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Article: Stat1

Imitola, Jaime / Hollingsworth, Ethan W / Watanabe, Fumihiro / Olah, Marta / Elyaman, Wassim / Starossom, Sarah / Kivisäkk, Pia / Khoury, Samia J

Frontiers in cellular neuroscience

2023 Volume 17, Page(s) 1156802

Abstract: A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of endogenous stem cells in response to injury and disease. Interferons increase hematopoietic stem cells during infection by activating STAT1, but ... ...

Abstract	A central issue in regenerative medicine is understanding the mechanisms that regulate the self-renewal of endogenous stem cells in response to injury and disease. Interferons increase hematopoietic stem cells during infection by activating STAT1, but the mechanisms by which STAT1 regulates intrinsic programs in neural stem cells (NSCs) during neuroinflammation is less known. Here we explored the role of STAT1 on NSC self-renewal. We show that overexpressing
Language	English
Publishing date	2023-08-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2023.1156802
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Article ; Online: An integrated toolkit for human microglia functional genomics.

Haq, Imdadul / Ngo, Jason C / Roy, Nainika / Pan, Richard L / Nawsheen, Nadiya / Chiu, Rebecca / Zhang, Ya / Fujita, Masashi / Soni, Rajesh K / Wu, Xuebing / Bennett, David A / Menon, Vilas / Olah, Marta / Sher, Falak

Stem cell research & therapy

2024 Volume 15, Issue 1, Page(s) 104

Abstract: Background: Microglia, the brain's resident immune cells, play vital roles in brain development, and disorders like Alzheimer's disease (AD). Human iPSC-derived microglia (iMG) provide a promising model to study these processes. However, existing iMG ... ...

Abstract	Background: Microglia, the brain's resident immune cells, play vital roles in brain development, and disorders like Alzheimer's disease (AD). Human iPSC-derived microglia (iMG) provide a promising model to study these processes. However, existing iMG generation protocols face challenges, such as prolonged differentiation time, lack of detailed characterization, and limited gene function investigation via CRISPR-Cas9. Methods: Our integrated toolkit for in-vitro microglia functional genomics optimizes iPSC differentiation into iMG through a streamlined two-step, 20-day process, producing iMG with a normal karyotype. We confirmed the iMG's authenticity and quality through single-cell RNA sequencing, chromatin accessibility profiles (ATAC-Seq), proteomics and functional tests. The toolkit also incorporates a drug-dependent CRISPR-ON/OFF system for temporally controlled gene expression. Further, we facilitate the use of multi-omic data by providing online searchable platform that compares new iMG profiles to human primary microglia: https://sherlab.shinyapps.io/IPSC-derived-Microglia/ . Results: Our method generates iMG that closely align with human primary microglia in terms of transcriptomic, proteomic, and chromatin accessibility profiles. Functionally, these iMG exhibit Ca2 + transients, cytokine driven migration, immune responses to inflammatory signals, and active phagocytosis of CNS related substrates including synaptosomes, amyloid beta and myelin. Significantly, the toolkit facilitates repeated iMG harvesting, essential for large-scale experiments like CRISPR-Cas9 screens. The standalone ATAC-Seq profiles of our iMG closely resemble primary microglia, positioning them as ideal tools to study AD-associated single nucleotide variants (SNV) especially in the genome regulatory regions. Conclusions: Our advanced two-step protocol rapidly and efficiently produces authentic iMG. With features like the CRISPR-ON/OFF system and a comprehensive multi-omic data platform, our toolkit equips researchers for robust microglial functional genomic studies. By facilitating detailed SNV investigation and offering a sustainable cell harvest mechanism, the toolkit heralds significant progress in neurodegenerative disease drug research and therapeutic advancement.
MeSH term(s)	Humans ; Microglia/metabolism ; Proteomics ; Amyloid beta-Peptides ; Neurodegenerative Diseases ; Genomics ; Alzheimer Disease/genetics ; Chromatin/genetics ; Chromatin/metabolism
Chemical Substances	Amyloid beta-Peptides ; Chromatin
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2548671-8
ISSN	1757-6512 ; 1757-6512
ISSN (online)	1757-6512
ISSN	1757-6512
DOI	10.1186/s13287-024-03700-9
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Article ; Online: Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer's disease risk in humans.

