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MAFB controls the acquisition of the anti-inflammatory transcriptional profile of M-MØ.

ABSTRACT: Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, while the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knock-down of MAFB impairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the co-expression of MAFB and MAFB-target genes in CD163+ tissue-resident and tumor associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from Multicentric Carpo Tarsal Osteolysis (OMIM#166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the anti-inflammatory transcriptional and functional profiles of human macrophages.

ORGANISM(S): Homo sapiens

PROVIDER: GSE84617 | GEO | 2019/05/03

REPOSITORIES: GEO

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Project description:Background Cell therapy based on macrophages is promising in solid tumors, but effective acquisition of macrophages is a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a good source but are time-consuming and costly. Macrophages derived from somatic cells by reprogramming technologies have the potential to enable the development of cell-based therapies for numerous malignant diseases. Methods The composition of CD45+ myeloid-like cell complex (MCC) was analyzed by flow cytometry and single-cell sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of induced macrophages were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of induced macrophages. Results Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in suspension culture and continuously generated functional and highly pure-induced macrophage (iMac) just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulates the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells display significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. Conclusions Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts could help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy. Keywords c-Myc, fibroblast, macrophage, immunotherapy, reprogramming