# Functional and Mechanistic Analysis of Mesenchymal Stem Cell Secretome to Ameliorate Ischemic Damage of Rodent Hearts in situ and Human Myocardium-on-a-Chip

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Use of heart transplantation is limited by severe shortage in donor organ supply, resulting in death of many
heart transplantation candidates before a suitable donor heart becomes available.1, 2 In addition to the scarcity
of total donor hearts, national transplant data collected by the Association of Organ Procurement Organizations
indicates that nationwide approximately 70% of cardiac allografts were rejected for transplantation during
2009–2011. The majority of these hearts were discarded due to stringent acceptance criteria, one of which is
the limited acceptable time between procurement and transplantation. This time correlates with progression of
myocardial ischemia/reperfusion (I/R) injury, and constrains the acceptable geographic distance between the
sites of donor heart explantation and transplantation. Overall, there is an urgent need to develop effective
approaches to increase transplantable grafts by improving the numbers of organs which will fulfill acceptance
criteria. Amelioration of I/R injury despite prolonged transport times and in organs felt to be potentially marginal
will improve preservation of graft function, thus expanding the donor pool and increasing access.
 Human adipose-derived stem/stromal cells (hASC) represent a uniquely practical subtype of MSC, due to
their abundance, the simplicity of isolation from adipose tissue and their rapid in vitro expansion capacity. We3
and others4 have shown that hASC produce paracrine factors that provide therapeutically beneficial effects in
multiple pathological conditions. In the context of myocardial infarction, we have shown that hASC preserve
myocardial function, inhibit apoptosis, and stimulate angiogenesis primarily through ASC-secreted factors.5
Moreover, we previously reported that pre-treatment of explanted hearts with hASC improved myocardial
functional recovery following acute I/R injury in an ex-vivo heart perfusion system.6 Our preliminary data
indicates that pre-ischemic infusion of ASC-derived paracrine factors also improves myocardial function during
recovery from cold ischemia, with significant preservation of a normal molecular pattern “fingerprint” of the
myocardial transcriptome, as defined by deep RNA sequencing. These RNASeq experiments specifically
indicate that cold ischemia leads to prominent disruption of a set of genes (Arnt/Bmal, Esrra, Per2, Per3, Cry2)
governing the circadian clock within the myocardium, which in turn prompts a coordinated increase in
transcription directing mitochondrial biogenesis; and that these disruptions are specifically counteracted by
hASC factors.
 Accordingly, we propose the hypothesis that infusion of hASC-derived factors into the cardiac
circulation will ameliorate ischemia/reperfusion-induced functional deterioration of model donor hearts
ex vivo as well as of human iPS-derived cardiomyocytes in vitro, by mechanisms mediated by soluble
growth factors as well as exosomes, which limit damage to cardiomyocytes by preserving a ...

## Key facts

- **NIH application ID:** 10394875
- **Project number:** 5I01BX003888-06
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** KEITH LEONARD MARCH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10394875

## Citation

> US National Institutes of Health, RePORTER application 10394875, Functional and Mechanistic Analysis of Mesenchymal Stem Cell Secretome to Ameliorate Ischemic Damage of Rodent Hearts in situ and Human Myocardium-on-a-Chip (5I01BX003888-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10394875. Licensed CC0.

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