Infection of Brain Pericytes Underlying Neuropathology of COVID-19 Patients

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69.5 years; n = 7 control, median age = 68 years) and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in perivascular cells. Viral dsRNA was identified in the vascular wall and paralleled by perivascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood–brain barrier. Notably, cerebrospinal fluid from additional 16 individuals (n = 8 COVID-19, median age = 67 years; n = 8 control, median age = 69.5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to perivascular inflammation and a locally compromised blood–brain barrier.

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Infection of brain pericytes underlying neuropathology of COVID-19 patients

10.1101/2021.05.24.445532 ◽

2021 ◽

Author(s):

Matteo Bocci ◽

Clara Oudenaarden ◽

Xavier Saenz-Sardà ◽

Joel Simrén ◽

Arvid Edén ◽

...

Keyword(s):

Blood Brain Barrier ◽

Vascular Inflammation ◽

Vascular Wall ◽

Brain Barrier ◽

Blood Brain ◽

Viral Particles ◽

Brain Pericytes ◽

Wide Range ◽

Human Brains ◽

Pericyte Marker

A wide range of neurological manifestations have been associated with the development of COVID-19 following SARS-CoV-2 infection. However, the etiology of the neurological symptomatology is still largely unexplored. Here, we used state-of-the-art multiplexed immunostaining of human brains (n = 6 COVID-19, median age = 69,5 years; and n = 7 control, median age = 68 years), and demonstrated that expression of the SARS-CoV-2 receptor ACE2 is restricted to a subset of neurovascular pericytes. Strikingly, neurological symptoms were exclusive to, and ubiquitous in, patients that exhibited moderate to high ACE2 expression in peri-vascular cells. Viral particles were identified in the vascular wall and paralleled by peri-vascular inflammation, as signified by T cell and macrophage infiltration. Furthermore, fibrinogen leakage indicated compromised integrity of the blood-brain barrier. Notably, cerebrospinal fluid from an additional 16 individuals (n = 8 COVID-19, median age = 67 years; and n = 8 control, median age = 69,5 years) exhibited significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected cases, indicative of disrupted pericyte homeostasis. We conclude that pericyte infection by SARS-CoV-2 underlies virus entry into the privileged central nervous system space, as well as neurological symptomatology due to peri-vascular inflammation and a locally compromised blood-brain barrier.

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Role of thrombin-PAR1-PKCθ/δ axis in brain pericytes in thrombin-induced MMP-9 production and blood–brain barrier dysfunction in vitro

Neuroscience ◽

10.1016/j.neuroscience.2017.03.026 ◽

2017 ◽

Vol 350 ◽

pp. 146-157 ◽

Cited By ~ 28

Author(s):

Takashi Machida ◽

Shinya Dohgu ◽

Fuyuko Takata ◽

Junichi Matsumoto ◽

Ikuya Kimura ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Brain Pericytes

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Inflammatory Mediators Released by Brain Pericytes as Sensors and Effectors in Blood-Brain Barrier Dysfunction

Stem Cell Biology and Regenerative Medicine - Biology of Pericytes – Recent Advances ◽

10.1007/978-3-030-62129-2_6 ◽

2021 ◽

pp. 145-164

Author(s):

Shinya Dohgu ◽

Fuyuko Takata ◽

Yasufumi Kataoka

Keyword(s):

Blood Brain Barrier ◽

Inflammatory Mediators ◽

Brain Barrier ◽

Barrier Dysfunction ◽

Blood Brain ◽

Brain Pericytes

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Human pluripotent stem cell–derived brain pericyte–like cells induce blood-brain barrier properties

Science Advances ◽

10.1126/sciadv.aau7375 ◽

2019 ◽

Vol 5 (3) ◽

pp. eaau7375 ◽

Cited By ~ 40

Author(s):

Matthew J. Stebbins ◽

Benjamin D. Gastfriend ◽

Scott G. Canfield ◽

Ming-Song Lee ◽

Drew Richards ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Blood Brain Barrier ◽

Neurovascular Unit ◽

Barrier Properties ◽

Cell Types ◽

Brain Barrier ◽

Human Model ◽

Blood Brain ◽

Brain Pericytes

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte–like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte–like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte–like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte–like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

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Human pluripotent stem cell-derived brain pericyte-like cells induce blood-brain barrier properties

10.1101/387100 ◽

2018 ◽

Author(s):

Matthew J. Stebbins ◽

Benjamin D. Gastfriend ◽

Scott G. Canfield ◽

Ming-Song Lee ◽

Drew Richards ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Blood Brain Barrier ◽

Pluripotent Stem Cells ◽

Neurovascular Unit ◽

Human Pluripotent Stem Cells ◽

Brain Barrier ◽

Blood Brain ◽

Brain Pericytes ◽

The Brain

ABSTRACTBrain pericytes play an important role in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system (CNS) disorders. While human pluripotent stem cells (hPSCs) have been used to model other components of the NVU including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, cells having brain pericyte-like phenotypes have not been described. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from human pluripotent stem cells (hPSCs) and subsequently differentiated NCSCs to brain pericyte-like cells. The brain pericyte-like cells expressed marker profiles that closely resembled primary human brain pericytes, and they self-assembled with endothelial cells to support vascular tube formation. Importantly, the brain pericyte-like cells induced blood-brain barrier (BBB) properties in BMECs, including barrier enhancement and reduction of transcytosis. Finally, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human NVU model that should prove useful for the study of the BBB in CNS health, disease, and therapy.

