Inflammatory hydrocephalus

Robert, Stephanie M.; Reeves, Benjamin C.; Marlier, Arnaud; Duy, Phan Q.; DeSpenza, Tyrone; Kundishora, Adam J.; Kiziltug, Emre; Singh, Amrita; Allington, Garrett; Alper, Seth L.; Kahle, Kristopher T.

doi:10.1007/s00381-021-05255-z

Cited by 10 publications

(5 citation statements)

References 152 publications

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“…ChP-mediated CSF hypersecretion can occur in the context of ChP hyperplasia 95,[106][107][108] , ChP papilloma or carcinoma [109][110][111] , and ChP inflammation 112,113 . Notably, the frequency of ChP hyperplasia (see Fig.…”

Section: Pten-mutant Csf Hypersecretion Is Associated With Inflammati...mentioning

confidence: 99%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

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Expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles (ventriculomegaly) is the quintessential feature of congenital hydrocephalus (CH) but also seen in autism spectrum disorder (ASD) and several neuropsychiatric diseases. PTEN is frequently mutated in ASD; here, we show PTEN is a bona fide risk gene for the development of ventriculomegaly, including neurosurgically-treated CH. Pten-mutant hydrocephalus is associated with aqueductal stenosis due to the hyperproliferation of periventricular Nkx2.1+ neural precursors (NPCs) and CSF hypersecretion from inflammation-dependent choroid plexus hyperplasia. The hydrocephalic Pten-mutant cortex exhibits ASD-like network dysfunction due to impaired activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or post-natal Everolimus corrects ventriculomegaly, rescues cortical deficits, and increases survival by antagonizing mTORC1-dependent Nkx2.1+ cell pathology. These results implicate a dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of NPCs and their interneuron descendants. These data identify a non-surgical treatment target for hydrocephalus and have implications for other developmental brain disorders.

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Section: Pten-mutant Csf Hypersecretion Is Associated With Inflammati...mentioning

confidence: 99%

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

DeSpenza¹,

Kiziltug²,

Allington³

et al. 2023

Preprint

Self Cite

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“…Inflammation and microglial activation have been proven to be key events in the different forms of congenital and acquired fetal-neonatal hydrocephalus, including those of GMH/IVH origin 13,31,[66][67][68][69][70] . In the present investigation, the observed effects of MSC-pretreatment can be related to their immunomodulatory properties 71,72 .…”

Section: A Combination Of Mesenchymal Stem Cells and Ependymal Progen...mentioning

confidence: 99%

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

Rodríguez-Pérez

Ojeda-Pérez

García-Bonilla

et al. 2023

Preprint

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Germinal matrix hemorrhages (GMH) and the consequent posthemorrhagic hydrocephalus (PHH) are among the most common and severe neurological complications of preterm birth that require lifelong complex neurosurgical care. GMH and PHH provoke disruption of neuroepithelium/ependyma development, a key structure implicated in brain development and homeostasis. Neuroepithelial/ependymal damage causes lifelong cognitive and motor deficits; however, no therapy is directed to recover the damaged ependyma. This study is aimed to test the possibilities of ependymal repair in GMH/PHH using neural stem cells (NSCs) or ependymal progenitors (EpPs). Thus, it sets the basis for a therapeutic approach to treating ependymal damage and preventing brain developmental deficits. GMH/PHH was induced in 4-day-old mice using different experimental procedures involving collagenase, blood, or blood serum injections. PHH severity was characterized using magnetic resonance, immunofluorescence, and protein expression quantification with mass spectrometry. Additionally, a newexvivoapproach using ventricular walls from mice developing moderate and severe GMH/PHH was generated to study ependymal restoration and wall regeneration after stem cell treatments. NSCs or EpPs obtained from newborn mice were transplanted in the explants, and pretreatment with mesenchymal stem cells (MSCs) was tested. Ependymal differentiation and the effect of MSC-conditioned microenvironment were investigated in both explants and primary cultures. In the animals, PHH severity was correlated with the extension of GMH, ependymal disruption, astroglial/microglial reactions, and ventriculomegaly. In the explants, the severity and extension of GMH hindered the survival rates of the transplanted NSCs/EpPs. In the explants affected with GMH, new multiciliated ependymal cells could be generated from transplanted NSCs and, more efficiently, from EpPs. Blood and TNFα negatively affected ciliogenesis in cells expressing Foxj1. Pretreatment with mesenchymal stem cells (MSC) improved the survival rates of EpPs and ependymal differentiation while reducing the edematous and inflammatory conditions in the explants. In conclusion, in GMH/PHH, the ependyma can be restored from either NSC or EpP transplantation, being EpPs in an MSC-conditioned microenvironment more efficient for this purpose. Modifying the neuroinflammatory microenvironment by MSC pretreatment positively influenced the success of the ependymal restoration.

