# Synergistic effects of ECM and heterotypic crosstalk on cellular responses in non-alcoholic fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $559,114

## Abstract

ABSTRACT / PROJECT SUMMARY
Non-alcoholic steatohepatitis (NASH) represents a rapidly growing epidemic of liver disease that can predispose
affected individuals to advanced fibrosis and hepatocellular carcinoma. Strategies for targeting cellular mediators
of liver fibrosis, such as activated hepatic stellate cells (HSCs), remain limited due to an incomplete
understanding of the mechanisms governing myofibroblastic differentiation and the signaling between liver
parenchymal and non-parenchymal cell (NPC) types. The importance of microenvironmental signal crosstalk,
including interactions between extracellular matrix (ECM) protein composition and mechanical stiffness in cell
phenotypic alterations, is increasingly appreciated. Although animal models have provided insights into NASH,
significant differences across species in drug metabolism and disease pathways exist. Thus, there is a need for
human-relevant in vitro approaches that enable the investigation of hepatocellular phenotypes within
physiological and NASH-like microenvironments and could facilitate the high-throughput discovery of novel
therapeutics. The goal of this project is to implement engineered culture platforms for selectively modulating
microenvironmental signals and utilize these systems to reveal key phenotypic programming pathways and
interaction mechanisms within the context of a NASH-like microenvironment. Our approach will enable
hypothesis-driven studies incorporating controlled perturbations of extracellular signals. In Aim 1, we will
investigate the microenvironmental regulation of myofibroblastic phenotype. Utilizing defined ECM compositions
and mechanical stiffness regimes in engineered cultures, we will examine the role of epigenetic gene regulatory
mechanisms and test the hypothesis that combinatorial microenvironmental cues regulate epigenetic changes
that are critical for the myofibroblastic programming of human hepatic stellate cells within the context of normal
and NASH-like soluble triggers. In Aim 2, we will examine the influence of ECM composition and stiffness on
Kupffer cell (KC) and primary human hepatocyte (PHH) functions including reciprocal intercellular interactions
and cooperative effects of NASH-like soluble stimuli. Our approach will facilitate modular control and
deconvolution of the effects of ECM composition, substrate stiffness, and soluble signals. In Aim 3, we will
develop and implement multicellular 3D liver microtissues for the systematic analysis of multicellular phenotype
regulation in the context of disease-like ECM alterations. We will investigate heterotypic cellular crosstalk
mechanisms between non-parenchymal cell types (HSC, KC, and liver sinusoidal endothelial cells), and their
collective influence on primary human hepatocyte functions. We will further establish capabilities for assessing
NASH-relevant therapeutics within the multicellular liver platform. The proposed studies will provide a)
fundamental insights into the microenvironme...

## Key facts

- **NIH application ID:** 10872177
- **Project number:** 5R01DK115747-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Salman R Khetani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,114
- **Award type:** 5
- **Project period:** 2018-02-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872177

## Citation

> US National Institutes of Health, RePORTER application 10872177, Synergistic effects of ECM and heterotypic crosstalk on cellular responses in non-alcoholic fatty liver disease (5R01DK115747-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10872177. Licensed CC0.

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