Abstract
Mesenchymal stromal cells (MSCs) are multipotent cells with abilities to exert immunosuppressive response promoting tissue repair. Studies have shown that MSCs can secrete extracellular vesicles (MVs-MSCs) with similar regulatory functions to the parental cells. Furthermore, strong evidence suggesting that MVs-MSCs can modulate several immune cells (i.e., Th1, Th17, and Foxp3+ T cells). However, their precise effect on macrophages (Mϕs) remains unexplored. We investigated the immunoregulatory effect of MVs-MSCs on activated M1-Mϕs in vitro and in vivo using differentiated bone marrow Mϕs and an acute experimental model of thioglycollate-induced peritonitis, respectively. We observed that MVs-MSCs shared surface molecules with MSCs (CD44, CD105, CD90, CD73) and expressed classical microvesicle markers (Annexin V and CD9). The in vitro treatment with MVs-MSCs exerted a regulatory-like phenotype in M1-Mϕs, which showed higher CD206 level and reduced CCR7 expression. This was associated with decreased levels of inflammatory molecules (IL-1β, IL-6, nitric oxide) and increased immunoregulatory markers (IL-10 and Arginase) in M1-Mϕs. In addition, we detected that MVs-MSCs promoted the downregulation of inflammatory miRNAs (miR-155 and miR-21), as well as, upregulated its predicted target gene SOCS3 in activated M1-Mϕs. In vivo MVs-MSCs treatment reduced the Mϕs infiltrate in the peritoneal cavity inducing a M2-like regulatory phenotype in peritoneal Mϕs (higher arginase activity and reduced expression of CD86, iNOS, IFN-γ, IL-1β, TNF-α, IL-1α, and IL-6 molecules). This in vivo immunomodulatory effect of MVs-MSCs on M1-Mϕs was partially associated with the upregulation of CX3CR1 in F4/80+/Ly6C+/CCR2+ Mϕs subsets. In summary, our findings indicate that MVs-MSCs can modulate an internal program in activated Mϕs establishing an alternative regulatory-like phenotype.
Highlights
Mesenchymal stromal cells (MSCs) are multipotent cells with mesodermal differentiation capacity into adipocytes, osteoblasts, and chondroblasts [1]
Further coculture analysis confirmed that MSCs decreased the expression of costimulatory molecules (CD86/B7-2) and chemokine receptor (CCR7) in M1-Mφs previously stimulated with LPS/IFN-γ (Figures S1B,C in Supplementary Material)
Unstimulated Mφs presented similar behavior to MSCs-modulated M1-Mφs (Figures S1B,D). These findings indicate that MSCs in direct contact with M1-Mφs can promote a prominent immunomodulatory effect
Summary
Mesenchymal stromal cells (MSCs) are multipotent cells with mesodermal differentiation capacity into adipocytes, osteoblasts, and chondroblasts [1]. The MSCs ability to support tissue repair has been primarily associated with its capacity to modulate the immune response promoting a pro-resolution microenvironment [5]. Extensive evidence has shown that MSCs can modulate dendritic cells, T lymphocytes (CD4 and CD8), natural killer, B cells, and more recently macrophages (Mφs) [6,7,8,9]. In light of this evidence, it has been reported that MSCs are effective to reprogram and educate classically activated macrophages (M1-Mφs) to an alternative regulatory phenotype (M2-Mφs) [10]. It was observed that Mφs in contact with MSCs exhibit downregulation of pro-inflammatory markers (i.e., TNF−α, IL-1α, IL-6, IL-1β, IL-12p70, MCP-1, iNOS, and CD86) and upregulation of anti-inflammatory molecules such as IL-10, arginase-1, and CD206 [10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
