Laufey Geirsdottir | Weizmann Institute of Science (original) (raw)

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Papers by Laufey Geirsdottir

Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. T... more Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. The innate immune system plays a significant role in the pathogenesis of autoimmune diseases. However, its role in the differentiation and function of human CD4 + induced TRegs (iTRegs) is currently unclear. In this study we investigated the effect of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β upon the differentiation and function of human CD4 + FoxP3 + iTRegs.

Cell, 2019

Microglia, the brain-resident immune cells, are critically involved in many physiological and pat... more Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

Nature Neuroscience, 2019

Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and ... more Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and contribute to several neurological and psychiatric diseases. Little is known about human microglia and how they orchestrate their highly plastic, context-specific adaptive responses during pathology. Here we combined two high-dimensional technologies, single-cell RNA-sequencing and time-of-flight mass cytometry, to identify microglia states in the human brain during homeostasis and disease. This approach enabled us to identify and characterize a previously unappreciated spectrum of transcriptional states in human microglia. These transcriptional states are determined by their spatial distribution, and they further change with aging and brain tumor pathology. This description of multiple microglia phenotypes in the human CNS may open promising new avenues for subset-specific therapeutic interventions.Sankowski et al. have combined high-throughput techniques to characterize human microglia, identifying a spectrum of microglia phenotypes that are determined by localization, aging and glioblastoma.

BIO-PROTOCOL, 2019

Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and... more Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and can self-maintain long-term in an adult organism without contribution of monocytes. AM are located in the pulmonary alveoli and can be harvested by washing the lungs using the method of bronchoalveolar lavage (BAL). Here, we compared different conditions of BAL to obtain high yields of murine AM for in vitro culture and expansion of AM. In addition, we describe specific culture conditions, under which AM proliferate long-term in liquid culture in the presence of granulocyte-macrophage colony-stimulating factor. This method can be used to obtain large numbers of AM for in vivo transplantation or for in vitro experiments with primary mouse macrophages.

Alveolar macrophages (AM) are tissue resident macrophages of the lung that can be expanded in cul... more Alveolar macrophages (AM) are tissue resident macrophages of the lung that can be expanded in culture, but it is unknown to what extent culture affects their in vivo identity. Here we show that long-term ex vivo expanded mouse AM (exAM) maintain core AM gene expression but show culture adaptations related to adhesion, metabolism and proliferation. Strikingly, even after several months in culture exAM reacquired full transcriptional and epigenetic identity upon transplantation into the lung and could self-maintain in the natural niche long-term. Changes in open chromatin regions (OCR) observed in culture were fully reversible in transplanted exAM (texAM) and resulted in a gene expression profile indistinguishable from resident AM. Our results demonstrate that long-term proliferation of AM in culture does not compromise cellular identity in vivo. The demonstrated robustness of exAM identity provides new opportunities for mechanistic analysis and highlights the therapeutic potential of...

Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. T... more Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. The innate immune system plays a significant role in the pathogenesis of autoimmune diseases. However, its role in the differentiation and function of human CD4+ induced TRegs (iTRegs) is currently unclear. In this study we investigated the effect of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β upon the differentiation and function of human CD4+FoxP3+ iTRegs. Naïve human CD4+CD25T cells, isolated from both cord blood (CB) and adult peripheral blood (PB) were cultured under various stimulatory conditions with/without TNFα and IL-1β. The CD4+FoxP3+ iTRegs were characterized as CD4 +CD127-CD25highFoxP3high iTRegs and their suppressive function evaluated. TNFα and IL-1β significantly affected the differentiation of human CD4+FoxP3+ iTRegs in a dose and time dependent manner. Low dose and short term conditions promoted their differentiation while high dose and lo...

Cell, 2019

Microglia, the brain-resident immune cells, are critically involved in many physiological and pat... more Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia path-ways across evolution, with important implications for future development of microglia-based therapies in humans.

