Emerging roles for CNS fibroblasts in health, injury and disease

Dorrier, Cayce; Jones, Hannah; Pintarić, Lucija; Siegenthaler, Julie A.; Daneman, Richard

doi:10.1038/s41583-021-00525-w

Cited by 113 publications

(127 citation statements)

References 126 publications

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“…Classical spinal cord glial scars also contain fibroblasts that originate from meninges, choroid plexus, and perivascular spaces ( Dorrier et al, 2021 ; Silver and Miller, 2004 ; Xu and Yao, 2021 ). In the rat DFP study, no trauma was involved.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Gage

Gard

Thippeswamy

2022

Front. Cell Dev. Biol.

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Glial scars have been observed following stab lesions in the spinal cord and brain but not observed and characterized in chemoconvulsant-induced epilepsy models. Epilepsy is a disorder characterized by spontaneous recurrent seizures and can be modeled in rodents. Diisopropylfluorophosphate (DFP) exposure, like other real-world organophosphate nerve agents (OPNAs) used in chemical warfare scenarios, can lead to the development of status epilepticus (SE). We have previously demonstrated that DFP-induced SE promotes epileptogenesis which is characterized by the development of spontaneous recurrent seizures (SRS), gliosis, and neurodegeneration. In this study, we report classical glial scars developed in the piriform cortex, but not in the hippocampus, by 8 days post-exposure. We challenged both male and female rats with 4–5 mg/kg DFP (s.c.) followed immediately by 2 mg/kg atropine sulfate (i.m.) and 25 mg/kg pralidoxime (i.m.) and one hour later by midazolam (i.m). Glial scars were present in the piriform cortex/amygdala region in 73% of the DFP treated animals. No scars were found in controls. Scars were characterized by a massive clustering of reactive microglia surrounded by hypertrophic reactive astrocytes. The core of the scars was filled with a significant increase of IBA1 and CD68 positive cells and a significant reduction in NeuN positive cells compared to the periphery of the scars. There was a significantly higher density of reactive GFAP, complement 3 (C3), and inducible nitric oxide synthase (iNOS) positive cells at the periphery of the scar compared to similar areas in controls. We found a significant increase in chondroitin sulfate proteoglycans (CS-56) in the periphery of the scars compared to a similar region in control brains. However, there was no change in TGF-β1 or TGF-β2 positive cells in or around the scars in DFP-exposed animals compared to controls. In contrast to stab-induced scars, we did not find fibroblasts (Thy1.1) in the scar core or periphery. There were sex differences with respect to the density of iNOS, CD68, NeuN, GFAP, C3 and CS-56 positive cells. This is the first report of cortical glial scars in rodents with systemic chemoconvulsant-induced SE. Further investigation could help to elucidate the mechanisms of scar development and mitigation strategies.

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Section: Discussionmentioning

confidence: 99%

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Gage

Gard

Thippeswamy

2022

Front. Cell Dev. Biol.

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“…ALS patients in whom fibroblast protein product accumulates in perivascular space have shorter survival times [95]. In fact, as one of the indispensable components of the vasculature, the function of fibroblasts is somewhat unclear, and there may be unknown functions in SMA [85].…”

Section: Discussionmentioning

confidence: 99%

“…vasculature is a crucial source of material and energy metabolism in the CNS, and their integrity is key to ensuring the normal function of the spinal cord. Structural and functional abnormalities of the vasculature are widespread in neurodegenerative diseases [84; 85]. Vascular defects have been identified in SMA patients and mouse models through morphological observation [21; 86; 87; 88].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

Sun

Qiu

Yang

et al. 2022

Preprint

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Although spinal muscular atrophy (SMA) is a motor neuron disease caused by the loss of survival of motor neuron proteins, there is growing evidence that lesions in nonmotor neuron cells are involved in SMA pathogenesis. Transcriptome alterations occurring at the single-cell level in SMA spinal cord are unknown. Here, we performed single-cell RNA sequencing of the spinal cord of a severe SMA mouse model, and characterized ten cell types as well as their differentially expressed genes. Using CellChat, we found that cellular communication between different cell types in the spinal cord of SMA mice is substantially reduced. A dimensionality reduction analysis revealed 29 cell subtypes and differentially expressed genes for each subtype. Among them, the most significant change in the SMA spinal cord at the single-cell level was observed in a subpopulation of vascular fibroblasts. This subpopulation was greatly reduced, which may be responsible for vascular defects in SMA mice and may lead to widespread reductions in protein synthesis and energy metabolism. This study is the first to report a single-cell atlas of the spinal cord of mice with severe SMA, providing new insights into SMA pathogenesis.

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“…The meningeal layers are the dura mater, the arachnoid mater, and the pia mater and cover the entire surface of the brain, and spinal cord (Figure 1A) and are mainly composed of fibroblasts (18)(19)(20). The dura mater is the outermost layer and is directly attached to the skull.…”

Section: The Leptomeningeal Blood-cerebrospinal Fluid (Csf) Barriermentioning

confidence: 99%

How Does the Immune System Enter the Brain?

Mapunda

Tibar²,

Regragui³

et al. 2022

Front. Immunol.

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Multiple Sclerosis (MS) is considered the most frequent inflammatory demyelinating disease of the central nervous system (CNS). It occurs with a variable prevalence across the world. A rich armamentarium of disease modifying therapies selectively targeting specific actions of the immune system is available for the treatment of MS. Understanding how and where immune cells are primed, how they access the CNS in MS and how immunomodulatory treatments affect neuroinflammation requires a proper knowledge on the mechanisms regulating immune cell trafficking and the special anatomy of the CNS. The brain barriers divide the CNS into different compartments that differ with respect to their accessibility to cells of the innate and adaptive immune system. In steady state, the blood-brain barrier (BBB) limits immune cell trafficking to activated T cells, which can reach the cerebrospinal fluid (CSF) filled compartments to ensure CNS immune surveillance. In MS immune cells breach a second barrier, the glia limitans to reach the CNS parenchyma. Here we will summarize the role of the endothelial, epithelial and glial brain barriers in regulating immune cell entry into the CNS and which immunomodulatory treatments for MS target the brain barriers. Finally, we will explore current knowledge on genetic and environmental factors that may influence immune cell entry into the CNS during neuroinflammation in Africa.

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Emerging roles for CNS fibroblasts in health, injury and disease

Cited by 113 publications

References 126 publications

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Characterization of Cortical Glial Scars in the Diisopropylfluorophosphate (DFP) Rat Model of Epilepsy

Single-cell RNA sequencing reveals dysregulation of spinal cord cell types in a severe spinal muscular atrophy mouse model

How Does the Immune System Enter the Brain?

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