# A Model for Human Liver Fibrosis

> **NIH NIH R56** · STANFORD UNIVERSITY · 2022 · $772,327

## Abstract

Abstract
Liver fibrosis is a pathological condition that results from extracellular matrix (ECM) accumulation in response to
chronic liver injury and is a major global cause of death in adults (~1M per year) due to inadequate therapeutic
options. To address this limitation, we have developed human hepatic organoid models that enable hypothesis-
driven, mechanistic evaluation of novel drug candidates for treatment of liver fibrosis. One model is produced by
engineering iPSC to express a common causative mutation for Autosomal Recessive Polycystic Kidney Disease
(ARPKD). ARPKD organoids develop the key hallmarks of hepatic fibrosis: they accumulate thick collagen fibers;
and have a marked increase in collagen-producing myofibroblasts whose transcriptomic profile is like those
present in liver tissues obtained from patients with commonly occurring (acquired) forms of liver fibrosis (viral-
induced cirrhosis and advanced non-alcoholic steatohepatitis, NASH). We also developed a NASH organoid
fibrosis model; along with two live cell imaging methods for monitoring for the appearance of collagen fibers and
collagen producing cells. We hypothesize that since the fibrosis that develops in this human, multi-lineage,
hepatic organoid resembles that in patients with congenital and acquired forms of liver fibrosis, it can be used to
advance liver fibrosis research and to discover and characterize anti-fibrotic therapies. In Aim 1, ARPKD and
NASH organoids are used to develop a novel platform for assessing the anti-fibrotic efficacy of 10 agents whose
mechanism of action is relevant to liver fibrosis, and to identify drug combinations with increased anti-fibrotic
efficacy. Since nine are FDA-approved drugs, but none are currently used to treat liver fibrosis, these studies
could have significant translational importance. In Aim 2, these models evaluate the fibrogenic effect of ECM
cues using a novel, fully chemically defined, biosynthetic matrix. ECM changes are widely thought to promote
fibrotic remodeling. A novel, synthetic chemistry scheme enables tuning of the key mechanical (stiffness,
viscoelasticity) and biochemical (cell-adhesive ligand identity) matrix properties. ARPKD and NASH organoids
grown in synthetic matrices will enable us to examine the effects that matrix cues have on fibrosis, and this
analysis includes single cell RNA sequencing (scRNA-Seq). In Aim 3, to identify common pathogenetic drivers
that are shared among congenital and acquired forms of liver fibrosis, we extend our modeling approach to
generate and characterize organoid models for Joubert Syndrome Related Disorder (JSRD), which is a multi-
system genetic disease that causes liver fibrosis in some cases, and we characterize a unique NASH organoid
model. JSRD liver disease cannot be modeled in animals. JSRD and NASH organoids and isogenic controls will
be analyzed using scRNA-Seq, high-dimensional time of flight mass cytometry (CyTOF) and two semi-targeted
metabolomic methods. JSRD...

## Key facts

- **NIH application ID:** 10685178
- **Project number:** 1R56DK129309-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** GARY A PELTZ
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $772,327
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10685178

## Citation

> US National Institutes of Health, RePORTER application 10685178, A Model for Human Liver Fibrosis (1R56DK129309-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10685178. Licensed CC0.

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