Nature Neuroscience, 2019

Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and ... more Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and contribute to several neurological and psychiatric diseases. Little is known about human microglia and how they orchestrate their highly plastic, context-specific adaptive responses during pathology. Here we combined two high-dimensional technologies, single-cell RNA-sequencing and time-of-flight mass cytometry, to identify microglia states in the human brain during homeostasis and disease. This approach enabled us to identify and characterize a previously unappreciated spectrum of transcriptional states in human microglia. These transcriptional states are determined by their spatial distribution, and they further change with aging and brain tumor pathology. This description of multiple microglia phenotypes in the human CNS may open promising new avenues for subset-specific therapeutic interventions.

Bio Protoc., 2019

Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and... more Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and can self-maintain long-term in an adult organism without contribution of monocytes. AM are located in the pulmonary alveoli and can be harvested by washing the lungs using the method of bronchoalveolar lavage (BAL). Here, we compared different conditions of BAL to obtain high yields of murine AM for in vitro culture and expansion of AM. In addition, we describe specific culture conditions, under which AM proliferate long-term in liquid culture in the presence of granulocyte-macrophage colony-stimulating factor. This method can be used to obtain large numbers of AM for in vivo transplantation or for in vitro experiments with primary mouse macrophages.

Science, 2016

Differentiated macrophages can self--renew in tissues and expand long--term in culture, but the g... more Differentiated macrophages can self--renew in tissues and expand long--term in culture, but the gene regulatory mechanisms that accomplish self--renewal in the differentiated state have remained unknown. Here we show that low levels of the transcription factors MafB and c--Maf relieve direct repression of a macrophage--specific enhancer repertoire associated with a gene network controlling self--renewal. Single cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down--regulation of Maf transcription factors. The network also controls embryonic stem cell self--renewal but is associated with distinct ES--cell specific enhancers. This indicates that distinct lineage--specific enhancer platforms regulate a shared network of genes that control self--renewal potential in both stem and mature cells.

Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. T... more Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. The innate immune system plays a significant role in the pathogenesis of autoimmune diseases. However, its role in the differentiation and function of human CD4 + induced TRegs (iTRegs) is currently unclear. In this study we investigated the effect of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β upon the differentiation and function of human CD4 + FoxP3 + iTRegs.

Cell, 2019

Microglia, the brain-resident immune cells, are critically involved in many physiological and pat... more Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

Nature Neuroscience, 2019

Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and ... more Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and contribute to several neurological and psychiatric diseases. Little is known about human microglia and how they orchestrate their highly plastic, context-specific adaptive responses during pathology. Here we combined two high-dimensional technologies, single-cell RNA-sequencing and time-of-flight mass cytometry, to identify microglia states in the human brain during homeostasis and disease. This approach enabled us to identify and characterize a previously unappreciated spectrum of transcriptional states in human microglia. These transcriptional states are determined by their spatial distribution, and they further change with aging and brain tumor pathology. This description of multiple microglia phenotypes in the human CNS may open promising new avenues for subset-specific therapeutic interventions.Sankowski et al. have combined high-throughput techniques to characterize human microglia, identifying a spectrum of microglia phenotypes that are determined by localization, aging and glioblastoma.

BIO-PROTOCOL, 2019

Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and... more Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and can self-maintain long-term in an adult organism without contribution of monocytes. AM are located in the pulmonary alveoli and can be harvested by washing the lungs using the method of bronchoalveolar lavage (BAL). Here, we compared different conditions of BAL to obtain high yields of murine AM for in vitro culture and expansion of AM. In addition, we describe specific culture conditions, under which AM proliferate long-term in liquid culture in the presence of granulocyte-macrophage colony-stimulating factor. This method can be used to obtain large numbers of AM for in vivo transplantation or for in vitro experiments with primary mouse macrophages.

