Multinucleation resets human macrophages for specialized functions at the expense of their identity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE219114 | GEO | 2023/01/08
REPOSITORIES: GEO
Similar Datasets
Project description:Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced downregulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.
| S-EPMC9986822 | biostudies-literature
Project description:Macrophages undergo plasma membrane fusion and cell multinucleation to form multinucleated giant cells (MGCs) such as osteoclasts in bone, Langhans giant cells (LGCs) as part of granulomas or foreign-body giant cells (FBGCs) in reaction to exogenous material. How multinucleation per se contributes to functional specialization of mature mononuclear macrophages remains poorly understood in humans. Here, we integrate comparative transcriptomics with functional assays in purified mature mononuclear and multinucleated human osteoclasts, LGCs and FBGCs. Strikingly, in all three types of MGCs, multinucleation causes a pronounced down-regulation of macrophage identity. We show enhanced lysosome-mediated intracellular iron homeostasis promoting MGC formation. The transition from mononuclear to multinuclear state is accompanied by cell specialization specific to each polykaryon. Enhanced phagocytic and mitochondrial function associate with FBGCs and osteoclasts, respectively. Moreover, human LGCs preferentially express B7-H3 (CD276) and can form granuloma-like clusters in vitro, suggesting that their multinucleation potentiates T cell activation. These findings demonstrate how cell-cell fusion and multinucleation reset human macrophage identity as part of an advanced maturation step that confers MGC-specific functionality.
| S-SCDT-10_15252-EMBR_202256310 | biostudies-other
Project description:Multinucleation resets human macrophages for specialized functions at the expense of their identity
| PRJNA907051 | ENA
Project description:Macrophage multinucleation (MM) is essential for various biological processes such as osteoclast-mediated bone resorption and multinucleated giant cell-associated inflammatory reactions. Here we study the molecular pathways underlying multinucleation in the rat through an integrative approach combining MS-based quantitative phosphoproteomics and transcriptome (high throughput RNA-sequencing) to identify new regulators of MM. We show that a strong metabolic shift towards HIF1-mediated glycolysis occurs at transcriptomic level during MM, together with modifications in phosphorylation of over 50 proteins including several ARF GTPase activators and polyphosphate inositol phosphatases. These results will provide a new framework for the combined analysis of transcriptional and post-translational changes during macrophage multinucleation, prioritizing essential genes and revealing the sequential events leading to the multinucleation of macrophages.
2016-07-06 | PXD001269 | Pride
Project description:While the majority of cells contain a single nucleus, cell types such as trophoblasts, osteoclasts, and skeletal myofibers require multinucleation. One advantage of multinucleation can be the assignment of distinct functions to different nuclei, but comprehensive interrogation of transcriptional heterogeneity within multinucleated tissues has been challenging due to the presence of a shared cytoplasm. Here, we utilized single-nucleus RNA-sequencing (snRNA-seq) to determine the extent of transcriptional diversity within multinucleated skeletal myofibers. Nuclei from mouse skeletal muscle were profiled across the lifespan, which revealed the emergence of distinct myonuclear populations in postnatal development and their reactivation in aging muscle. Our datasets also provided a platform for discovery of novel genes associated with rare specialized regions of the muscle cell, including markers of the myotendinous junction and functionally validated factors expressed at the neuromuscular junction. These findings reveal that myonuclei within syncytial muscle fibers possess distinct transcriptional profiles that regulate muscle biology.
2020-10-11 | GSE147127 | GEO
Project description:Osteoclasts are multinucleated giant cells generated by the fusion of precursors in response to stimulation with macrophage colony stimulating factor (MCSF) and receptor activator of NF-kB ligand (RANKL). These cells are the only cells capable of resorbing bone. Tartarate-resistant acid phosphatase is an enzyme secreted by osteoclasts that acts in bone resorption. Mice that are deficient for TRAP have shorter bones and their osteoclasts have decreased resorption capacity. In this project, we will isolate bone marrow macrophages from wild type and TRAP deficient mice, and differentiate the cells in osteoclasts in vitro. RNA will be extracted from macrophages and from macrophages stimulated with RANKL for both mouse lines (n=3/group) yielding 4 groups: Group 1 – macrophages from wild type mice, Group 2 – osteoclasts from wild type mice, Group 3 – macrophages from TRAP deficient mice, Group 4 – osteoclasts from TRAP deficient mice. The differential gene expression will be analyzed by RNAseq.
