# Functional and Mechanistic Analysis of Mesenchymal Stem Cell Secretome to Ameliorate Ischemic Damage of Porcine Heart ex vivo and Human Myocardium

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Heart transplantation is a key life-saving therapy for patients with end-stage heart failure. However, donor
hearts are in severely short supply, resulting in death of many transplantation candidates before a suitable donor
heart becomes available. Despite this, approximately 70% of cardiac allografts were rejected for transplantation
during 2019-2021; the majority do not meet acceptance criteria, including the limited acceptable time that the
heart experiences warm ischemia, which is longer with donation after circulatory death (DCD) compared to
donation after brain death, the traditional method. This time correlates with progression of myocardial
ischemia/reperfusion (I/R) injury. Ameliorating I/R injury, that occurs both during heart procurement and
transport, would improve preservation of graft function, expand the donor pool and increase access to heart
transplantation. Human adipose-derived stromal cells (hASC) are abundant, simple to isolate and expand rapidly
in vitro, and produce paracrine factors that improve many pathologies, including ischemia/reperfusion injury. In
the context of myocardial infarction, they improve myocardial function, inhibit apoptosis, and stimulate
angiogenesis. Pre-treatment of explanted hearts with hASC improves myocardial functional recovery following
acute I/R injury in an ex-vivo heart perfusion system. Similarly, pre-ischemic infusion of ASC-derived factors
(secretome, ASC-S) improved myocardial function during recovery from cold ischemia, and almost completely
preserved normal expression of myocardial genes governing mitochondrial processes. A media supplement,
B27, with many similarities to hASC-S, ameliorated mitochondrial metabolic problems associated with cold
ischemic exposure of both rodent hearts and human iPS-derived cardiomyocytes (hiPS-CM). Finally, both hASC-
S and B27 enhanced recovery of beating rate and velocity in hiPS-CM after DCD-like ischemia/reperfusion.
 Accordingly, the hypothesis that hASC-secretome will ameliorate warm ischemia/reperfusion-induced
deterioration of adult human and pig heart slice cultures in vitro, and model donor hearts ex vivo, by
mechanisms mediated by soluble factors as well as exosomes, which limit damage to cardiomyocytes
by preserving mitochondrial energetics and mitigating reactive oxygen species production and
apoptosis will be tested. To do that, three specific aims will be employed:
 Aim 1. Evaluate the protective effect of ASC-S on pig and human adult heart slices in long-term
culture in conditions modeling procurement and transport conditions of DCD hearts, and whether this
is best mediated by secretome, its components or B27. Slices of adult human or pig hearts exposed to warm
ischemia in vitro in the context of cardiac procurement will be incubated with either ASC-S, or ASC-S derived
exosomes, the exosome-free fraction or B27. Time and dose-dependent effects of treatments will be evaluated
on apoptosis, infarct area, beat recovery and markers of cell dam...

## Key facts

- **NIH application ID:** 10703841
- **Project number:** 2I01BX003888-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** KEITH LEONARD MARCH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2017-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10703841

## Citation

> US National Institutes of Health, RePORTER application 10703841, Functional and Mechanistic Analysis of Mesenchymal Stem Cell Secretome to Ameliorate Ischemic Damage of Porcine Heart ex vivo and Human Myocardium (2I01BX003888-07). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10703841. Licensed CC0.

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