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“…Hydrocephalus is a condition in which abnormal amounts of CSF accumulates within the CNS, typically resulting in increased intracranial pressure, macrocephaly, cognitive dysfunction, and death, if not properly diagnosed and treated. Although hydrocephalus has a wide range of etiologies, including congenital malformations, trauma, or tumor formation, research has shown that the most common cause world-wide is induced by infection, termed post-infectious hydrocephalus (PIH) [ 125 , 126 ]. Furthermore, recent research has shown that post-hemorrhagic hydrocephalus (PHH), another common cause, shares many similar pathophysiological pathways with PIH, namely through shared inflammatory mechanisms [ 125 , 127 , 128 ].…”

Section: The Cellular Response Of the Choroid Plexus To Specific Path...mentioning

confidence: 99%

“…Although hydrocephalus has a wide range of etiologies, including congenital malformations, trauma, or tumor formation, research has shown that the most common cause world-wide is induced by infection, termed post-infectious hydrocephalus (PIH) [ 125 , 126 ]. Furthermore, recent research has shown that post-hemorrhagic hydrocephalus (PHH), another common cause, shares many similar pathophysiological pathways with PIH, namely through shared inflammatory mechanisms [ 125 , 127 , 128 ]. The build-up of CSF has been commonly attributed to intraventricular obstruction of both CSF flow and reabsorption (choroid plexitis, tumor formation, narrowing of passages such as the foramen of Monro, or ablation of arachnoid granulations) [ 128 – 130 ].…”

Section: The Cellular Response Of the Choroid Plexus To Specific Path...mentioning

confidence: 99%

The choroid plexus and its role in the pathogenesis of neurological infections

Thompson

Brissette

Watt

2022

Fluids Barriers CNS

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The choroid plexus is situated at an anatomically and functionally important interface within the ventricles of the brain, forming the blood-cerebrospinal fluid barrier that separates the periphery from the central nervous system. In contrast to the blood–brain barrier, the choroid plexus and its epithelial barrier have received considerably less attention. As the main producer of cerebrospinal fluid, the secretory functions of the epithelial cells aid in the maintenance of CNS homeostasis and are capable of relaying inflammatory signals to the brain. The choroid plexus acts as an immunological niche where several types of peripheral immune cells can be found within the stroma including dendritic cells, macrophages, and T cells. Including the epithelia cells, these cells perform immunosurveillance, detecting pathogens and changes in the cytokine milieu. As such, their activation leads to the release of homing molecules to induce chemotaxis of circulating immune cells, driving an immune response at the choroid plexus. Research into the barrier properties have shown how inflammation can alter the structural junctions and promote increased bidirectional transmigration of cells and pathogens. The goal of this review is to highlight our foundational knowledge of the choroid plexus and discuss how recent research has shifted our understanding towards viewing the choroid plexus as a highly dynamic and important contributor to the pathogenesis of neurological infections. With the emergence of several high-profile diseases, including ZIKA and SARS-CoV-2, this review provides a pertinent update on the cellular response of the choroid plexus to these diseases. Historically, pharmacological interventions of CNS disorders have proven difficult to develop, however, a greater focus on the role of the choroid plexus in driving these disorders would provide for novel targets and routes for therapeutics.

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Inflammatory hydrocephalus

Cited by 10 publications

References 152 publications

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

Design of a stem cell-based therapy for ependymal repair in hydrocephalus associated with germinal matrix hemorrhages

The choroid plexus and its role in the pathogenesis of neurological infections

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