11 results on '"iPSC-microglia"'
Search Results
2. Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia
- Author
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Brownjohn, Philip W., Smith, James, Solanki, Ravi, Lohmann, Ebba, Houlden, Henry, Hardy, John, Dietmann, Sabine, and Livesey, Frederick J.
- Published
- 2018
- Full Text
- View/download PDF
3. Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.
- Author
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Lorenzini, Ileana, Alsop, Eric, Levy, Jennifer, Gittings, Lauren M, Lall, Deepti, Rabichow, Benjamin E, Moore, Stephen, Pevey, Ryan, Bustos, Lynette M, Burciu, Camelia, Bhatia, Divya, Singer, Mo, Saul, Justin, McQuade, Amanda, Tzioras, Makis, Mota, Thomas A, Logemann, Amber, Rose, Jamie, Almeida, Sandra, Gao, Fen-Biao, Marks, Michael, Donnelly, Christopher J, Hutchins, Elizabeth, Hung, Shu-Ting, Ichida, Justin, Bowser, Robert, Spires-Jones, Tara, Blurton-Jones, Mathew, Gendron, Tania F, Baloh, Robert H, Van Keuren-Jensen, Kendall, and Sattler, Rita
- Subjects
C9orf72 ,amyotrophic lateral sclerosis ,frontotemporal dementia ,iPSC-microglia ,neuroinflammation ,Aging ,Neurosciences ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,ALS ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Stem Cell Research ,Brain Disorders ,Rare Diseases ,Dementia ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease Related Dementias (ADRD) ,Genetics ,Stem Cell Research - Induced Pluripotent Stem Cell ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Biochemistry and Cell Biology - Abstract
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.
- Published
- 2023
4. Particulate matter from car exhaust alters function of human iPSC-derived microglia
- Author
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Henna Jäntti, Steffi Jonk, Mireia Gómez Budia, Sohvi Ohtonen, Ilkka Fagerlund, Mohammad Feroze Fazaludeen, Päivi Aakko-Saksa, Alice Pebay, Šárka Lehtonen, Jari Koistinaho, Katja M. Kanninen, Pasi I. Jalava, Tarja Malm, and Paula Korhonen
- Subjects
Microglia ,Particulate matter ,Traffic-related ,iPSC ,iPSC-microglia ,Neuroinflammation ,Toxicology. Poisons ,RA1190-1270 ,Industrial hygiene. Industrial welfare ,HD7260-7780.8 - Abstract
Abstract Background Air pollution is recognized as an emerging environmental risk factor for neurological diseases. Large-scale epidemiological studies associate traffic-related particulate matter (PM) with impaired cognitive functions and increased incidence of neurodegenerative diseases such as Alzheimer’s disease. Inhaled components of PM may directly invade the brain via the olfactory route, or act through peripheral system responses resulting in inflammation and oxidative stress in the brain. Microglia are the immune cells of the brain implicated in the progression of neurodegenerative diseases. However, it remains unknown how PM affects live human microglia. Results Here we show that two different PMs derived from exhausts of cars running on EN590 diesel or compressed natural gas (CNG) alter the function of human microglia-like cells in vitro. We exposed human induced pluripotent stem cell (iPSC)-derived microglia-like cells (iMGLs) to traffic related PMs and explored their functional responses. Lower concentrations of PMs ranging between 10 and 100 µg ml−1 increased microglial survival whereas higher concentrations became toxic over time. Both tested pollutants impaired microglial phagocytosis and increased secretion of a few proinflammatory cytokines with distinct patterns, compared to lipopolysaccharide induced responses. iMGLs showed pollutant dependent responses to production of reactive oxygen species (ROS) with CNG inducing and EN590 reducing ROS production. Conclusions Our study indicates that traffic-related air pollutants alter the function of human microglia and warrant further studies to determine whether these changes contribute to adverse effects in the brain and on cognition over time. This study demonstrates human iPSC-microglia as a valuable tool to study functional microglial responses to environmental agents.
