Tissue extracellular vesicles suppress neonatal cardiac regeneration: a Pak2-Erk1/2-mediated macrophage paracrine signaling

Yongwei Li, Laihai Zhang, Lu Wei, Yating Wu, Zhenchun Zhang, Hanling Mo, Zhongmin Liu, Xianyun Wang, Yunli Shen, and Hongming Zhu

The regenerative potential of cardiomyocytes following myocardial infarction has long been a central focus in cardiovascular research. While studies have established that mammalian cardiomyocytes retain significant proliferative capacity within the first seven days after birth, the mechanisms driving the abrupt cessation of this regenerative ability beyond postnatal day 7 (P7) remain poorly understood. In this study, we reveal that extracellular vesicles derived from postnatal day 8 mouse hearts (P8-EVs) are phagocytosed by macrophages, triggering their polarization toward the M1 phenotype and activating Pak2-Erk-mediated paracrine signaling. This cascade ultimately suppresses cardiomyocyte proliferation and limits cardiac regenerative potential. In the cover, vibrant red blossoms represent healthy proliferating cardiomyocytes, serene green algae depict resting or mildly activated macrophages, whereas menacing black spiked algae embody P8-EV-engulfed “activated” macrophages. These activated macrophages release inhibitory factors through Pak2-Erk paracrine signaling, casting a shadow of suppression over the cardiomyocyte blooms and restricting their growth. Our work uncovers a novel mechanism underlying the developmental loss of cardiac regenerative capacity in P8 mice, highlighting the pivotal role of immune cells and cardiac-derived extracellular vesicles in this process. These findings provide crucial insights for developing targeted interventions in myocardial regeneration therapy.

This cover is designed by Yinxi Zhou and Jianfeng Jin from Hainan Medical University.