# Complement Activation and Initiation of Heart Regeneration

> **NIH NIH R01** · HARVARD UNIVERSITY · 2020 · $422,500

## Abstract

The adult human heart fails to repopulate the myocardium with sufficient new cardiomyocytes following
injury, and this limited capacity for regeneration can lead to systolic heart failure. In contrast, organisms from
diverse taxa including adult salamanders and zebrafish have remarkable abilities to achieve complete
regeneration of the myocardium following heart injury. We collaborated with multiple other laboratories to
perform an unbiased genomic screen to identify genes that are differentially expressed during heart
regeneration in three well-described model systems with enhanced regenerative capabilities: zebrafish, axolotl
(Ambystoma mexicanum, or the Mexican salamander) and neonatal mice. We identified the gene for the
complement 5a receptor, C5aR1, to be induced in the regenerating heart within the first 48 hours following
injury in all of these species, and further showed that this increase in expression is primarily localized to
cardiomyocytes and endothelial cells. C5aR1 is a G-protein coupled receptor that is one of the key receptors
activated by the C5a peptide of the complement cascade. The complement pathway is an ancient and highly
conserved immune response system that can activate inflammation and promote clearance of foreign and
damaged materials. When the complement system is activated, a series of sequential cleavage and
downstream activation steps occur, leading to amplification and eventually a common pathway activation of
multiple G-protein coupled receptors, including C5aR1, the focus of this project. Here we show preliminary
data demonstrating that inhibition of the C5aR1 receptor following cardiac injury impairs the cardiomyocyte cell
cycle response to apical resection in axolotl as well as in the neonatal mouse, suggesting that complement
activation and signaling could represent an evolutionarily conserved pathway in successful heart regeneration.
As described in this proposal, this project aims to reveal the mechanism of how the activated complement
pathway promotes heart regeneration. Our central theory is that the complement pathway plays an
evolutionarily-conserved role in the heart regenerative response by orchestrating molecular signaling between
acute injury and cardiomyocyte proliferation, a crucial component of heart regeneration. The project has three
hypothesis-drive mechanistic aims, focusing on neonatal mice as the mammalian heart regeneration system.
Understanding the early events in successful heart regeneration may allow us to intervene rationally to
promote regeneration in the acutely injured adult human heart, such as in the first days after a sizable
infarction.

## Key facts

- **NIH application ID:** 9858445
- **Project number:** 5R01HL137710-03
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** RICHARD T LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,500
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858445

## Citation

> US National Institutes of Health, RePORTER application 9858445, Complement Activation and Initiation of Heart Regeneration (5R01HL137710-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858445. Licensed CC0.

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