Macrophage polarization by MSC-derived CXCL12 determines tumor growth

Abstract

Background Phenotypic and functional heterogeneity of macrophages is known to be the main reason for their ability to regulate inflammation and promote tumorigenesis. Mesenchymal stem cells (MSCs) are one of the principal cells commonly found in the tumor stromal niche, with capability of macrophage phenotypic switching. The objective of this study was to evaluate the role of C-X-C motif chemokine ligand 12 (CXCL12) produced by marrow-derived MSCs in the phenotypic and functional pattern of bone marrow-derived macrophages (BMDMs). Methods First, the CRISPR/Cas9 system was used for the CXCL12 gene knock-out in MSCs. Then, coculture systems were used to investigate the role of MSCsCXCL12−/− and MSCsCXCL12+/+ in determination of macrophage phenotype. To further analyze the role of the MSC-derived CXCL12 niche, cocultures of 4T1 mammary tumor cells and macrophages primed with MSCsCXCL12−/− or MSCsCXCL12+/+ as well as in-vivo limiting dilution assays were performed. Results Our results revealed that the expression of IL-4, IL-10, TGF-β and CD206 as M2 markers was significantly increased in macrophages co-cultured with MSCsCXCL12+/+ , whereas the expression of IL-6, TNF-α and iNOS was conversely decreased. The number and size of multicellular tumor spheroids were remarkably higher when 4T1 cells were cocultured with MSCCXCL12+/+-induced M2 macrophages. We also found that the occurrence of tumors was significantly higher in coinjection of 4T1 cells with MSCCXCL12+/+-primed macrophages. Tumor initiating cells were significantly decreased after coinjection of 4T1 cells with macrophages pretreated with MSCsCXCL12−/−. Conclusions In conclusion, our findings shed new light on the role of MSC-derived CXCL12 in macrophage phenotypic switching to M2, affecting their function in tumorigenesis.

Mg2+‐mediated autophagy‐dependent polarization of macrophages mediates the osteogenesis of bone marrow stromal stem cells by interfering with macrophage‐derived exosomes containing miR‐381

“…A recent study disclosed that NLRP3 inflammasomes can be blocked by autophagy, together with the polarization of M1 macrophages being impaired 49 . TGF‐β has been demonstrated to express in M2 macrophage and has been regarded as one of the markers of M2 macrophage 50 . TGF‐β is critical in maintaining immune tolerance and pathological repair, 51 including balancing the osteoclast/osteoblast during bone fracture 52 .…”

“…49 TGF-β has been demonstrated to express in M2 macrophage and has been regarded as one of the markers of M2 macrophage. 50 TGF-β is critical in maintaining immune tolerance and pathological repair, 51 including balancing the osteoclast/osteoblast during bone fracture. 52 In our current study, exosomes were extracted from macrophages by using methods described in a previous study, 53 and then identified by measuring the expression of proteins (CD63 and HSP70) known to be present in exosomes and the GRP94 protein, which is absent in exosomes.…”

Stromal Cells Promote Matrix Deposition, Remodelling and an Immunosuppressive Tumour Microenvironment in a 3D Model of Colon Cancer

“…As well as its role in chemotaxis of neutrophils and macrophages, CXCL12 secretion from stromal cells has been shown to polarise macrophages to IL-10-expressing macrophages in the colon, highlighting an important stromal cell macrophage-signalling axis that regulates inflammation [ 88 ]. CXCL12 suppresses the anti-tumour functions in macrophages in the TME [ 89 ]. Whether the stromal cells express these chemokines or cytokines in the TME, or induce expression in cancer cells or macrophages, is unclear.…”

The role of macrophage subtypes and exosomes in immunomodulation

“…In fact, recent evidence shows a continuum of different macrophages with different markers and phenotypes that strongly depend on their microenvironment. Therefore, they can be considered as a spectrum [84][85][86], although simplified macrophage classification (M1/M2) is used for better understanding. M1 and M2 macrophages can be reprogrammed by different stimuli signals.…”