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The Roof is Leaking and a Storm is Raging: Repairing the Blood–Brain Barrier in the Fight Against Epilepsy

Epilepsy Currents ◽

10.1177/1535759719844750 ◽

2019 ◽

Vol 19 (3) ◽

pp. 177-181 ◽

Cited By ~ 11

Author(s):

J.A. Gorter ◽

E. Aronica ◽

E.A. van Vliet

Keyword(s):

Blood Brain Barrier ◽

Large Body ◽

Causal Link ◽

Brain Barrier ◽

Blood Brain ◽

Prolonged Seizure ◽

Perivascular Inflammation ◽

Post Traumatic ◽

Genetic Epilepsies

A large body of evidence that has accumulated over the past decade strongly supports the role of both blood–brain barrier (BBB) dysfunction and perivascular inflammation in the pathophysiology of epilepsy. Recent preclinical studies indicate that prolonged seizure- or brain injury-induced BBB dysfunction and subsequent perivascular inflammation may play an important role in post-traumatic epileptogenesis. In turn, perivascular inflammation can further sustain BBB dysfunction. In genetic epilepsies, such as tuberous sclerosis complex and other related epileptogenic developmental pathologies, there is an association between the underlying gene mutation, BBB dysfunction, and perivascular inflammation, but evidence for a causal link to epilepsy is lacking. Future neuroimaging studies might shed light on the role of BBB function in different epilepsies and address the potential for disease modification by targeting both the BBB and perivascular inflammation in acquired and genetic epilepsies.

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Oatp58Dc contributes to blood-brain barrier function by excluding organic anions from the Drosophila brain

AJP Cell Physiology ◽

10.1152/ajpcell.00408.2012 ◽

2013 ◽

Vol 305 (5) ◽

pp. C558-C567 ◽

Cited By ~ 9

Author(s):

Sara Seabrooke ◽

Michael J. O'Donnell

Keyword(s):

Blood Brain Barrier ◽

Organic Anion ◽

Complex Structure ◽

Critical Role ◽

Organic Anions ◽

Molecular Techniques ◽

Brain Barrier ◽

Blood Brain ◽

Wide Range ◽

The Brain

The blood-brain barrier (BBB) physiologically isolates the brain from the blood and, thus, plays a vital role in brain homeostasis. Ion transporters play a critical role in this process by effectively regulating access of chemicals to the brain. Organic anion-transporting polypeptides (Oatps) transport a wide range of amphipathic substrates and are involved in efflux of chemicals across the vertebrate BBB. The anatomic complexity of the vascularized vertebrate BBB, however, creates challenges for experimental analysis of these processes. The less complex structure of the Drosophila BBB facilitates measurement of solute transport. Here we investigate a physiological function for Oatp58Dc in transporting small organic anions across the BBB. We used genetic manipulation, immunocytochemistry, and molecular techniques to supplement a whole animal approach to study the BBB. For this whole animal approach, the traceable small organic anion fluorescein was injected into the hemolymph. This research shows that Oatp58Dc is involved in maintaining a chemical barrier against fluorescein permeation into the brain. Oatp58Dc expression was found in the perineurial and subperineurial glia, as well as in postmitotic neurons. We specifically targeted knockdown of Oatp58Dc expression in the perineurial and subperineurial glia to reveal that Oatp58Dc expression in the perineurial glia is necessary to maintain the barrier against fluorescein influx into the brain. Our results show that Oatp58Dc contributes to maintenance of a functional barrier against fluorescein influx past the BBB into the brain.

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Differing associations between Aβ accumulation, hypoperfusion, blood–brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer's disease

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17690761 ◽

2017 ◽

Vol 38 (1) ◽

pp. 103-115 ◽

Cited By ~ 48

Author(s):

J Scott Miners ◽

Isabel Schulz ◽

Seth Love

Keyword(s):

Alzheimer’S Disease ◽

White Matter ◽

Growth Factor ◽

Blood Brain Barrier ◽

Platelet Derived Growth Factor ◽

Brain Barrier ◽

Factor Level ◽

Blood Brain ◽

Plaque Load ◽

Pericyte Marker

Recent studies implicate loss of pericytes in hypoperfusion and blood–brain barrier (BBB) leakage in Alzheimer's disease (AD). In this study, we have measured levels of the pericyte marker, platelet-derived growth factor receptor-β (PDGFRB), and fibrinogen (to assess blood–brain barrier leakage), and analyzed their relationship to indicators of microvessel density (von Willebrand factor level), ante-mortem oxygenation (myelin-associated glycoprotein:proteolipid protein-1 ratio and vascular endothelial growth factor level), Aβ level and plaque load, in precuneus and underlying white matter from 49 AD to 37 control brains. There was reduction in PDGFRB and increased fibrinogen in the precuneus in AD. These changes correlated with reduction in oxygenation and with plaque load. In the underlying white matter, increased fibrinogen correlated with reduced oxygenation, but PDGFRB level was unchanged. The level of platelet-derived growth factor-ββ (PDGF-BB), important for pericyte maintenance, was increased in AD but mainly in the insoluble tissue fraction, correlating with insoluble Aβ level. Loss of the PDGFRB within the precuneus in AD is associated with fibrinogen leakage and reduced oxygenation, and related to fibrillar Aβ accumulation. In contrast, fibrinogen leakage and reduced oxygenation of underlying white matter occur independently of loss of PDGFRB, perhaps secondary to reduced transcortical perfusion.

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