Ma, Yiyi / Yu, Lei / Olah, Marta / Smith, Rebecca / Oatman, Stephanie R / Allen, Mariet / Pishva, Ehsan / Zhang, Bin / Menon, Vilas / Ertekin-Taner, Nilüfer / Lunnon, Katie / Bennett, David A / Klein, Hans-Ulrich / De Jager, Philip L

Alzheimer's & dementia : the journal of the Alzheimer's Association

2021 Volume 18, Issue 4, Page(s) 688–699

Abstract: Not all apolipoprotein E (APOE) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4-attenuating signals from methylome-wide association analyses (N = 572, ε4+ ... ...

Abstract	Not all apolipoprotein E (APOE) ε4 carriers who survive to advanced age develop Alzheimer's disease (AD); factors attenuating the risk of ε4 on AD may exist. Guided by the top ε4-attenuating signals from methylome-wide association analyses (N = 572, ε4+ and ε4-) of neurofibrillary tangles and neuritic plaques, we conducted a meta-analysis for pathological AD within the ε4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA-seq and microglial morphology measurements were used in functional analyses. Three out of the four significant CpG dinucleotides were captured by one principal component (PC1), which interacts with ε4 on AD, and is associated with expression of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 58% (odds ratio = 2.39, 95% confidence interval = [1.64,3.46], P = 7.08 × 10
MeSH term(s)	Alleles ; Alzheimer Disease/pathology ; Apolipoprotein E4/genetics ; Apolipoproteins E/genetics ; Epigenomics ; Genotype ; Humans ; Microglia/pathology ; Neurofibrillary Tangles/pathology
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E
Language	English
Publishing date	2021-09-05
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12425
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Article ; Online: Immune Response following FLASH and Conventional Radiation in Diffuse Midline Glioma.

Padilla, Oscar / Minns, Hanna E / Wei, Hong-Jian / Fan, Weijia / Webster-Carrion, Andrea / Tazhibi, Masih / McQuillan, Nicholas M / Zhang, Xu / Gallitto, Matthew / Yeh, Rebecca / Zhang, Zhiguo / Hei, Tom K / Szalontay, Luca / Pavisic, Jovana / Tan, Yuewen / Deoli, Naresh / Garty, Guy / Garvin, James H / Canoll, Peter D /

Vanpouille-Box, Claire / Menon, Vilas / Olah, Marta / Rabadan, Raul / Wu, Cheng-Chia / Gartrell, Robyn D

International journal of radiation oncology, biology, physics

2024

Abstract: Purpose: Diffuse midline glioma (DMG) is a fatal tumor traditionally treated with radiation therapy (RT) and previously characterized as having a noninflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose ... ...

Abstract	Purpose: Diffuse midline glioma (DMG) is a fatal tumor traditionally treated with radiation therapy (RT) and previously characterized as having a noninflammatory tumor immune microenvironment (TIME). FLASH is a novel RT technique using ultra-high dose rate that is associated with decreased toxicity and effective tumor control. However, the effect of FLASH and conventional (CONV) RT on the DMG TIME has not yet been explored. Methods and materials: Here, we performed single-cell RNA sequencing (scRNA-seq) and flow cytometry on immune cells isolated from an orthotopic syngeneic murine model of brainstem DMG after the use of FLASH (90 Gy/sec) or CONV (2 Gy/min) dose-rate RT and compared to unirradiated tumor (SHAM). Results: At day 4 post-RT, FLASH exerted similar effects as CONV in the predominant microglial (MG) population, including the presence of two activated subtypes. However, at day 10 post-RT, we observed a significant increase in the type 1 interferon α/β receptor (IFNAR+) in MG in CONV and SHAM compared to FLASH. In the non-resident myeloid clusters of macrophages (MACs) and dendritic cells (DCs), we found increased type 1 interferon (IFN1) pathway enrichment for CONV compared to FLASH and SHAM by scRNA-seq. We observed this trend by flow cytometry at day 4 post-RT in IFNAR+ MACs and DCs, which equalized by day 10 post-RT. DMG control and murine survival were equivalent between RT dose rates. Conclusions: Our work is the first to map CONV and FLASH immune alterations of the DMG TIME with single-cell resolution. Although DMG tumor control and survival were similar between CONV and FLASH, we found that changes in immune compartments differed over time. Importantly, although both RT modalities increased IFN1, we found that the timing of this response was cell-type and dose-rate dependent. These temporal differences, particularly in the context of tumor control, warrant further study.
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	197614-x
ISSN	1879-355X ; 0360-3016
ISSN (online)	1879-355X
ISSN	0360-3016
DOI	10.1016/j.ijrobp.2024.01.219
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Article ; Online: Dynamic changes in Ezh2 gene occupancy underlie its involvement in neural stem cell self-renewal and differentiation towards oligodendrocytes.

