# Deciphering the mechanisms of c-kit+ cells in heart repair

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $393,750

## Abstract

PROJECT SUMMARY
The c-kit-positive (c-kit+) cells are the first putative population of cardiac stem cells (CSCs) identified in
mammals, with self-renewing, clonogenic and multipotent activities in vitro. It also reported that adult cardiac c-
kit+ cells are necessary and sufficient for myocardial regeneration. While these findings are encouraging, a
recent lineage tracing study in mice indicated that cardiac resident c-kit+ cells have minimal potential to
differentiate into cardiomyocytes in vivo. To ascertain the true identity of cardiac c-kit+ cells, we generated a
series of new mouse models by targeting reporter genes (H2B-tdTomato, nuclear lacZ and H2B-GFP) and
MerCreMer cassette into the start codon of c-kit in mice. With them, we first uncovered that c-kit in fact labels a
subpopulation (~43%) of PECAM+ cardiac endothelial cells. After acute cardiac injury, the resident c-kit+ cells
still retain their endothelial identity, and have little or no potential to become cardiomyocytes. However,
disregard the low myogenic potential of cardiac resident c-kit+ cells during development and after cardiac
injury, transplantation of exogenously expanded c-kit+ cells has been consistently shown to improve heart
function and attenuate adverse left ventricular remodeling in both ischemic and non-ischemic cardiomyopathy.
Thus, there must be unrecognized mechanisms underlying c-kit+ cell therapy. Given our new finding that c-kit
actually labels a subpopulation of cardiac endothelial cells, we hypothesized transplanted c-kit+ cells repair the
injured heart through their endothelial nature. c-kit+ cells may improve self-renew of the recipient heart by
generating new coronary vasculature, or by releasing paracrine factors. Transplanted c-kit+ cells may also be
reprogramed and gain multipotency after in vitro expansion. In this research program, we will use state-of-the-
art mouse models and human c-kit+ cardiac endothelial cells to test these hypotheses with three Aims: Aim 1
will determine if the endothelial nature of c-kit+ cells contributes to heart repair; Aim 2 will determine if the
transplanted c-kit+ endothelial cells promote self-renew of the recipient heart, and if they serve as progenitors
to regenerate coronary vessels and/or cardiomyocytes; Aim 3 will determine if the paracrine factors from
transplanted c-kit+ cells are essential for heart repair. This project will provide definitive answers to elucidate
ultimate mechanisms by which c-kit+ cells promote heart repair.

## Key facts

- **NIH application ID:** 10166901
- **Project number:** 5R01HL137036-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** WEINIAN SHOU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,750
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166901

## Citation

> US National Institutes of Health, RePORTER application 10166901, Deciphering the mechanisms of c-kit+ cells in heart repair (5R01HL137036-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10166901. Licensed CC0.

---

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