2024-02-02 | E-MTAB-11403 | biostudies-arrayexpress
Project description:Monocytes/macrophages have the ability to fuse in multinucleated giant cells (MGCs). Except for osteoclasts that resorb bones on large surfaces, the function of other macrophage-derived MGCs, which appear under pathological situations associated with granulomatous inflammation such as tuberculosis, is not understood. Here we deciphered functions and gene expression profiles of MGCs obtained after stimulation of human monocytes with IFN-gM-BM- and concanavalin A. First, we show that the competence of MGCs in phagocytosis and O2- production was similar to those of monocytes-derived macrophages (MDMs) and that MGCs exhibited a M1 polarization. Second, we analyzed the transcriptional profile of MGCs using gene categories and the building of gene networks. The signature of MGCs was markedly distinct from that of resting or stimulated MDMs. It consisted of the up-regulation of genes involved in adhesion and cytoskeleton organization while genes associated with immune response were down-regulated. Hence, MGC formation was associated with a profound and original modulation of gene expression repertoire suggesting that macrophage immune were not prominent in MGC. This expression gene repertoire may be instrumental to understand the specific function of this giant macrophages in human pathologies 9 samples of monocytes-derived macrophages and 3 samples of mulitnucleated giant cells. 3 samples of MDM treated with concanavalin A, 3 samples of MDM treated with IFN-g, and 3 control MDM.
2012-12-07 | E-GEOD-30273 | biostudies-arrayexpress
Project description:Bone marrow-derived macrophages can form multinucleated giant cells upon FSL-1 stimulation in vitro, which can be prevented by supplementation with nutlin-3a
2017-12-06 | GSE92561 | GEO
Project description:Purpose: Transvaginal meshes for the treatment of Pelvic Organ Prolapse (POP) have been associated with severe adverse events and have been banned for clinical use in many countries. We recently reported the design of degradable poly (L-lactic acid)-co-poly (e-caprolactone) nanofibrous mesh (P nanomesh) bioengineered with endometrial mesenchymal stem/stromal cells (eMSC) for POP repair. We showed that such bioengineered meshes had high tissue integration as well as immunomodulatory effects in vivo. This study aimed to determine the key molecular players enabling eMSC- based foreign body response modulation. Methods: SUSD2+ eMSC were purified from single cell suspensions obtained from endometrial biopsies from cycling women by magnetic bead sorting. Electrospun P nanomeshes with and without eMSC were implanted in a NSG mouse skin wound repair model for 1 and 6 weeks. Quantitative PCR was used to assess the expression of extracellular matrix (ECM), cell adhesion, angiogenesis and inflammation genes as log2 fold changes compared to sham controls. Histology and immunostaining was used to visualize the ECM, blood vessels and multinucleated foreign body giant cells around implants. Results: Bioengineered P nanomesh/ eMSC constructs explanted after 6 weeks showed significant increase in 35 genes associated with ECM, ECM regulation, cell adhesion angiogenesis and immune response in comparison to P nanomesh alone. In the absence of eMSC, acute inflammatory genes were significantly elevated at 1 week. However, in presence of eMSC, there was an increased expression of anti-inflammatory genes including Mrc1 and Arg1 by 6 weeks. There was formation of multinucleated foreign body giant cells around both implants at 6 weeks that expressed CD206, a M2 macrophage marker. Conclusion: This study reveals that eMSC modulate the foreign body response to degradable P nanomeshes in vivo by altering the expression profile of mouse genes. eMSC reduce acute inflammatory and increase ECM synthesis, angiogenesis and anti-inflammatory gene expression at 6 weeks while forming newly synthesized collagen within the nanomeshes and neo-vasculature in close proximity. From a tissue engineering perspective, this is a hallmark of a highly successful implant, suggesting significant potential as alternative surgical constructs for the treatment of POP.
2020-03-05 | GSE141960 | GEO
Project description:Osteoclast is the primary bone resorbing multinucleated cell. However, human osteooclastoma bone tumor derived osteoclat cellsare However, gene expression profile of giant osteoclat cells is unclear. Here, we performed gene expression profiling of enriched giant cells to elucidate the neoplastic effects and dynamic changes in gene expression responsible for abnormal hyperactive osteoclast formation in the tumor bone microenvironment.
2020-04-15 | GSE148616 | GEO