# Ex-vivo bioengineered technology to unravel dysfunction due to non-alcoholic steatohepatitis (NASH)

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $659,671

## Abstract

SUMMARY
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver function tests in the US
and its progressive form, termed non-alcoholic steatohepatitis (NASH), will soon be the leading indication for
liver transplantation. There are currently no effective medications to treat NASH, no biomarkers to determine
disease progression or risk of post-transplant recurrence and no effective platforms for high-throughput drug
screening. Although NASH is related to obesity and diabetes, the pathogenic factors that cause disease
progression to NASH/Cirrhosis are poorly understood. Compared to an invasive liver biopsy, peripheral blood
mononuclear cells (PBMCs) can be easily obtained from patients with NASH and end-stage NASH/Cirrhosis
patients requiring liver transplantation and re-programmed into induced pluripotent stem cells (iPSCs). These
iPSCs may then be differentiated into iPSC-hepatocytes, which are human liver-like cells that can be cultured in
ex vivo bioengineered systems tailored to normal and cirrhotic liver stiffness, enabling an investigation that is
independent of the compounding metabolic and environmental factors that complicate analysis within human or
animal systems. In this proposal, we will utilize an iPSC-hepatocyte platform to determine the effects of
extracellular matrix (ECM) stiffness and unfolded protein response (UPR) cell signaling on hepatic lipid
metabolism. We will initially unwind the impact and interplay between matrix stiffness and patient-specific
propensity for NASH in patient-derived iPSCs and analyze the impact on lipid metabolism and lipidomics (Aim
1). ER stress and the unfolded protein response (UPR) has been shown to be important in the pathogenesis of
NASH. Thus, we will use iPSC-hepatocytes to develop a platform for determining the interaction between UPR
signaling and lipid metabolism relevant to NASH (Aim 2). iPSC-hepatocytes will be treated with ER stress
reducing compounds including the chemical chaperone tauroursodeoxycholic acid (TUDC) or FXR/bile acid
agonists, and the effects on cell differentiation, gene expression and lipid metabolism will investigated. Finally,
iPSC-hepatocytes will be used to study the cell signaling and pathogenic mechanisms of NASH in iPSCs from
patients with rapidly progressive NASH/Cirrhosis that require liver transplantation. We will develop an iPSC-
hepatocyte platform identifying matrix and UPR factors responsible for NASH using iPSC-hepatocytes from
NASH/Cirrhosis patients listed for liver transplantation (Aim 3). This MPI proposal leverages the collaboration
between three PIs at two institutions with extensive experience investigating 1) iPSCs, bioengineering matrices,
ECM biology, and transplant surgery, 2) hepatic lipid metabolism, cell signaling and transplant hepatology, and
3) lipidomics and metabolomics. The development and optimization of these iPSC-hepatocyte platforms will have
important implications for determining the pathophysiology of...

## Key facts

- **NIH application ID:** 10862734
- **Project number:** 5R01DK132873-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Richard M Green
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $659,671
- **Award type:** 5
- **Project period:** 2023-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862734

## Citation

> US National Institutes of Health, RePORTER application 10862734, Ex-vivo bioengineered technology to unravel dysfunction due to non-alcoholic steatohepatitis (NASH) (5R01DK132873-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862734. Licensed CC0.

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