Sher, Falak / Boddeke, Erik / Olah, Marta / Copray, Sjef

PloS one

2012 Volume 7, Issue 7, Page(s) e40399

Abstract: Background: The polycomb group protein Ezh2 is an epigenetic repressor of transcription originally found to prevent untimely differentiation of pluripotent embryonic stem cells. We previously demonstrated that Ezh2 is also expressed in multipotent ... ...

Abstract	Background: The polycomb group protein Ezh2 is an epigenetic repressor of transcription originally found to prevent untimely differentiation of pluripotent embryonic stem cells. We previously demonstrated that Ezh2 is also expressed in multipotent neural stem cells (NSCs). We showed that Ezh2 expression is downregulated during NSC differentiation into astrocytes or neurons. However, high levels of Ezh2 remained present in differentiating oligodendrocytes until myelinating. This study aimed to elucidate the target genes of Ezh2 in NSCs and in premyelinating oligodendrocytes (pOLs). Methodology/principal findings: We performed chromatin immunoprecipitation followed by high-throughput sequencing to detect the target genes of Ezh2 in NSCs and pOLs. We found 1532 target genes of Ezh2 in NSCs. During NSC differentiation, the occupancy of these genes by Ezh2 was alleviated. However, when the NSCs differentiated into oligodendrocytes, 393 of these genes remained targets of Ezh2. Analysis of the target genes indicated that the repressive activity of Ezh2 in NSCs concerns genes involved in stem cell maintenance, in cell cycle control and in preventing neural differentiation. Among the genes in pOLs that were still repressed by Ezh2 were most prominently those associated with neuronal and astrocytic committed cell lineages. Suppression of Ezh2 activity in NSCs caused loss of stem cell characteristics, blocked their proliferation and ultimately induced apoptosis. Suppression of Ezh2 activity in pOLs resulted in derangement of the oligodendrocytic phenotype, due to re-expression of neuronal and astrocytic genes, and ultimately in apoptosis. Conclusions/significance: Our data indicate that the epigenetic repressor Ezh2 in NSCs is crucial for proliferative activity and maintenance of neural stemness. During differentiation towards oligodendrocytes, Ezh2 repression continues particularly to suppress other neural fate choices. Ezh2 is completely downregulated during differentiation towards neurons and astrocytes allowing transcription of these differentiation programs. The specific fate choice towards astrocytes or neurons is apparently controlled by epigenetic regulators other than Ezh2.
MeSH term(s)	Animals ; Apoptosis ; Brain/cytology ; Cell Cycle ; Cell Differentiation ; Cell Proliferation ; Chromatin Immunoprecipitation ; Enhancer of Zeste Homolog 2 Protein ; Genome/genetics ; Histones/metabolism ; Immunoglobulin G ; Lysine/metabolism ; Mice ; Mice, Inbred C57BL ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Oligodendroglia/cytology ; Oligodendroglia/metabolism ; Polycomb Repressive Complex 2/genetics ; Polycomb Repressive Complex 2/metabolism ; RNA, Small Interfering/metabolism ; Signal Transduction ; Transforming Growth Factor beta/metabolism
Chemical Substances	Histones ; Immunoglobulin G ; RNA, Small Interfering ; Transforming Growth Factor beta ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) ; Ezh2 protein, mouse (EC 2.1.1.43) ; Polycomb Repressive Complex 2 (EC 2.1.1.43) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2012-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0040399
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Article ; Online: EPIGENOMIC FEATURES RELATED TO MICROGLIA ARE ASSOCIATED WITH ATTENUATED EFFECT OF APOE ε4 ON ALZHEIMER'S DISEASE RISK IN HUMANS.

Alzheimer's & dementia : the journal of the Alzheimer's Association

2020 Volume 16, Issue Suppl 2

Abstract: ... Not ... ...

