# Project 2 - Role of Inflammation in CMC-Induced Myocardal Repair

> **NIH NIH P01** · UNIVERSITY OF LOUISVILLE · 2020 · $326,543

## Abstract

The mechanism by which cell therapy improves cardiac function remains unclear. Although injected cells
minimally differentiate into cardiomyocytes or vessels, and only a small fraction survive long term in the
recipient, common beneficial effects are observed regardless of injected cell type: improvement in pump
function, reduction of fibrosis, and enhanced angiogenesis. These results are consistent with the idea that cell
therapy recruits endogenous repair mechanisms which, however, have not been identified. The immune
system has been implicated in a variety of sterile diseases, including processes regulating myocardial damage
and repair. Although unresolved inflammatory processes controlled by infiltrating and tissue-resident immune
cells worsen heart failure, depletion of macrophages in the infarcted myocardium leads to LV rupture and
death. Thus, immune cells appear to play diametrically opposite roles in the heart. Macrophages have been
shown to be required for spontaneous regeneration of neonatal mammalian myocardium after injury, and
recent findings implicate them as direct contributors to cell therapy-mediated myocardial repair. Nevertheless,
how immune cells regulate myocardial repair and what determines their harmful versus salutary actions
remains unknown. Furthermore, the impact of cell therapy on reparative immune cells has not yet been studied
in the heart. Our preliminary data show that injection of cardiac mesenchymal cells (CMCs) into the infarcted
heart promotes accumulation of reparative macrophages. Thus, the central hypothesis of this proposal is that
CMCs facilitate recruitment of monocytes and activation of reparative macrophages, which are essential
endogenous mediators of repair. By generating detailed flow cytometric analyses of immune cell populations
following CMC administration, we will not only resolve the time course of immune cell recruitment, but also
determine how inflammation is eventually extinguished in the heart after cell therapy. To elucidate the
mechanism whereby CMCs regulate inflammatory processes in monocyte-derived macrophages, we will
determine how these cells regulate NFκB-p65 subunit expression, with emphasis on horizontal transfer of
miRNAs to macrophages through CMC-derived EVs. Finally, using macrophage genetic fate mapping and
genetically modified CMCs, we will elucidate the role of monocyte-derived macrophages in CMC-induced
myocardial repair. This project will be the first systematic analysis of how cell therapy modulates immune cells
– a mechanism that has been relatively understudied. The results will provide novel insights not only into the
mechanisms regulating cell therapy-mediated myocardial repair, but also into how endogenous reparative
activities of macrophages are recruited. We will also determine whether EVs recapitulate the salutary effects of
CMCs on immune cells. Thus, these studies have far-reaching implications for our understanding of how the
immune system regulates myocardial...

## Key facts

- **NIH application ID:** 9980484
- **Project number:** 5P01HL078825-14
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Marcin Wysoczynski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $326,543
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980484

## Citation

> US National Institutes of Health, RePORTER application 9980484, Project 2 - Role of Inflammation in CMC-Induced Myocardal Repair (5P01HL078825-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980484. Licensed CC0.

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