# Protective and fibrosis-independent functions of hepatic stellate cells

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $499,972

## Abstract

Hepatic stellate cells (HSC) are well-characterized as key fibrogenic cell type of the liver, contributing to the
development of liver fibrosis in a wide range of diseases. While it widely believed that the development of
pathological liver fibrosis is the result of “maladaptive” or overshooting HSC activation, the field also believes
that “physiological” HSC activation serve provides benefits in acute and/or chronic liver disease. However, there
is currently no understanding of what precisely the benefits of HSC activation constitute and whether there may
be “costs” at which these benefits come in addition to the negative long-term effects of prolonged fibrosis.
Purported functions of HSC activation include the mechanical stabilization of injured tissue and promotion of
hepatocyte survival by HSC-secreted collagen. However, these protective functions have not been
experimentally validated in vivo, and to date, it is not known which hepatic functions, injury responses and cell
types are affected by HSC. Moreover, there is little understanding on the role of HSC in homeostasis beyond the
fact that they store a large amount of the body’s retinyl esters. These fundamental gap are mostly due to the
field’s focus on pathogenic HSC activation and fibrosis as key determinant of outcomes; and the lack of tools to
study protective functions of HSC and HSC-derived mediators in vivo. Related to the field’s focus on pathogenic
fibrosis, HSC are commonly viewed as final and most downstream executors, which respond to signals from
injured hepatocytes and/or activated macrophages and thus represent the last step of an injury cascade.
However, this view ignores the fact that their anatomical position and prototypical protrusions endeavors HSC
with close connection to almost all hepatic cell types, pointing towards HSC as a potential hub in the liver’s
cellular network. We have generated several tools including HSC depletion, HSC-selective gene deletion, and
single cell RNA-sequencing based bioinformatics allowing us to determine the role of HSC in vivo and the efferent
signals through which HSC may orchestrate cell-cell communication in the homeostatic and injured state. These
tools have enabled us to generate a preliminary data supporting a key role for HSC in modulating hepatocyte
proliferation and injury, and will enable us to uncover protective and fibrosis-independent functions of HSC in
vivo. In Aim 1, we seek to test the contribution of HSC-hepatocyte crosstalk to liver regeneration (Aim 1),
focusing on responsible mechanisms and mediators and the hypothesis that HSC and hepatocytes form a
functional unit. In Aim 2, we will study the role of HSC as regulators of hepatocyte death, focusing on underlying
mediators and mechanisms and our hypothesis that HSC can both promote and protect from injury. Besides
providing better understanding novel HSC functions in the complex cellular crosstalk of the liver, our studies may
(i) reveal therapeutically targetable p...

## Key facts

- **NIH application ID:** 10813007
- **Project number:** 5R01DK128955-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert F. Schwabe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $499,972
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10813007

## Citation

> US National Institutes of Health, RePORTER application 10813007, Protective and fibrosis-independent functions of hepatic stellate cells (5R01DK128955-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10813007. Licensed CC0.

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