Abstract	Not all
MeSH term(s)	Aged ; Alleles ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Apolipoprotein E4/genetics ; Brain/pathology ; Epigenomics ; Female ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Male ; Microglia/metabolism
Chemical Substances	Apolipoprotein E4
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.043533
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Article ; Online: A cortical immune network map identifies distinct microglial transcriptional programs associated with β-amyloid and Tau pathologies.

Patrick, Ellis / Olah, Marta / Taga, Mariko / Klein, Hans-Ulrich / Xu, Jishu / White, Charles C / Felsky, Daniel / Agrawal, Sonal / Gaiteri, Chris / Chibnik, Lori B / Mostafavi, Sara / Schneider, Julie A / Bennett, David A / Bradshaw, Elizabeth M / De Jager, Philip L

Translational psychiatry

2021 Volume 11, Issue 1, Page(s) 50

Abstract: Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co- ... ...

Abstract	Microglial dysfunction has been proposed as one of the many cellular mechanisms that can contribute to the development of Alzheimer's disease (AD). Here, using a transcriptional network map of the human frontal cortex, we identify five modules of co-expressed genes related to microglia and assess their role in the neuropathologic features of AD in 540 subjects from two cohort studies of brain aging. Two of these transcriptional programs-modules 113 and 114-relate to the accumulation of β-amyloid, while module 5 relates to tau pathology. We replicate these associations in brain epigenomic data and in two independent datasets. In terms of tau, we propose that module 5, a marker of activated microglia, may lead to tau accumulation and subsequent cognitive decline. We validate our model further by showing that three representative module 5 genes (ACADVL, TRABD, and VASP) encode proteins that are upregulated in activated microglia in AD.
MeSH term(s)	Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism ; Brain/metabolism ; Cognitive Dysfunction ; Humans ; Microglia/metabolism ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Amyloid beta-Peptides ; tau Proteins
Language	English
Publishing date	2021-01-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-020-01175-9
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Article ; Online: Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer's dementia.

Kaneshwaran, Kirusanthy / Olah, Marta / Tasaki, Shinya / Yu, Lei / Bradshaw, Elizabeth M / Schneider, Julie A / Buchman, Aron S / Bennett, David A / De Jager, Philip L / Lim, Andrew S P

Science advances

2019 Volume 5, Issue 12, Page(s) eaax7331

Abstract: Sleep disruption is associated with cognitive decline and dementia in older adults; however, the underlying mechanisms are unclear. In rodents, sleep disruption causes microglial activation, inhibition of which improves cognition. However, data from ... ...

Abstract	Sleep disruption is associated with cognitive decline and dementia in older adults; however, the underlying mechanisms are unclear. In rodents, sleep disruption causes microglial activation, inhibition of which improves cognition. However, data from humans are lacking. We studied participants in two cohort studies of older persons-the Rush Memory and Aging Project and the Religious Orders Study. We assessed sleep fragmentation by actigraphy and related this to cognitive function, to neocortical microglial marker gene expression measured by RNA sequencing, and to the neocortical density of microglia assessed by immunohistochemistry. Greater sleep fragmentation was associated with higher neocortical expression of genes characteristic of aged microglia, and a higher proportion of morphologically activated microglia, independent of chronological age- and dementia-related neuropathologies. Furthermore, these were, in turn, associated with worse cognition. This suggests that sleep fragmentation is accompanied by accelerated microglial aging and activation, which may partially underlie its association with cognitive impairment.
MeSH term(s)	Aged, 80 and over ; Aging/genetics ; Aging/pathology ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/genetics ; Alzheimer Disease/physiopathology ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/physiopathology ; Dementia/diagnostic imaging ; Dementia/genetics ; Dementia/physiopathology ; Female ; Humans ; Male ; Memory/physiology ; Microglia/metabolism ; Microglia/pathology ; Sequence Analysis, RNA ; Sleep/genetics ; Sleep/physiology ; Sleep Deprivation/genetics ; Sleep Deprivation/physiopathology ; Sleep Wake Disorders/diagnostic imaging ; Sleep Wake Disorders/genetics ; Sleep Wake Disorders/physiopathology
Language	English
Publishing date	2019-12-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.aax7331
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Article ; Online: Functional consequences of retinopetal fibers originating in the dorsal raphe nucleus.

