# The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2020 · $385,000

## Abstract

Clinical trials for cell therapy reveal only modest benefits on cardiac function in heart failure (HF) patients –
leaving the future of this therapeutic modality uncertain. Despite years of research on the topic, the cell
therapy field remains engrossed in controversies regarding the mechanism(s) of action of donor cells and the
cell type best suited to promote cardiac repair. Two competing hypotheses have been forwarded to explain the
mechanisms underlying cell therapy-mediated cardiac repair, namely donor cell direct differentiation
(contributing to new cardiac parenchyma) and paracrine signaling (promotion of endogenous repair
mechanisms through cytokine and/or extracellular vesicle (EV) secretion). Given that donor cell populations
exhibit poor rates of retention and limited long-term persistence after delivery in HF models, paracrine signaling
is viewed as a major mechanism of cell-mediated cardiac repair. However, there is also evidence implicating a
link between therapeutic efficacy and donor cell cardiovascular fate decisions; although the mechanisms
remain unknown. It is known that different cell types possess distinct trophic factor secretion profiles and
paracrine signaling activities. Thus, we posit that cardiovascular cell lineage commitment-dependent variations
in paracrine signaling are likely to have a significant impact on donor cell reparative capacity in cell-mediated
cardiac repair. Further, as EVs have been identified as important mediators of progenitor cell-induced cardiac
regeneration, we hypothesize that donor cell cardiomyogenic lineage commitment regulates the expression
and synthesis of EV-resident cardiotrophic factors, which mediate cardiac repair. To test this hypothesis, we
will use genetic and pharmacologic approaches for enhancing cardiogenic factor expression to assess the
effects of cardiomyogenic lineage commitment on the reparative capacity of cardiac mesenchymal cells
(CMCs) and lineage-dependent adaptations in CMC EV signaling. Aim 1 will interrogate the impact of genetic-
and pharmacologic-mediated induction of cardiogenic factor expression on CMC cardiovascular lineage
commitment and EV paracrine signaling. Aim 2 will assess the effect of cardiomyogenic lineage commitment
on the reparative capacity of CMCs following administration in a chronic infarct model. Aim 3 will evaluate the
consequences of EV administration, derived from naïve and cardiomyogenic lineage-committed CMCs, on
cardiac repair. The results of this project will establish an unidentified link between progenitor cell
cardiovascular lineage commitment and modifications in EV secretion/paracrine signaling, as well as elucidate
novel targets and pathways that may be exploited to enhance the efficacy of cell therapy.

## Key facts

- **NIH application ID:** 9870949
- **Project number:** 5R01HL141081-03
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Joseph B Moore IV
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870949

## Citation

> US National Institutes of Health, RePORTER application 9870949, The Role of Cardiomyogenic Lineage Commitment in Cardiac Mesenchymal Cell-Mediated Extracellular Vesicle Signaling and Cardiac Repair (5R01HL141081-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9870949. Licensed CC0.

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