mean age 53+/- 16.5 years) were studied. HA staining was continuous throughout the five major anatomic compartments of the lung: alveolar walls, subpleural connective tissue, centrilobular peribronchovascular compartment, interlobular septal compartment, and axial peribronchovascular of the hilum, with similar findings in murine lung tissue. Continuity with interstitial spaces of the perineurium and adventitia was confirmed. The distribution of APP corresponded to known routes of lymphatic drainage, superficial and deep. APP within perineurium and perivascular adventitia further demonstrated continuity between intra- and extrapulmonary interstitium. To conclude, all segments of the lung interstitium are connected and are linked along nerves and the vascular tree to a body-wide communication network. These findings have significant implications for understanding lung physiology and pathobiology, suggesting routes of passage for inflammatory cells and mediators, malignant cells, and infectious agents. Interstitial spaces may be important in microbiome signaling within and beyond the lung and may be a component of the lung-brain axis.

  PublisherOA PDFDOI

• Congestion Enriches Intra-hepatic Macrophages Through Reverse Zonation of CXCL9 in Liver Sinusoidal Endothelial Cells

  Cellular and Molecular Gastroenterology and Hepatology · 2025-01-01 · 8 citations

  articleOpen access

  BACKGROUND & AIMS: Congestion alters the microenvironment of the liver sinusoid along the portal-central axis. We studied spatial changes in immune cells in the sinusoid that contribute to congestive fibrosis and portal hypertension (PHTN). METHODS: To visualize the distribution of immune cells in congestive hepatopathy (CH), we performed imaging mass cytometry (IMC) on liver tissue from patients with CH, Fontan-associated liver disease (FALD), and controls. We performed partial ligation of the inferior vena cava (pIVCL) to simulate CH in mice and isolated primary liver cells for single-cell RNA-sequencing (scRNA-seq) to study zonation of liver sinusoidal endothelial cells (LSECs). After pIVCL, mice were treated with intraperitoneal injections of AMG487, an inhibitor of the CXCL9 receptor, or a neutralizing antibody to CXCL9. RESULTS: Intra-hepatic macrophages are enriched in CH and FALD. Given the role of CXCL9 in macrophage patterning in the liver, we performed RNA in situ hybridization (RNAish) in CH and determined that CXCL9 was highly expressed in LSECs in FALD, suggesting that LSECs recruit macrophages in CH. After pIVCL, treatment with AMG487 or an antibody to CXCL9 attenuated portal pressures, fibrosis, and intra-hepatic macrophages. To study changes in LSECs that promote macrophage chemotaxis, we performed scRNA-seq after pIVCL and sham procedures. Analysis revealed 3 LSEC subpopulations according to sinusoidal location. RNAish identified peri-central LSECs as the predominant source of CXCL9 in FALD. In vitro analyses revealed that β-catenin and hypoxia inducible factor-1 α regulate CXCL9 transcription in peri-central LSECs. CONCLUSIONS: CXCL9 derived from peri-central LSECs enriches intra-hepatic macrophages in CH and FALD, contributing to congestive fibrosis and PHTN. Strategies to target LSEC-derived CXCL9 may prevent the progression of CH and FALD.

  PublisherDOI

• Evaluating hybrid teaching practices: a case study of staff and student experiences at City St George’s, University of London

  Cogent Education · 2025-01-10 · 2 citations

  articleOpen access

  This paper evaluates the hybrid teaching practices at City St. George’s, University of London through a unique study of the experiences of staff and students in using these spaces for learning. The university was an early adopter of hybrid teaching in UK higher education and implemented it at scale and continues to use and develop this practice. Our evaluation focuses on practical insights gathered from two mixed-methods surveys, which included both qualitative and quantitative questions, conducted over the academic year 2021-2022. Additionally, staff focus groups were held to further explore survey findings. Responses highlighted the benefits of inclusivity in the hybrid teaching approach, though it also revealed mixed engagement levels among online students. The study also uncovered various challenges and technical issues faced by staff and students, providing valuable insights for improving future hybrid teaching practices. As this was an early implementation of this practice in a planned way, this snapshot analysis provides a useful baseline for understanding how hybrid teaching and experience will continue to develop. These findings will inform strategic decisions related to engagement, pedagogy, technology, space design, and staff development, as well as support a community of practice with other educational institutions.

  PublisherDOI

• Protocol for fabricating a vascularized bile duct-on-a-chip

  Biophysics Reports · 2025-01-01 · 1 citations

  articleOpen access

  models for disease modeling and drug screening. Although the pathogenesis of cholestatic liver diseases like PSC remains unknown, the importance of the vascular-biliary interface is clear. Cholangiocyte injury not only impairs barrier function such that bile leaks and damages periductal tissue, but also activates cholangiocytes to secret pro-inflammatory and pro-fibrogenic mediators to stimulate immune cells and mesenchymal cells, ultimately causing damage to the liver. Here we describe a detailed protocol for fabricating a human vascularized bile duct-on-a-chip (VBDOC) that consists of a vascular channel, biliary channel, and neighboring mesenchymal cells in a collagen gel that models the vascular-biliary interface structurally and functionally in three dimensions. This device is notable in maintaining cholangiocyte polarity and barrier function, recapitulating physiological functions and responses of the large bile ducts, and enabling manipulation of components of the mechanical microenvironment such as matrix stiffness and shear flow in the lumens. This practical workflow could help researchers manufacture the VBDOC in their own labs and apply it to studies of various cholestatic liver diseases.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R56DK092111

  NIH · $448k · 2016

• Pathological consequences of altered tissue mechanics in fibrosis

  NIH · $6.3M · 2014–2026

• NIH Grant K01MH076175

  NIH · $816k · 2012

• Liver Cancer: pre-Malignant Stiffening, Membrane Transduction, & Nuclear Rheology

  NIH · $20.5M · 2015–2021

• NIH Grant R01DK065772

  NIH · $1.2M · 2009

Frequent coauthors

• Paul A. Janmey

  University of Pennsylvania

  59 shared

• Yu Du

  Fujian Agriculture and Forestry University

  43 shared

• Jessica Llewellyn

  University of Pennsylvania

  42 shared

• Matthias A. Hediger

  University Hospital of Bern

  42 shared

• Harvey F. Lodish

  Whitehead Institute for Biomedical Research

  39 shared

• Dongning Chen

  University of Pennsylvania

  37 shared

• Yoav I. Henis

  Tel Aviv University

  32 shared

• Orith Waisbourd‐Zinman

  Tel Aviv University

  29 shared

Labs

• Rebecca G. Wells LabPI