# IL10 Regulation of Fibroblast Progenitor Cell Mediated Cardiac Fibrosis

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $371,250

## Abstract

Abstract
Activated cardiac fibroblasts (myofibroblast; myoFBs) are crucial players in excessive fibrosis, which
ultimately results in myocardial stiffness and heart failure development. Thus, regulation of fibroblasts
activation and associated fibrosis would be a potential therapeutic strategy in the treatment of cardiac
diseases. Previous studies suggest that in addition to resident fibroblasts, bone marrow fibroblast
progenitor cells (FPCs) may home to the failing heart and contribute to excessive fibrosis. The overall goal
of this application is to determine the role of BM-derived FPCs and their paracrine signaling (via
exosomes) on pressure overload (PO)-induced cardiac fibrosis, and to determine whether inhibition of
function of this cell population results in the reduction of cardiac fibrosis and remodeling. We have
reported that PO-induced cardiac fibrosis is attenuated by systemic IL10 treatment and IL10-knockout
mice (IL10 KO) display exaggerated cardiac fibrosis. But the precise mechanism of anti-fibrotic role of IL10
is not well defined. Thus we hypothesized that “IL10 inhibits fibroblast progenitor cell (FPCs) homing and
trans-differentiation into myoFB and modifies FPC pro-fibrotic paracrine signaling thereby reducing cardiac
fibrosis and improving cardiac function”. We will use WT (some with GFP reporter system), IL10 KO,
TGFbr1/2 KO and CCR2KO (RFP reporter system) mice in this study. In SA1, via bone marrow
transplantation strategy, we will determine whether FPC contributes in Ang II-induced cardiac fibrosis in
WT and IL10 Knock out mice and whether IL10 treatment inhibits it. In specific aim 2 we will identify the
TGFb downstream signaling targets [both canonical (Smad2/3), non-canonical (ERK-MAP kinase) and
miR associated with fibrosis] and their roles in FPC's trans-differentiation. To identify their role, we will
infect/transfect dominant negative adenovirus or kinase-dead construct (Smad/ERK) or antagomir (miRs)
with their respective control in WT and IL10KO FPCs. In specific aim 3 we propose to study the paracrine
regulation of FPCs on resident cardiac fibroblast activation and exaggerated fibrosis in IL10KO mice. In
this aim we will explore whether pro-fibrotic factors secreted by FPC (WT/IL10KO) via exosomes, induce
cardiac fibroblast transition to myoFB. To translate this finding in preclinical settings, in specific aim 3 we
will investigate whether transplantation of exosomes-derived from ex vivo-modified FPC (for target
miRs/proteins) in IL10 KO mice heart inhibits Ang II-induced fibrosis. The significance of this study is to
identify the novel mechanism(s) of IL10 in regulation of cardiac fibrosis. Our proposed experiments can
potentially identify novel therapeutic strategies for cardiac repair based on manipulation of bone marrow
fibroblast progenitor cells signaling after pressure overload-induced cardiac injury.

## Key facts

- **NIH application ID:** 9949432
- **Project number:** 5R01HL135060-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Suresh K Verma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949432

## Citation

> US National Institutes of Health, RePORTER application 9949432, IL10 Regulation of Fibroblast Progenitor Cell Mediated Cardiac Fibrosis (5R01HL135060-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9949432. Licensed CC0.

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