Single cell molecular alterations reveal target cells and pathways of concussive brain injury

Arneson, Douglas; Zhang, Guanglin; Ying, Zhe; Zhuang, Yizhou; Byun, Hyae Ran; Ahn, In Sook; Gómez‐Pinilla, Fernando; Yang, Xia

doi:10.1038/s41467-018-06222-0

Cited by 135 publications

(174 citation statements)

References 62 publications

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“…45 ), MGP 46 ), choroid cells (LCN2 (ref. 47 ), 1500015O10Rik 48 ), endothelial cells (ITM2A 49 , FLT1 (ref. 50 )), GABAergic neuron (NPY 51 , NR2F2 (ref.…”

Section: Resultsmentioning

confidence: 99%

Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

Boreland

et al. 2020

Nat Commun

131

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Microglia, the brain-resident macrophages, exhibit highly dynamic functions in neurodevelopment and neurodegeneration. Human microglia possess unique features as compared to mouse microglia, but our understanding of human microglial functions is largely limited by an inability to obtain human microglia under homeostatic states. Here, we develop a human pluripotent stem cell (hPSC)-based microglial chimeric mouse brain model by transplanting hPSC-derived primitive macrophage progenitors into neonatal mouse brains. Single-cell RNAsequencing of the microglial chimeric mouse brains reveals that xenografted hPSC-derived microglia largely retain human microglial identity, as they exhibit signature gene expression patterns consistent with physiological human microglia and recapitulate heterogeneity of adult human microglia. Importantly, the engrafted hPSC-derived microglia exhibit dynamic response to cuprizone-induced demyelination and species-specific transcriptomic differences in the expression of neurological disease-risk genes in microglia. This model will serve as a tool to study the role of human microglia in brain development and degeneration.

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“…45 ), MGP 46 ), choroid cells (LCN2 (ref. 47 ), 1500015O10Rik 48 ), endothelial cells (ITM2A 49 , FLT1 (ref. 50 )), GABAergic neuron (NPY 51 , NR2F2 (ref.…”

Section: Resultsmentioning

confidence: 99%

Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

Boreland

et al. 2020

Nat Commun

131

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“…To study the dynamics of Wnt signaling both in the mesenchyme and in the epithelium, we cultured E60 mandible slices for 12 and 24 h and compared β‐catenin expression levels between the nucleus and cytoplasm among the E60 (cultured for 0 h), E90, E60 (cultured for 12 h), and E60 (cultured for 24 h) groups via an RNAscope assay—an RNA ISH technique for single‐molecule detection that can identify the subcellular location of signal (i.e., in the nucleus and cytoplasm) (Arneson et al , ; Schulz et al , ). Quantification results indicated that during PC initiation from E60 to E90, the nuclear β‐catenin signal of the mesenchyme decreased approximately 10‐fold, while the nuclear β‐catenin signal of the epithelium increased approximately threefold.…”

Section: Resultsmentioning

confidence: 99%

Biomechanical stress regulates mammalian tooth replacement via the integrin β1‐RUNX2‐Wnt pathway

et al. 2019

The EMBO Journal

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Renewal of integumentary organs occurs cyclically throughout an organism's lifetime, but the mechanism that initiates each cycle remains largely unknown. In a miniature pig model of tooth development that resembles tooth development in humans, the permanent tooth did not begin transitioning from the resting to the initiation stage until the deciduous tooth began to erupt. This eruption released the accumulated mechanical stress inside the mandible. Mechanical stress prevented permanent tooth development by regulating expression and activity of the integrin b1-ERK1-RUNX2 axis in the surrounding mesenchyme. We observed similar molecular expression patterns in human tooth germs. Importantly, the release of biomechanical stress induced downregulation of RUNX2-wingless/integrated (Wnt) signaling in the mesenchyme between the deciduous and permanent tooth and upregulation of Wnt signaling in the epithelium of the permanent tooth, triggering initiation of its development. Consequently, our findings identified biomechanical stress-associated Wnt modulation as a critical initiator of organ renewal, possibly shedding light on the mechanisms of integumentary organ regeneration.

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“…Recent scRNA seq technologies have made it possible to study transcriptional 71 differences in each cell-type in healthy and diseased brains, as well as in brain injuries such as 72 traumatic brain injury (Keren-Shaul, Spinrad et al 2017, Arneson, Zhang et al 2018, Batiuk,73 Martirosyan et al 2020). In this study, we were interested in the transcriptional changes that 74 occur after astrocyte-specific activation using the Gq-DREADD.…”

Section: Introduction 44mentioning

confidence: 99%

Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia

Philtjens

Turnbull

Thedy

et al. 2020

Preprint

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25Astrocytes are the most common glial cell type in the brain, yet, it is still not clear how their 26activation affects the transcriptome of other brain cells such as microglia and neurons. 27Engineered G protein-coupled receptors called Designer Receptors Exclusively Activated by 28Designer Drugs (DREADDS) make it possible to selectively activate specific cell types, such as 29 neurons and astrocytes. By combining the selective activation of astrocytes with single cell RNA 30 sequencing, we were able to study transcriptional changes that occur in response to the 31 activation of astrocytes at the single cell level. Interestingly, our data shows that long-term 32 activation of astrocytes in healthy mice results in dramatic alteration in the transcriptome of 33 astrocytes and microglia. Genes that were differentially expressed in these Gq-DREADD-34 activated astrocytes were involved in neurogenesis and low density lipoprotein particle biology, 35while those in the microglia were involved in the response to lipoproteins, and the migration and 36 chemotaxis of immune cells. Furthermore, network analysis showed that Gq-DREADD-37 mediated activation in astrocytes resulted in an upregulation of genes involved in the G protein-38 coupled receptor signaling pathway and calcium ion homeostasis. This confirmed the activation 39 of astrocytes through the expressed DREADDS. Our findings show the importance of 40considering the transcriptomic alteration in microglia and neurons after the activation of 41 astrocytes in in vivo models. Therefore, our data will serve as a resource for the broader 42 neuroscience community.

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Single cell molecular alterations reveal target cells and pathways of concussive brain injury

Cited by 135 publications

References 62 publications

Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain

Biomechanical stress regulates mammalian tooth replacement via the integrin β1‐RUNX2‐Wnt pathway

Single-cell resolution analysis of the crosstalk between chemogenically activated astrocytes and microglia

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