- Published
- 2024
- Full Text
- View/download PDF
5. Particulate matter from car exhaust alters function of human iPSC-derived microglia
- Author
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Jäntti, Henna, Jonk, Steffi, Gómez Budia, Mireia, Ohtonen, Sohvi, Fagerlund, Ilkka, Fazaludeen, Mohammad Feroze, Aakko-Saksa, Päivi, Pebay, Alice, Lehtonen, Šárka, Koistinaho, Jari, Kanninen, Katja M., Jalava, Pasi I., Malm, Tarja, and Korhonen, Paula
- Published
- 2024
- Full Text
- View/download PDF
6. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer’s disease mice
- Author
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Shabestari, Sepideh Kiani, Morabito, Samuel, Danhash, Emma Pascal, McQuade, Amanda, Sanchez, Jessica Ramirez, Miyoshi, Emily, Chadarevian, Jean Paul, Claes, Christel, Coburn, Morgan Alexandra, Hasselmann, Jonathan, Hidalgo, Jorge, Tran, Kayla Nhi, Martini, Alessandra C, Rothermich, Winston Chang, Pascual, Jesse, Head, Elizabeth, Hume, David A, Pridans, Clare, Davtyan, Hayk, Swarup, Vivek, and Blurton-Jones, Mathew
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Alzheimer's Disease ,Neurosciences ,Genetics ,Vascular Cognitive Impairment/Dementia ,Neurodegenerative ,Aging ,Cerebrovascular ,Dementia ,Alzheimer's Disease Related Dementias (ADRD) ,Prevention ,2.1 Biological and endogenous factors ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Animals ,Brain ,Cerebral Amyloid Angiopathy ,Disease Models ,Animal ,Humans ,Induced Pluripotent Stem Cells ,Membrane Glycoproteins ,Mice ,Mice ,Transgenic ,Microglia ,Plaque ,Amyloid ,Receptors ,Immunologic ,Alzheimer’s disease ,Alzheimer’s disease co-pathologies ,CP: Neuroscience ,TREM2 ,brain calcification ,cerebral amyloid angiopathy ,hemorrhage ,iPSC-microglia ,microglia ,mortality ,neurovascular ,Medical Physiology ,Biological sciences - Abstract
Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.
- Published
- 2022
7. Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features
- Author
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Ileana Lorenzini, Eric Alsop, Jennifer Levy, Lauren M. Gittings, Deepti Lall, Benjamin E. Rabichow, Stephen Moore, Ryan Pevey, Lynette M. Bustos, Camelia Burciu, Divya Bhatia, Mo Singer, Justin Saul, Amanda McQuade, Makis Tzioras, Thomas A. Mota, Amber Logemann, Jamie Rose, Sandra Almeida, Fen-Biao Gao, Michael Marks, Christopher J. Donnelly, Elizabeth Hutchins, Shu-Ting Hung, Justin Ichida, Robert Bowser, Tara Spires-Jones, Mathew Blurton-Jones, Tania F. Gendron, Robert H. Baloh, Kendall Van Keuren-Jensen, and Rita Sattler
- Subjects
amyotrophic lateral sclerosis ,C9orf72 ,frontotemporal dementia ,iPSC-microglia ,neuroinflammation ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G4C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration.
- Published
- 2023
- Full Text
- View/download PDF
8. Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer's disease mouse models
- Author
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Jimena Monzón-Sandoval, Elena Burlacu, Devika Agarwal, Adam E. Handel, Liting Wei, John Davis, Sally A. Cowley, M. Zameel Cader, and Caleb Webber
- Subjects
ipsc-microglia ,alzheimer's disease ,atpγs ,ifn-γ ,lps ,pge2 ,Medicine ,Pathology ,RB1-214 - Published
- 2022
- Full Text
- View/download PDF
9. Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice
- Author
-
Sepideh Kiani Shabestari, Samuel Morabito, Emma Pascal Danhash, Amanda McQuade, Jessica Ramirez Sanchez, Emily Miyoshi, Jean Paul Chadarevian, Christel Claes, Morgan Alexandra Coburn, Jonathan Hasselmann, Jorge Hidalgo, Kayla Nhi Tran, Alessandra C. Martini, Winston Chang Rothermich, Jesse Pascual, Elizabeth Head, David A. Hume, Clare Pridans, Hayk Davtyan, Vivek Swarup, and Mathew Blurton-Jones
- Subjects
Amyloid ,Aging ,brain calcification ,neurovascular ,Medical Physiology ,Induced Pluripotent Stem Cells ,microglia ,Mice, Transgenic ,Plaque, Amyloid ,Neurodegenerative ,Alzheimer's Disease ,General Biochemistry, Genetics and Molecular Biology ,Transgenic ,Mice ,Immunologic ,Alzheimer Disease ,Receptors ,TREM2 ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Animals ,Humans ,Alzheimer’s disease co-pathologies ,Aetiology ,Receptors, Immunologic ,cerebral amyloid angiopathy ,Plaque ,iPSC-microglia ,Amyloid beta-Peptides ,Membrane Glycoproteins ,Animal ,Neuroscience [CP] ,Prevention ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain ,mortality ,Brain Disorders ,Cerebral Amyloid Angiopathy ,Disease Models, Animal ,Disease Models ,Neurological ,Dementia ,Biochemistry and Cell Biology ,Microglia ,hemorrhage ,Alzheimer’s disease - Abstract
Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.
