Abstract
Background-
Exosomes derived from human umbilical cord mesenchymal stem cells (UMSCs-Exo) were recommended as ideal substitutes for cell-free cardiac regenerative medicine, which had presented encouraging effects in regulating inflammation and attenuating myocardial injury. The phenotype of macrophages resident in myocardium were regulated dynamically in response to environmental cues, which may either protect against injury or promote maladaptive remodeling. However, the underlying mechanisms about UMSCs-Exo regulating macrophage polarization are still not well understood. Herein, we aimed to explore the effects of UMSCs-Exo on macrophage polarization and their roles in cardiac repair after myocardial infarction (MI).
Methods and Results-
Exosomes were isolated from the supernatant of human umbilical cord mesenchymal stem cells (UMSCs) and transplanted by intramyocardial injection after MI. Our results showed that UMSCs-Exo improved cardiac function by increasing M2 macrophage polarization and reducing excessive inflammation. After depletion of macrophages with clodronate liposomes, the therapeutic effects of UMSCs-Exo were disrupted. Administrated with UMSC-Exo, macrophages are inclined to polarize towards M2 phenotype in inflammatory environment in vitro. The results of RNA-sequencing indicated Plcb3 was a key gene concerned in UMSCs-Exo facilitated M2 macrophage polarization. Further bioinformatics analysis revealed exosomal miR-24-3p as a potential effector mediated Plcb3 down regulation in macrophages. Increasing miR-24-3p expression in macrophages effectively enhanced M2 macrophage polarization by suppressing Plcb3 expression and NF-κB pathway activation in inflammatory environment. Furthermore, diminishing miR-24-3p expression in UMSCs-Exo attenuated the effects of UMSCs-Exo on M2 macrophage polarization.
Conclusions-
Our study demonstrated that macrophages, as important inflammatory regulators, participated in UMSCs-Exo mediated myocardial repair after MI. And the therapeutical effects were at least partially carried out by UMSCs-Exo promoting M2 macrophage polarization in an inflammatory microenvironment. Mechanically, exosomal miR-24-3p inhibits the expression of Plcb3 and NF-κB pathway activation to promote M2 macrophage polarization.
Microvesicles Derived from Human Umbilical Cord Mesenchymal Stem Cells Facilitate Tubular Epithelial Cell Dedifferentiation and Growth via Hepatocyte Growth Factor Induction
