scholarly journals A MAC2-positive progenitor-like microglial population is resistant to CSF1R inhibition in adult mouse brain

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Lihong Zhan ◽  
Li Fan ◽  
Lay Kodama ◽  
Peter Dongmin Sohn ◽  
Man Ying Wong ◽  
...  

Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglia rely on CSF1R signaling for survival. However, a small subset of microglia in mouse brains can survive without CSF1R signaling and reestablish the microglial homeostatic population after CSF1R signaling returns. Using single-cell transcriptomic analysis, we characterized the heterogeneous microglial populations under CSF1R inhibition, including microglia with reduced homeostatic markers and elevated markers of inflammatory chemokines and proliferation. Importantly, MAC2/Lgals3 was upregulated under CSF1R inhibition, and shared striking similarities with microglial progenitors in the yolk sac and immature microglia in early embryos. Lineage-tracing studies revealed that these MAC2+ cells were of microglial origin. MAC2+ microglia were also present in non-treated adult mouse brains and exhibited immature transcriptomic signatures indistinguishable from those that survived CSF1R inhibition, supporting the notion that MAC2+ progenitor-like cells are present among adult microglia.

2019 ◽  
Author(s):  
Lihong Zhan ◽  
Peter Dongmin Sohn ◽  
Yungui Zhou ◽  
Yaqiao Li ◽  
Li Gan

ABSTRACTMicroglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglial population relies on Csf1r signaling for survival and maintenance. However, a small subset of microglia in the murine brain can survive without Csf1r signaling, and reestablishes homeostasis after Csf1r signaling returns. Using single-cell RNA-seq, we characterized the heterogeneous microglial populations under Csf1r inhibition, including microglia lacking homeostatic markers and populations with elevated markers of monocytes, granulocytes and dendritic cells. Importantly, Mac2 is distinctively expressed in a subset of Csf1r-independent microglia cells, which were highly proliferative and shared striking similarities with those of microglial progenitors in yolk sac and early embryos. Lineage-tracing revealed that the Mac2+ population is of microglial origin and does not come from periphery monocytes. In non-treated mouse brains, Mac2+ microglia exhibited progenitor transcriptomic signature indistinguishable from those survived csf1r inhibition, supporting Mac2+ progenitor-like cells are present among homeostatic microglia.


2021 ◽  
Vol 288 (1945) ◽  
pp. 20202793
Author(s):  
Alexander Yermanos ◽  
Daniel Neumeier ◽  
Ioana Sandu ◽  
Mariana Borsa ◽  
Ann Cathrin Waindok ◽  
...  

Neuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer's disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system. Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor and T cell receptor repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system of aged male mice. Furthermore, many of these B cells were of the IgM and IgD isotypes, and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.


2020 ◽  
Vol 6 (3) ◽  
pp. eaay6324 ◽  
Author(s):  
Jason R. Plemel ◽  
Jo Anne Stratton ◽  
Nathan J. Michaels ◽  
Khalil S. Rawji ◽  
Eric Zhang ◽  
...  

Microglia and infiltrating macrophages are thought to orchestrate the central nervous system (CNS) response to injury; however, the similarities between these cells make it challenging to distinguish their relative contributions. We genetically labeled microglia and CNS-associated macrophages to distinguish them from infiltrating macrophages. Using single-cell RNA sequencing, we describe multiple microglia activation states, one of which was enriched for interferon associated signaling. Although blood-derived macrophages acutely infiltrated the demyelinated lesion, microglia progressively monopolized the lesion environment where they surrounded infiltrating macrophages. In the microglia-devoid sciatic nerve, the infiltrating macrophage response was sustained. In the CNS, the preferential proliferation of microglia and sparse microglia death contributed to microglia dominating the lesion. Microglia ablation reversed the spatial restriction of macrophages with the demyelinated spinal cord, highlighting an unrealized macrophages-microglia interaction. The restriction of peripheral inflammation by microglia may be a previously unidentified mechanism by which the CNS maintains its “immune privileged” status.


2020 ◽  
Author(s):  
Alexander Yermanos ◽  
Daniel Neumeier ◽  
Ioana Sandu ◽  
Mariana Borsa ◽  
Ann Cathrin Waindok ◽  
...  

AbstractNeuroinflammation plays a crucial role during ageing and various neurological conditions, including Alzheimer’s disease, multiple sclerosis and infection. Technical limitations, however, have prevented an integrative analysis of how lymphocyte immune receptor repertoires and their accompanying transcriptional states change with age in the central nervous system (CNS). Here, we leveraged single-cell sequencing to simultaneously profile B cell receptor (BCR) and T cell receptor (TCR) repertoires and accompanying gene expression profiles in young and old mouse brains. We observed the presence of clonally expanded B and T cells in the central nervous system (CNS) of aged mice. Furthermore, many of these B cells were of the IgM and IgD isotype and had low levels of somatic hypermutation. Integrating gene expression information additionally revealed distinct transcriptional profiles of these clonally expanded lymphocytes. Our findings implicate that clonally related T and B cells in the CNS of elderly mice may contribute to neuroinflammation accompanying homeostatic ageing.


Cephalalgia ◽  
2019 ◽  
Vol 40 (5) ◽  
pp. 517-523
Author(s):  
Angeliki Vgontzas ◽  
William Renthal

Background Genome-wide association studies have implicated dozens of genes with migraine susceptibility, but it remains unclear in which nervous system cell types these genes are expressed. Methods Using single-cell RNA sequencing data from the central and peripheral nervous system, including the trigeminal ganglion, the expression of putative migraine-associated genes was compared across neuronal, glial and neurovascular cell types within these tissues. Results Fifty-four putative migraine-associated genes were expressed in the central nervous system, peripheral nervous system or neurovascular cell types analyzed. Six genes (11.1%) were selectively enriched in central nervous system cell types, three (5.5%) in neurovascular cell types, and two (3.7%) in peripheral nervous system cell types. The remaining genes were expressed in multiple cell types. Conclusions Single-cell RNA sequencing of the brain and peripheral nervous system localizes each migraine-associated gene to its respective nervous system tissue and the cell types in which it is expressed. While the majority of migraine-associated genes are broadly expressed, we identified several cell-type-specific migraine-associated genes in the central nervous system, peripheral nervous system, and neurovasculature. Trial registration: not applicable.


1988 ◽  
Vol 5 (4) ◽  
pp. 273-298 ◽  
Author(s):  
Miyuki Yamamoto ◽  
Patricia Marshall ◽  
Lisa M. Hemmendinger ◽  
Anne B. Boyer ◽  
Verne S. Caviness

Science ◽  
2021 ◽  
Vol 372 (6540) ◽  
pp. eabf1230 ◽  
Author(s):  
Iain C. Clark ◽  
Cristina Gutiérrez-Vázquez ◽  
Michael A. Wheeler ◽  
Zhaorong Li ◽  
Veit Rothhammer ◽  
...  

Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.


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