CCR2 Positive Exosome Released by Mesenchymal Stem Cells Suppresses Macrophage Functions and Alleviates Ischemia/Reperfusion-Induced Renal Injury

Abstract

Mesenchymal stem cells (MSCs) derived exosomes have been shown to have protective effects on the kidney in ischemia/reperfusion-induced renal injury. However, the key components in the exosomes and their potential mechanisms for the kidney protective effects are not well understood. In our current study, we focused on the abundant proteins in exosomes derived from MSCs (MSC-exo) and found that the C-C motif chemokine receptor-2 (CCR2) was expressed on MSC-exo with a high ability to bind to its ligand CCL2. We also proved that CCR2 high-expressed MSC-exo could reduce the concentration of free CCL2 and suppress its functions to recruit or activate macrophage. Further, knockdown of CCR2 expression on the MSC-exo greatly abolished these effects. Finally, we also found that CCR2 knockdown impaired the protective effects of MSC-exo for the renal ischemia/reperfusion injury in mouse. The results indicate that CCR2 expressed on MSC-exo may play a key role in inflammation regulation and renal injury repair by acting as a decoy to suppress CCL2 activity. Our study may cast new light on understanding the functions of the MSC-exo and these receptor proteins expressed on exosomes.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in Tissue Regeneration

“…Analysis of the expression of inflammation-related proteins in EVs showed that C-C motif chemokine receptor-2 (CCR2) was highly expressed on the surface of the vesicles. Subsequent in vivo and in vitro experiments confirmed that CCR2-positive EVs can inhibit the migration and activation of macrophages by reducing the level of its ligand (CCL2), thereby promoting the repair of acute renal injury induced by ischemia-reperfusion 71 .…”

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…SCs are capable of self-renewal and indefinite proliferation, participating in maintenance of cell cycle, tissue repair and regeneration, and immune response regulation. SC-EVs are internalized by target cells primarily through specific receptorligand interaction modes to exert biological functions (26)(27)(28). Intercellular communication between SCs and immune cells is achieved through their respective EVs.…”

Extracellular micro/nanovesicles rescue kidney from ischemia‐reperfusion injury

“…They also found that knock down of CCR2 greatly abolished the protective effects of MSC-exosomes against kidney IRI. This study indicates that CCR2 is a key molecule on MSCexosomes, which regulates inflammation and acts as a decoy for CCL2 suppression (Shen et al, 2016). Gatti Endothelial cells were subjected to hypoxia and then were incubated with ECFC-EVs.…”