Neuronal and glial regulation of CNS angiogenesis and barriergenesis

Biswas, Saptarshi; Cottarelli, Azzurra; Agalliu, Dritan

doi:10.1242/dev.182279

Cited by 72 publications

(85 citation statements)

References 132 publications

(173 reference statements)

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“…In the retina, VEGF is expressed in multiple cell types, including neuronal cells, astrocytes, and Müller cells. 6 The distribution pattern of VEGF immunoreactivity in the retina was consistent with previous findings. 19,20 The degree of hypoxia at the peripheral avascular retina was lower in NMDA-treated eyes than in saline-treated eyes (Figure 7Aa,Ab,Ba,Bb).…”

Section: Changes In Hypoxic Status and Vegf Expression In Krn633-trsupporting

confidence: 91%

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus

Morita

Yoshizumi

Arima

et al. 2020

Developmental Dynamics

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Background: In mice, a tri-layered (superficial, intermediate, and deep) vascular structure is formed in the retina during the third postnatal week. Shortterm treatment of newborn mice with vascular endothelial growth factor (VEGF) receptor inhibitors delays the formation of superficial vascular plexus and this allows us to investigate the developmental process of superficial and deep vascular plexuses at the same time. Using this model, we examined the effect of pharmacological depletion of retinal neurons on the formation of superficial and deep vascular plexuses. Results: Neuronal cell loss induced by an intravitreal injection of N-methyl-Daspartic acid on postnatal day (P) 8 delayed vascular development in the deep layer but not in the superficial layer in mice treated with KRN633, a VEGF receptor inhibitor, on P0 and P1. In KRN633-treated mice, neuronal cell loss decreased the number of vertical sprouts originating from the superficial plexus without affecting the number of angiogenic sprouts growing in front. Neuronal cell loss did not impair networks of fibronectin and astrocytes in the superficial layer. Conclusions: Our results suggest that inner retinal neurons play a crucial role in forming the deep vascular plexus by directing the sprouts from the superficial blood vessels to the deep layer. K E Y W O R D S astrocyte, hypoxia, neuronal cell, vascular development, vascular endothelial growth factor 1 | INTRODUCTION In the mouse retina, three planar (superficial, intermediate, and deep) vascular networks are established during the third postnatal week. 1,2 Superficial vascular plexus forms during the first postnatal week, and the vascularization in the deep layer starts after the vasculature covers the entire retinal surface (7-10 days of postnatal age). Afterward, the intermediate vascular plexus is formed. 2 Vascular endothelial growth factor (VEGF) plays an important role in the formation of retinal vascular network. Hypoxia and hypoxia-inducible factors (particularly their subunits HIF-1α and HIF-2α) regulate VEGF expression. 3-5 In the retina, neuronal cells and glial cells produce VEGF and contribute to the development of the retinal vasculature. 6 For example, previous studies have demonstrated that endothelial cells failed to migrate to the retina from the optic disc in retinal ganglion cell

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Section: Changes In Hypoxic Status and Vegf Expression In Krn633-trsupporting

confidence: 91%

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus

Morita

Yoshizumi

Arima

et al. 2020

Developmental Dynamics

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“…Over the past decade many groups aimed to advance in vitro models of the BBB to circumvent the technical complexity of studying the BBB in vivo. The main difficulty of designing such models is to phenocopy the high TEER observed in vivo considering that BBB traits are not intrinsic to ECs, but rather the result of complex interactions with other cell types such as pericytes and astrocytes ( 44 ). Consequently, brain microvascular ECs lose their BBB properties, especially high TEER, when cultured in vitro ( 45 – 48 ).…”

Section: Discussionmentioning

confidence: 99%

Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

Houghton

Magdeldin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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140

152

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Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood–brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (ETV2, ERG, and FLI1) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery.

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“…Microglia and astrocytes are the CNS resident cells most prominently involved in early innate responses to injury, autoimmune attack, or infection [27]. Unfortunately, pathogens can induce devastating in ammatory damage to the CNS, leading to rapid mortality or long-term neurological disabilities.…”

Section: Discussionmentioning

confidence: 99%

“…AG205 affects virus multiplication more in U251 cells than in SK-N-SH cells. Consistently, the innate immune surveillance is mainly coordinated by glial cells in the CNS [27]. These CNS resident cells are assumed to orchestrate the immune response, which assists in combating infections in the brain.…”

Section: Ag205 Inhibited the Iav-induced Rig-i-dependent Antiviral Rementioning

confidence: 99%

Influenza A Virus Mediated Downregulation of Progesterone Receptor Membrane Component-1 Inhibits RIG-I-dependent Antiviral Response in Central Nervous System

Huang¹,

Zhang²,

Gong³

et al. 2020

Preprint

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Background: The influenza A virus (IAV) enters the central nervous system (CNS) via multiple routes and causes neurological symptoms. In this process, it develops multiple strategies to escape the host anti-viral immune system, and infects the central nervous system (CNS). Progesterone receptor membrane component-1 (PGRMC1) is highly expressed in the CNS, where it exerts a neurotrophic effect. However, how PGRMC1 affects IAV remains unclear.Methods: In this study, we aimed to investigate the role of PGRMC1 in regulating antiviral defense response in brain tissue. Toward this, we used both mouse model of IAV infection and the human neuroblastoma cell line SK-N-SH and human brain glioma cell line U251 . High-throughput RNA sequencing (RNA-seq) was used to obtain an unbiased profile of the cellular response to IAV H5N6 infection in mice brain. Results: Here, RNA-seq revealed 240 differentially expressed genes in the IAV-infected brains. Among the significantly down-regulated genes, we focused on the gene encoding progesterone receptor membrane component-1 (PGRMC1) and observed that IAV H5N6 infection clearly inhibited PGRMC1 in both neuroblastoma and glioma cells. Furthermore, treatment with AG205, a PGRMC1-specific inhibitor, or PGRMC1 knockout promoted H5N6 multiplication in vitro, while overexpression of PGRMC1 resulted in opposite effects. Furthermore, AG205 treatment or PGRMC1 knockout significantly inhibited RIG-I-mediated IFN-β signaling pathway and reduced the levels of several antiviral proteins (Mx1 and ISG15). In addition, PGRMC1-mediated regulation of IFN signaling relied on inhibition of the expression and ubiquitination of RIG-I.Conclusion: Conclusively, our results show for the first time that IAV H5N6 down-regulates PGRMC1 expression to contribute to virus proliferation by inhibiting RIG-I-mediated IFN-β production in the brain. These findings may offer new insights regarding the interplay between IAV and host factors that may impact IAV pathogenicity in the brain.

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Neuronal and glial regulation of CNS angiogenesis and barriergenesis

Cited by 72 publications

References 132 publications

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus

Pharmacological depletion of retinal neurons prevents vertical angiogenic sprouting without affecting the superficial vascular plexus

Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

Influenza A Virus Mediated Downregulation of Progesterone Receptor Membrane Component-1 Inhibits RIG-I-dependent Antiviral Response in Central Nervous System

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