Lörincz, Magor L / Oláh, Márta / Juhász, Gábor

The International journal of neuroscience

2008 Volume 118, Issue 10, Page(s) 1374–1383

Abstract: The existence of centrifugal fibers projecting into the mammalian retina is well known. However, their precise physiological role is poorly understood. Here we report that stimulation of the dorsal raphe nucleus (DRN) in freely moving rats produces ... ...

Abstract	The existence of centrifugal fibers projecting into the mammalian retina is well known. However, their precise physiological role is poorly understood. Here we report that stimulation of the dorsal raphe nucleus (DRN) in freely moving rats produces profound effects on the electroretinogram (ERG). Most notably, activation of the dorsal raphe-retinal pathway causes a significant decrease in the latency of the b-wave and accompanying oscillatory potentials. In addition, dorsal raphe stimulation leads to a significant increase in the amplitude of oscillatory potentials. These results, therefore, provide the first demonstration of a functional role for the retinopetal fiber system originating in the and suggest that this structure can exert a powerful influence over the temporal sharpness and efficacy of retinal responsiveness.
MeSH term(s)	Afferent Pathways/physiology ; Animals ; Electric Stimulation/methods ; Electroencephalography/methods ; Electrooculography/methods ; Evoked Potentials/physiology ; Male ; Raphe Nuclei/physiology ; Rats ; Rats, Sprague-Dawley ; Reaction Time/physiology ; Retina/physiology ; Wakefulness
Language	English
Publishing date	2008-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3061-2
ISSN	1563-5279 ; 1543-5245 ; 0020-7454
ISSN (online)	1563-5279 ; 1543-5245
ISSN	0020-7454
DOI	10.1080/00207450601050147
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Article ; Online: Chi3l3 induces oligodendrogenesis in an experimental model of autoimmune neuroinflammation.

Starossom, Sarah C / Campo Garcia, Juliana / Woelfle, Tim / Romero-Suarez, Silvina / Olah, Marta / Watanabe, Fumihiro / Cao, Li / Yeste, Ada / Tukker, John J / Quintana, Francisco J / Imitola, Jaime / Witzel, Franziska / Schmitz, Dietmar / Morkel, Markus / Paul, Friedemann / Infante-Duarte, Carmen / Khoury, Samia J

Nature communications

2019 Volume 10, Issue 1, Page(s) 217

Abstract: In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of ... ...

Abstract	In demyelinating diseases including multiple sclerosis (MS), neural stem cells (NSCs) can replace damaged oligodendrocytes if the local microenvironment supports the required differentiation process. Although chitinase-like proteins (CLPs) form part of this microenvironment, their function in this differentiation process is unknown. Here, we demonstrate that murine Chitinase 3-like-3 (Chi3l3/Ym1), human Chi3L1 and Chit1 induce oligodendrogenesis. In mice, Chi3l3 is highly expressed in the subventricular zone, a stem cell niche of the adult brain, and in inflammatory brain lesions during experimental autoimmune encephalomyelitis (EAE). We find that silencing Chi3l3 increases severity of EAE. We present evidence that in NSCs Chi3l3 activates the epidermal growth factor receptor (EGFR), thereby inducing Pyk2-and Erk1/2- dependent expression of a pro-oligodendrogenic transcription factor signature. Our results implicate CLP-EGFR-Pyk2-MEK-ERK as a key intrinsic pathway controlling oligodendrogenesis.
MeSH term(s)	Animals ; Chitinase-3-Like Protein 1/metabolism ; Encephalomyelitis, Autoimmune, Experimental/etiology ; ErbB Receptors/metabolism ; Female ; HEK293 Cells ; Hexosaminidases/metabolism ; Humans ; Lectins/metabolism ; MAP Kinase Signaling System ; Mice ; Neural Stem Cells/metabolism ; Oligodendroglia/metabolism ; beta-N-Acetylhexosaminidases/metabolism
Chemical Substances	CHI3L1 protein, human ; Chitinase-3-Like Protein 1 ; Lectins ; EGFR protein, mouse (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; Hexosaminidases (EC 3.2.1.-) ; chitotriosidase (EC 3.2.1.-) ; Chil3 protein, mouse (EC 3.2.1.52) ; beta-N-Acetylhexosaminidases (EC 3.2.1.52)
Language	English
Publishing date	2019-01-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-018-08140-7
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