# Combating Chronic Liver Diseases via Understanding and Engineering Cell Competition and Fitness

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $683,339

## Abstract

Summary:
Cell competition removes mutated cells and enables robust tissue development, eliminates oncogenic cells
in adulthood, as well as damaged cells during aging. We identified activin A as an important player during
cell competition, which we uncovered to be a major actor in liver repopulation by transplanted cells. We
showed that activin A is produced by hepatocytes and increased in aging liver. Highly proliferative fetal liver
stem/progenitor cells exhibit reduced activin receptor expression, are resistant to activin A, and therefore
have a growth advantage compared to mature hepatocytes. As a result, transplanted fetal liver cells are
capable to repopulate normal liver. In livers with advanced fibrosis, fetal liver cells differentiate into
functional hepatic cells, effectively replace injured liver, and exhibit anti-fibrotic effects. Although fetal liver
cells exhibit the capability to repopulate the liver, they will likely not be used for human cell transplantation.
Thus, we hypothesize that modulating hepatocytes or induced pluripotent stem cell-derived tissues to
express crucial features of fetal liver cells will generate ‘winners’ capable of effectively restoring liver tissue
mass. Generating a cell source with growth-advantage that is adapted to an injured microenvironment will
allow us to elucidate the mechanism of cell competition, which can be of invaluable therapeutic benefit.
Here we first uncover the mechanism of cell competition in liver, using our rat cell transplantation model and
modulated hepatocytes. Second, we will investigate the liver repair efficacy of competing human
hepatocytes – induced by blocking specifically activin A-signaling, using a small-molecule-based highly
specific activin A antagonist – in diseased liver. Finally, we will use our recently developed human fetal liver
organoids from induced pluripotent stem cells to produce liver progenitor cells with competitive advantage to
repopulate liver in vivo. Our studies will pave the path towards novel approaches for therapeutic cell
transplantation in liver and application for a diverse set of liver diseases in human population.

## Key facts

- **NIH application ID:** 10942133
- **Project number:** 1R01DK140405-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Mo Reza Ebrahimkhani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,339
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942133

## Citation

> US National Institutes of Health, RePORTER application 10942133, Combating Chronic Liver Diseases via Understanding and Engineering Cell Competition and Fitness (1R01DK140405-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10942133. Licensed CC0.

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