Abstract Body: Background
Heart regeneration is a potential strategy to recover pumping function after cardiac injury and protect against heart failure. Macrophages have been demonstrated to promote heart regeneration, while its mechanism has not been addressed. Modulating the interaction between macrophages and cardiomyocytes through connexin 43 (CX43) may provide a clinical therapy for preventing further deterioration of patients with heart injury and restoring the lost myocardium.
Hypothesis
We hypothesize that macrophages can interact with cardiomyocytes via CX43, leading to promotion of cardiac proliferation and heart regeneration.
Aims
Our study aims to provide the evidence of macrophages contacting cardiomyocytes through CX43 and promoting heart regeneration.
Methods and Results
Through cell co-culture experiments, we found that macrophages attache to cardiomyocytes via CX43, subsequently promoting myocyte proliferation as evidenced by proliferative markers. Blocking the CX43 connection by SiRNA between two cells suspended cardiomyocyte proliferation in vitro. We generated macrophage-specific CX43 deficient mice (CX43^Mφ/-) by crosing CD11b-Cre mice and CX43-flox mice. We performed apical resection operation on 1 day-old CX43^Mφ/- mice and harvested the hearts at 21 day-post-resection. CX43^Mφ/- mice demonstrated either the heart regeneration ability nor pumping function. Applying single-cell RNA sequencing in CX43^Mφ/- hearts, we illustrated the unique transcriptional signature of macrophage and cardiomyocyte in macrophage-specific CX43 deficient mice.
Conclusion
Our study provides the evidence that macrophages attache to cardiomyocyte via CX43 after cardiac injury, promote cardiomyocyte proliferation and heart regeneration. This discovery may offer a new target for clinical treatment of myocardial infarction.