Multinucleation resets human macrophages for specialized functions at the expense of their identity
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ABSTRACT:
PROVIDER: PRJNA907051 | ENA |
REPOSITORIES: ENA
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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:To investigate the effects of macrophage cell fusion and multinucleation, we have sorted mononuclear and multinucleated macrophages from 3 types of polykaryons: osteoclasts, foreign body giant cells (FBGCs) and Langhans giant cells (LGCs).
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Project description:Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.
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Project description:Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.
2021-11-08 | GSE179217 | GEO
Project description:Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.
2021-11-08 | GSE179219 | GEO
Project description:Epigenetic control of lineage-specific gene expression is essential for cell differentiation, acquisition of specialized functions, and tissue homeostasis. Here, we uncovered a unique epigenetic pathway critical for governing lineage identity in cells presenting milieu-dependent phenotypic modulation in adult organisms, by using vascular smooth muscle cells (SMC) as a model of highly specialized and differentiated cell type retaining phenotypic plasticity. We found that the histone modification H3K4me2 is essential for the maintenance of vascular SMC lineage identity and functions by performing H3K4me2 demethylation selectively on a SMC lineage-specific subset of genes. Removal of H3K4me2 on the myocardin-regulated genes led to a marked loss of contractility and alteration in SMC adaptive response capacities during vascular remodeling. Rather than presenting intrinsic gene activation properties, H3K4me2 serves as a stable preferential hub for the dynamic recruitment of the DNA methylcytosine dioxygenase Ten-Eleven Translocation 2 (TET2). Besides the SMC contractile apparatus, the H3K4me2/TET2 complex controls the expression of miR-145, a central microRNA promoting SMC differentiation and participation in vascular remodeling. Finally, H3K4me2 editing induced a profound loss of SMC lineage identity and gain of plasticity, characterized by the redistribution of H3K4me2 on genes associated with stemness and developmental programs and the greater ability of H3K4me2 edited SMC to transdifferentiate into other lineages. These studies identified H3K4me2 as a central epigenetic mechanism controlling lineage identity and cell-specific specialized functions. Our findings may have broad implications for the understanding of mechanisms controlling multiple plastic cell type behaviors and functions in various pathophysiological processes.
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