# Therapeutic Mechanisms of Cardiac Progenitors in Ischemic Cardiomyopathy

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $840,689

## Abstract

Ischemic heart disease is a leading cause of death worldwide. Given the limited regenerative capacity of the
human heart following myocardial injury, stem cell-based therapies, including the recent cKit+ cell therapy have
emerged as a promising approach for improving cardiac repair and function. Clinical and preclinical data
suggests that benefits of cKit+ cell transplantation include improved cardiac function and myocardial mass.
However, the ability of cKit+ CPCs to differentiate into cardiomyocytes as a significant mode of cardiac repair is
controversial. Published data from our group has established the beneficial effects of stem cell factor (SCF), the
ligand for cKit, in improving the abundance of cKit+ cells, angiogenesis and cardiac function in both rat and pig
models of ischemic cardiomyopathy. Further, our preliminary data suggest that secreted paracrine factors,
particularly the membrane-bound exosomes, may mediate most of the pro-angiogenic paracrine activity of the
SCF-treated cKit+ cell. Our central hypothesis is that mobilization of a heterogeneous group of
endogenous CPCs using gene transfer for the receptor tyrosine cKit ligand stem cell factor (SCF) can
enhance cardiac tissue repair following myocardial injury via their paracrine secretion.
We will test the necessary and sufficient conditions of SCF-induced CPC recruitment using the MI model
of heart failure in swine to evaluate the roles of SCF-induced cKit, PW1 and PDGFR expressing CPCs in
myocardial repair, regeneration and restoration of function. We will test the hypothesis that cKit, PW1 and
PDGFR progenitor cells are sufficient for SCF induced cardiac repair by gain of function experiments using
SCF modRNA. We will test the hypothesis that cKit, PW1 and PDGFR progenitor cells are necessary for
cardiac repair by loss of function experiments using shRNA-mediated knockdown of cKit, PDGFR and PW1
receptors. RNAs will be delivered one-week post-MI by the clinically relevant intracoronary route and animals
will be evaluated for survival, cardiac remodeling, cardiac function, cell-specific proliferation and differentiation
and the molecular mechanisms involved.
We will determine the role of paracrine secretion from cKit+ CPCs in SCF-induced cardiac repair. Our
preliminary data suggest that exosomes, and not the exosomes-depleted fraction from swine post-MI cKit-
secretome have pro-angiogenic activity. Using specific expertise for exosomes research, we will identify the
miRNA expression of cKit+ exosomes in response to SCF. In addition, we will investigate the functional
mechanisms of cKit+ exosomes-induced proliferation and contractile function of cardiomyocytes and
angiogenesis of endothelial cells in vitro. Finally, we will determine the therapeutic benefits of cKit exosomes in
a swine model of heart failure.

## Key facts

- **NIH application ID:** 9846015
- **Project number:** 5R01HL135093-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Kenneth Michael Fish
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $840,689
- **Award type:** 5
- **Project period:** 2017-01-20 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846015

## Citation

> US National Institutes of Health, RePORTER application 9846015, Therapeutic Mechanisms of Cardiac Progenitors in Ischemic Cardiomyopathy (5R01HL135093-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9846015. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*