The Neonatal Myeloid Hypoxia Response Promotes a Cardiac Regenerative Response through Insulin-Like Growth Factor

The adult mammalian heart lacks the regenerative potential required to replenish depleted cardiomyocytes and restore cardiac function after injury. Ischemic cardiac injury contributes to heart failure, a leading cause of death worldwide. Neonatal mice possess the capacity to regenerate injured myocardium and macrophages contribute to this process. The mechanisms contributing to the regenerative crosstalk between macrophages and cardiomyocytes remain incompletely elucidated and offer potential to inform future therapeutic strategies.

To test the immune contribution during cardiac regeneration, we studied the response to myocardial ischemia in neonatal mice after silencing myeloid hypoxia inducible factor 1α ( Hif1α ) and reconstituting HIF-dependent mitogens. In parallel, we examined epigenetic and transcriptional signatures of the cardiac macrophage response and focused on intercellular crosstalk with cardiomyocytes.

In myeloid Hif1α deficient mice, cardiac regenerative function was lost after coronary ligation. This manifested through loss of ventricular systolic function and elevated myocardial scarring. HIF1α was found to be activated in resident-type cardiac macrophages after ischemic insult. Hypoxia stimulated macrophages to secrete insulin-like growth factor 1 (IGF-1), and this required Hif1α . Parallel multiomic analysis revealed epigenetic regenerative signatures.

The data reveal an age-restricted requirement for myeloid Hif1α in neonatal cardiac regeneration, likely through IGF-1 signaling.