# In Vitro Liver Models to Investigate the Progression of Liver Fibrosis

> **NIH NIH P20** · UNIVERSITY OF NEBRASKA LINCOLN · 2020 · $99,775

## Abstract

ABSTRACT 
Liver fibrosis, which results from chronic liver damage in conjunction with the accumulation of extracellular 
matrix (ECM) proteins, is characteristic of several chronic liver diseases. Dynamic changes to the liver 
microenvironment (LME) are widely recognized as a critical participant in liver fibrosis progression and 
therapeutic responses. LME components, including interactions between parenchymal (hepatocytes) and non- 
parenchymal cells (liver sinusoidal endothelial cells [LSECs], hepatic stellate cells, kupffer cells), signaling 
molecules (ligands-collagen, laminin), and mechanical cues from ECM, have been implicated in the 
progression of liver fibrosis. Stellate cells activation is the hallmark of liver fibrosis; however, the effect on 
hepatocytes and LSECs function has not been extensively understood. Also, the mechanisms by which the 
LME components regulate liver function and various signaling cascades are poorly understood, thus limiting 
the development of optimal diagnosis and treatment regimes for liver diseases (e.g., alcoholic liver disease, 
nonalcoholic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C). Therefore, there is a 
critical need to develop in vitro models that simulate the dynamic LME components and effectively study their 
role in liver fibrosis. To study the direct effects of LME on cell signaling, it is imperative to use in vitro liver 
models to simulate the fundamental complexity and dynamism of liver fibrosis and to achieve greater 
translational validity. The goal of this application is to use a multidisciplinary approach to develop three 
independent in vitro liver models to study how different LME components (hepatocytes-LSEC interactions, 
ECM stiffness, ligand type and density) regulate hepatocyte and LSEC function and what role these LME 
components play in the progression of liver fibrosis. The specific aims of the proposed study are to: 1) 
investigate the effect of hepatocytes-LSEC interaction(s) on hepatic function, 2) investigate how variation in 
stiffness alters hepatic cell function, and 3) determine the role of ligand type/density in regulating liver cell 
function. This work will provide a significant advancement in the ability to utilize in vitro liver models to 
accurately describe the liver function and metabolism in normal versus diseased states, and especially how the 
LME regulate the development and maintenance of liver function. Importantly, this model is innovative as it 
will chronologically emulate the fibrosis stage, is similar to clinical conditions, and boasts an environment that 
is more controlled and systematic than animal models. This project is expected to have a progressive impact 
on the study of liver fibrosis and related fields because the availability of a liver model that retains LME will 
facilitate understanding of the molecular mechanisms that underlie LME activities in mechanisms critical for the 
maintenance of liver biology.

## Key facts

- **NIH application ID:** 10016367
- **Project number:** 5P20GM113126-05
- **Recipient organization:** UNIVERSITY OF NEBRASKA LINCOLN
- **Principal Investigator:** Srivatsan Kidambi
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $99,775
- **Award type:** 5
- **Project period:** 2016-08-15 → 2021-09-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016367

## Citation

> US National Institutes of Health, RePORTER application 10016367, In Vitro Liver Models to Investigate the Progression of Liver Fibrosis (5P20GM113126-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10016367. Licensed CC0.

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