- Published
- 2021
- Full Text
- View/download PDF
10. Moderate intrinsic phenotypic alterations in C9orf72 ALS/FTD iPSC-microglia despite the presence of C9orf72 pathological features.
- Author
-
Lorenzini I, Alsop E, Levy J, Gittings LM, Lall D, Rabichow BE, Moore S, Pevey R, Bustos LM, Burciu C, Bhatia D, Singer M, Saul J, McQuade A, Tzioras M, Mota TA, Logemann A, Rose J, Almeida S, Gao FB, Marks M, Donnelly CJ, Hutchins E, Hung ST, Ichida J, Bowser R, Spires-Jones T, Blurton-Jones M, Gendron TF, Baloh RH, Van Keuren-Jensen K, and Sattler R
- Abstract
While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G
4 C2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lorenzini, Alsop, Levy, Gittings, Lall, Rabichow, Moore, Pevey, Bustos, Burciu, Bhatia, Singer, Saul, McQuade, Tzioras, Mota, Logemann, Rose, Almeida, Gao, Marks, Donnelly, Hutchins, Hung, Ichida, Bowser, Spires-Jones, Blurton-Jones, Gendron, Baloh, Van Keuren-Jensen and Sattler.)- Published
- 2023
- Full Text
- View/download PDF
11. Lipopolysaccharide distinctively alters human microglia transcriptomes to resemble microglia from Alzheimer's disease mouse models.
- Author
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Monzón-Sandoval J, Burlacu E, Agarwal D, Handel AE, Wei L, Davis J, Cowley SA, Cader MZ, and Webber C
- Subjects
- Animals, Dinoprostone metabolism, Disease Models, Animal, Humans, Interferon-gamma metabolism, Lipopolysaccharides metabolism, Lipopolysaccharides pharmacology, Mice, Transcriptome genetics, Alzheimer Disease metabolism, Microglia pathology
- Abstract
Alzheimer's disease (AD) is the most common form of dementia, and risk-influencing genetics implicates microglia and neuroimmunity in the pathogenesis of AD. Induced pluripotent stem cell (iPSC)-derived microglia (iPSC-microglia) are increasingly used as a model of AD, but the relevance of historical immune stimuli to model AD is unclear. We performed a detailed cross-comparison over time on the effects of combinatory stimulation of iPSC-microglia, and in particular their relevance to AD. We used single-cell RNA sequencing to measure the transcriptional response of iPSC-microglia after 24 h and 48 h of stimulation with prostaglandin E2 (PGE2) or lipopolysaccharide (LPS)+interferon gamma (IFN-γ), either alone or in combination with ATPγS. We observed a shared core transcriptional response of iPSC-microglia to ATPγS and to LPS+IFN-γ, suggestive of a convergent mechanism of action. Across all conditions, we observed a significant overlap, although directional inconsistency to genes that change their expression levels in human microglia from AD patients. Using a data-led approach, we identify a common axis of transcriptomic change across AD genetic mouse models of microglia and show that only LPS provokes a transcriptional response along this axis in mouse microglia and LPS+IFN-γ in human iPSC-microglia. This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interests M.Z.C. is co-founder and director of Oxford StemTech Ltd. and HumanCentric DD Ltd. C.W. is co-founder and director of HumanCentric DD Ltd., (© 2022. Published by The Company of Biologists Ltd.)
- Published
- 2022
- Full Text
- View/download PDF
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