# Cardioprotective mechanisms of cell therapy for myocardial infarction

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $437,500

## Abstract

PROJECT SUMMARY/ABSTRACT
Novel approaches to reduce infarct size (IS) have stalled in translation. A major obstacle is the fact that the
clinical care paradigm for acute myocardial infarction (AMI) has one dominant objective: to open the infarct-
related artery as quickly as possible. Only after flow is restored might the treating physician take time to think
about adjunctive therapies, but by then the window of opportunity to recruit classical cardioprotection has most
likely closed, or at least narrowed significantly. Here we characterize the novel phenomenon of cellular
postconditioning: cell therapy delivered 30 min post-reperfusion (or even longer; defining the precise timing is
an aim of this R01) can reduce the extent of lethal injury and improve functional recovery. The timing is
compatible with standard clinical practice in that the decision to treat can be delayed until after the artery has
been opened, if an off-the-shelf product is available. Allogeneic cardiosphere-derived cells (CDCs) are available
for immediate use and are currently in phase 2 clinical testing for chronic MI. Here we show preliminary data,
from both rats and pigs, that CDCs and their exosomes are cardioprotective when given with a reasonable delay
after reflow in AMI. We looked at 48 hr structural and functional endpoints to ensure a focus on acute
cardioprotection; otherwise it is impossible to exclude some contribution from longer-term regenerative effects
of CDCs, which are evident only weeks after treatment. In pigs subjected to 90 mins of ischemia and 30 mins of
reflow, the intracoronary infusion of CDCs decreased IS and also reduced the extent of microvascular
obstruction. In rats we see large decreases of IS when CDCs are administered 20 mins after a 45 min ischemic
episode, a finding now independently confirmed by a major unaffiliated laboratory. We further show preliminary
data that implicate macrophages as key players in the mechanism of cardioprotection. The major focus here is
on defining the mechanisms whereby CDCs reduce IS. We test the following overarching hypothesis: CDCs
secrete exosomes which modify macrophages so as to enhance efferocytosis. Precisely how macrophages are
modulated by CDCs (are RNAs transferred by exosomes involved?), and how macrophages mitigate lethal
injury, are major questions addressed here. Although we focus on the cardioprotective effects of CDCs, we
expect these to synergize with the regenerative effects, augmenting overall benefit. Two well-established animal
models will be subjected to AMI: rats for mechanistic studies, and Yucatan minipigs for translational studies. The
role of efferocytosis will be probed both by novel in vitro co-culture assays of macrophages, neutrophils, and
stressed cardiomyocytes, as well as by in vivo experiments in transgenic rats to quantify efferocytosis. The work
has the potential to elucidate the cardioprotective mechanisms of cell therapy.

## Key facts

- **NIH application ID:** 9906252
- **Project number:** 5R01HL133835-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** EDUARDO MARBAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,500
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906252

## Citation

> US National Institutes of Health, RePORTER application 9906252, Cardioprotective mechanisms of cell therapy for myocardial infarction (5R01HL133835-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9906252. Licensed CC0.

---

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