# Role of Sca-1+Cardiac Fibroblasts in Inflammatory Heart Disease`

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $409,375

## Abstract

Myocarditis is a rare but potentially devastating inflammatory heart disease characterized by myocardial
inflammation. Up to 30% of myocarditis patients go on to develop dilated cardiomyopathy (DCM), which is a
major cause of heart failure in children and young adults. The proposed project, when completed, will significantly
improve the understanding of the immunologic phenomenon leading to myocardial remodeling, fibrosis and heart
failure. The time window between the inflammatory phase and development of DCM and heart failure is variable,
but usually broad enough to allow secondary preventive treatment if specific targets are found. That knowledge
might lead to development of novel diagnostic approaches and targeted treatment to prevent dilated
cardiomyopathy. Furthermore, according to our preliminary data, those phenomena might be common to other
heart inflammatory diseases like myocardial infarction. We have discovered a novel pathway leading to DCM
development in experimental autoimmune myocarditis (EAM) mouse model. IL-17A signaling induces myeloid
cytokines, such as Granulocyte macrophage colony-stimulating factor (GM-CSF), and CCL2 (MCP1) expression
from cardiac fibroblasts (CF). GM-CSF then promotes differentiation of cardiac infiltrating monocytes toward
Ly6Chi inflammatory monocytes, which promote DCM. The novelty of our approach is the focus on the immune
modulatory role of cardiac fibroblasts. We propose that CD45−CD31−CD29+PDGFRα+Sca-1+ CF subset (Sca-1+
CFs) is the main producer of myeloid cytokines in EAM, Coxsackievirus B3-induced viral myocarditis, and
myocardial infarction mouse models. Moreover, Sca1+CFs are plastic and able to switch their cytokine profiles
based on microenvironments. Furthermore, we detected the same population of CFs expressing GM-CSF in
frozen endomyocardial biopsy samples from patients with chronic ischemic cardiomyopathy. Our overall
hypothesis is that Sca-1+ cardiac fibroblasts contribute to the disease progression from myocarditis to
dilated cardiomyopathy through IL-17A-induced GM-CSF production. First, in Aim 1, we will evaluate
whether the specific deletion of IL-17RA on Sca-1+ CFs will protect the mice from DCM. Next, we will block the
GM-CSF production in Sca-1+ CFs by Adenoviral-associated vector (AAV)-delivered shRNA, targeting GM-CSF
under Sca-1+ CF specific promoter. In Aim 2, we will investigate the plasticity of Sca-1+ CF cytokine profile using
CCL2-expressing (mCherry+) cells to trace the cytokine production of the same cell following the Th
microenvironment change. Next, we will determine the necessity of NF-κB/NFAT signaling pathway in IL-17A-
driven DCM through specific ablation of p65 in Sca-1+ CFs. Finally, in Aim 3, we will examine the human cardiac
fibroblasts plasticity and signaling pathways involved in GM-CSF production using human primary cardiac
fibroblasts and frozen endomyocardial biopsy samples from myocarditis and cardiomyopathy patients.

## Key facts

- **NIH application ID:** 10070636
- **Project number:** 5R01HL136586-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Daniela Cihakova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2017-12-09 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070636

## Citation

> US National Institutes of Health, RePORTER application 10070636, Role of Sca-1+Cardiac Fibroblasts in Inflammatory Heart Disease` (5R01HL136586-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10070636. Licensed CC0.

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