Alveolar macrophages (AM) are tissue resident macrophages of the lung that can be expanded in cul... more Alveolar macrophages (AM) are tissue resident macrophages of the lung that can be expanded in culture, but it is unknown to what extent culture affects their in vivo identity. Here we show that long-term ex vivo expanded mouse AM (exAM) maintain core AM gene expression but show culture adaptations related to adhesion, metabolism and proliferation. Strikingly, even after several months in culture exAM reacquired full transcriptional and epigenetic identity upon transplantation into the lung and could self-maintain in the natural niche long-term. Changes in open chromatin regions (OCR) observed in culture were fully reversible in transplanted exAM (texAM) and resulted in a gene expression profile indistinguishable from resident AM. Our results demonstrate that long-term proliferation of AM in culture does not compromise cellular identity in vivo. The demonstrated robustness of exAM identity provides new opportunities for mechanistic analysis and highlights the therapeutic potential of...

Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. T... more Regulatory T cells (TRegs) are critical for the maintenance of balanced human immune responses. The innate immune system plays a significant role in the pathogenesis of autoimmune diseases. However, its role in the differentiation and function of human CD4+ induced TRegs (iTRegs) is currently unclear. In this study we investigated the effect of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFα) and IL-1β upon the differentiation and function of human CD4+FoxP3+ iTRegs. Naïve human CD4+CD25T cells, isolated from both cord blood (CB) and adult peripheral blood (PB) were cultured under various stimulatory conditions with/without TNFα and IL-1β. The CD4+FoxP3+ iTRegs were characterized as CD4 +CD127-CD25highFoxP3high iTRegs and their suppressive function evaluated. TNFα and IL-1β significantly affected the differentiation of human CD4+FoxP3+ iTRegs in a dose and time dependent manner. Low dose and short term conditions promoted their differentiation while high dose and lo...

Cell, 2019

Microglia, the brain-resident immune cells, are critically involved in many physiological and pat... more Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer’s and Parkinson’s disease. Our study provides an essential resource of conserved and divergent microglia path-ways across evolution, with important implications for future development of microglia-based therapies in humans.

Nature Neuroscience, 2019

Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and ... more Microglia are tissue-resident macrophages of the CNS that orchestrate local immune responses and contribute to several neurological and psychiatric diseases. Little is known about human microglia and how they orchestrate their highly plastic, context-specific adaptive responses during pathology. Here we combined two high-dimensional technologies, single-cell RNA-sequencing and time-of-flight mass cytometry, to identify microglia states in the human brain during homeostasis and disease. This approach enabled us to identify and characterize a previously unappreciated spectrum of transcriptional states in human microglia. These transcriptional states are determined by their spatial distribution, and they further change with aging and brain tumor pathology. This description of multiple microglia phenotypes in the human CNS may open promising new avenues for subset-specific therapeutic interventions.

Bio Protoc., 2019

Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and... more Alveolar macrophages (AM) are tissue-resident macrophages that colonize the lung around birth and can self-maintain long-term in an adult organism without contribution of monocytes. AM are located in the pulmonary alveoli and can be harvested by washing the lungs using the method of bronchoalveolar lavage (BAL). Here, we compared different conditions of BAL to obtain high yields of murine AM for in vitro culture and expansion of AM. In addition, we describe specific culture conditions, under which AM proliferate long-term in liquid culture in the presence of granulocyte-macrophage colony-stimulating factor. This method can be used to obtain large numbers of AM for in vivo transplantation or for in vitro experiments with primary mouse macrophages.

Science, 2016

Differentiated macrophages can self--renew in tissues and expand long--term in culture, but the g... more Differentiated macrophages can self--renew in tissues and expand long--term in culture, but the gene regulatory mechanisms that accomplish self--renewal in the differentiated state have remained unknown. Here we show that low levels of the transcription factors MafB and c--Maf relieve direct repression of a macrophage--specific enhancer repertoire associated with a gene network controlling self--renewal. Single cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down--regulation of Maf transcription factors. The network also controls embryonic stem cell self--renewal but is associated with distinct ES--cell specific enhancers. This indicates that distinct lineage--specific enhancer platforms regulate a shared network of genes that control self--renewal potential in both stem and mature cells.