# The function of Runx1 in cardiac fibroblasts and post-myocardial infarction healing

> **NIH NIH R01** · LOUISIANA STATE UNIV AGRICULTURAL CENTER · 2024 · $404,351

## Abstract

Project Summary
 Myocardial infarction (MI) induces the massive death of cardiomyocytes. Quiescent cardiac fibroblasts
(CFs) are rapidly activated after MI. They proliferate and differentiate into cardiac myofibroblasts (CMFs),
mediating cardiac fibrosis. We recently found that in more stabilized infarct scar CMFs further differentiate into
matrifibrocytes, a state resembling partially differentiated chondrocytes, which indicated an advanced level of
fibrosis. The post-MI fibrotic response in the heart stabilizes the infarcted myocardium, which may prevent
cardiac rupture but also reduce ventricle wall compliance and conductivity, and even interfere with regeneration
efforts. Understanding the mechanisms regulating post-injury CF activities will help the development of treatment
strategies that enhance the beneficial effect of CFs and inhibit their deleterious effects. We found that in response
to MI the expression of runt-related transcription factor 1 (Runx1) in CFs increased significantly during both
myofibroblast and matrifibrocyte differentiation. Our preliminary study showed that Runx1 promoted CF
proliferation and inhibited their differentiation into myofibroblasts in vitro. In addition, we identified Ccn2 as a
potential target of Runx1. Ccn2 plays multiple roles in the regulation of cell proliferation and differentiation
through interacting with different cofactors. Thus, we hypothesize that Runx1 functions to balance the
proliferation and myofibroblast differentiation of CFs during the acute phase of MI and promote matrifibrocyte
differentiation in more stabilized infarct scars through direct targeting Ccn2, which is critical for maintaining tissue
integrity but also promotes adverse remodeling. In Aim #1, CF-specific tamoxifen-inducible Runx1 knockout (KO)
mice and wild type mice will be subjected to MI injury. Immunohistochemical staining, RNA-seq, and functional
assay will be employed to study the function of Runx1 in the proliferation, myofibroblast differentiation, and
matrifibrocyte differentiation of CFs after MI. In Aim #2, the mechanism through which Runx1 regulates the
expression of Ccn2 will be studied using CUT&RUN, ATAC-seq, Hi-C, and co-IP coupled to mass spectrometry.
The unbiased approach will also identify other direct and indirect targets of Runx1. In Aim #3, CF-specific
tamoxifen-inducible Ccn2 KO mice will be employed to compare the effect of Ccn2 KO and Runx1 KO on CF
proliferation and differentiation after MI. The requirement of Ccn2 in the regulation of CF proliferation and
differentiation by Runx1 will also be studied. The synergistic effect between Ccn2 and its cofactors, HB-EGF and
TGFβ3, on cardiac fibroblast proliferation and differentiation will be studied as well.

## Key facts

- **NIH application ID:** 10742905
- **Project number:** 5R01HL157519-03
- **Recipient organization:** LOUISIANA STATE UNIV AGRICULTURAL CENTER
- **Principal Investigator:** Xing Fu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $404,351
- **Award type:** 5
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10742905

## Citation

> US National Institutes of Health, RePORTER application 10742905, The function of Runx1 in cardiac fibroblasts and post-myocardial infarction healing (5R01HL157519-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10742905. Licensed CC0.

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