Understanding the Heterogeneity of Human Pericyte Subsets in Blood-Brain Barrier Homeostasis and Neurological Diseases

Bohannon, Diana G.; Long, Danielle; Kim, Woong‐Ki

doi:10.20944/preprints202103.0219.v1

Cited by 5 publications

(5 citation statements)

References 55 publications

(123 reference statements)

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“…Using patient-derived iPSCs is important as they can complement findings from transgenic mouse models, which can lack human disease resemblance and demonstrate structural and molecular differences to the human BBB 30 - 33 . Thus, we developed a sporadic AD patient iPSC-derived BBB-like in vitro model to study the effects of FUS +MB on cellular responses and drug delivery.…”

Section: Introductionmentioning

confidence: 99%

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Wasielewska¹,

Chaves²,

Johnston³

et al. 2022

Theranostics

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Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS +MB ) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS +MB is safe, however, the effects of FUS +MB on human BBB cells, especially in the context of AD, remain sparsely investigated. In addition, there currently are no cell platforms to test for FUS +MB -mediated drug delivery. Methods: Here we generated BBB cells (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 ( APOE4 , high sporadic AD risk) and allele E3 ( APOE3 , lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We established mono- and co-culture models of human sporadic AD and control BBB cells to investigate the effects of FUS +MB on BBB cell phenotype and to screen for the delivery of two potentially therapeutic AD antibodies, an Aducanumab-analogue (Aduhelm TM ; anti-amyloid-β) and a novel anti-Tau antibody, RNF5. We then developed a novel hydrogel-based 2.5D BBB model as a step towards a more physiologically relevant FUS +MB drug delivery platform. Results: When compared to untreated cells, the delivery of Aducanumab-analogue and RNF5 was significantly increased (up to 1.73 fold), across the Transwell-based BBB models following FUS +MB treatment. Our results also demonstrated the safety of FUS +MB indicated by minimal changes in iBEC transcriptome as well as little or no changes in iBEC or iAstrocyte viability and inflammatory responses within the first 24 h post FUS +MB . Furthermore, we demonstrated successful iBEC barrier formation in our novel 2.5D hydrogel-based BBB model with significantly increased delivery (1.4 fold) of Aducanumab-analogue following FUS +MB . Conclusion: Our results demonstrate a robust and reproducible approach to utilize patient cells for FUS +MB -mediated drug delivery screening in vitro . With such a cell platform for FUS +MB research previously not reported, it has the potential to identify novel FUS +MB -deliverable drugs as well as screen for cell- and patient-specific effects of FUS +MB , accelerating the use of FUS +MB as a therapeutic modality in AD.

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Section: Introductionmentioning

confidence: 99%

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Wasielewska¹,

Chaves²,

Johnston³

et al. 2022

Theranostics

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“…However, aging results in an increase in the population of inflammatory pericytes, which is consistent with enhanced inflammation and BBB permeability associated with age 85 . Both pericyte subtypes contribute to the basal lamina, but PC2s tend to produce a more irregular basal lamina, impacting both ECs and astrocytes 21,85 . Additionally, PC2s produce less laminin‐111 and laminin‐211, which leads to cell hypertrophy and BBB disruption 87,88 .…”

Section: Pericytesmentioning

confidence: 79%

“…Perivascular mural cells, or pericytes, have recently been shown to be more complex and varied than initially assumed. Pericytes are functionally heterogeneous 21,22 and further understanding of their diverse roles in the CNS is an active area of research. Pericytes were classically described to help govern vasoconstriction and dilation of capillaries, 23,24 which is highly regulated in the NVU, to limit BBB permeability.…”

Section: Structure and Organization Of The Nvumentioning

confidence: 99%

“…Pericytes were classically described to help govern vasoconstriction and dilation of capillaries, 23,24 which is highly regulated in the NVU, to limit BBB permeability. Recent studies are beginning to uncover pericyte coordination with other members of the NVU, particularly ECs and astrocytes 21,24 . Astrocytes are vital to the NVU and while the other members of the NVU have critical roles, it is largely the astrocytes that set the NVU apart from other capillary layers in the body 25,26 .…”

Section: Structure and Organization Of The Nvumentioning

confidence: 99%

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Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Smith

Tinkey

Shaw

et al. 2022

Immunological Reviews

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Summary The blood–brain barrier (BBB) is a selectively permeable barrier separating the periphery from the central nervous system (CNS). The BBB restricts the flow of most material into and out of the CNS, including many drugs that could be used as potent therapies. BBB permeability is modulated by several cells that are collectively called the neurovascular unit (NVU). The NVU consists of specialized CNS endothelial cells (ECs), pericytes, astrocytes, microglia, and neurons. CNS ECs maintain a complex “seal” via tight junctions, forming the BBB; breakdown of these tight junctions leads to BBB disruption. Pericytes control the vascular flow within capillaries and help maintain the basal lamina. Astrocytes control much of the flow of material that has moved beyond the CNS EC layer and can form a secondary barrier under inflammatory conditions. Microglia survey the border of the NVU for noxious material. Neuronal activity also plays a role in the maintenance of the BBB. Since astrocytes, pericytes, microglia, and neurons are all able to modulate the permeability of the BBB, understating the complex contributions of each member of the NVU will potentially uncover novel and effective methods for delivery of neurotherapies to the CNS.

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“…Thus, it is vital to understand the contribution of a disease polymorphism on drug delivery efficiency. Using patient-derived iPSCs is important as they can complement findings from transgenic mouse models, which can lack human disease resemblance and demonstrate structural and molecular differences to the human BBB [50][51][52][53]. Although questions have been raised about the accuracy of iPSC-derived iBECs in resembling in vivo BECs [54], these cells exhibit the highest TEER compared to any other BEC model making them ideal for mechanistic BBB opening studies such as FUS +MB [16,38].…”

Section: Discussionmentioning

confidence: 99%

A sporadic Alzheimer’s blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Wasielewska

Chaves

Johnston

et al. 2022

Preprint

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Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS+MB is safe, however the effects of FUS+MB on human BBB cells, especially in the context of AD, remain sparsely investigated. Methods: Here we generated BBB cells (induced brain endothelial cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We then developed a human sporadic AD BBB cell platform to investigate the effects of FUS+MB on BBB cells and screen for the delivery of two potentially therapeutic AD antibodies. Results: We utilized this robust and reproducible human BBB model to demonstrate increased delivery of therapeutic AD antibodies across the BBB following FUS+MB treatment, including an analogue of Aducanumab (AduhelmTM; anti-amyloid-β) and a novel anti-Tau antibody RNF5. Our results also demonstrate the safety of FUS+MB indicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within the first 24 h post FUS+MB. Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS+MB-mediated drug delivery screening, with potentially higher translational utility. Conclusion: Our results demonstrate an important translatable patient BBB cell model for identifying FUS+MB-deliverable drugs and screening for cell- and patient-specific effects of FUS+MB, accelerating the use of FUS+MB as a therapeutic modality in AD.

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Understanding the Heterogeneity of Human Pericyte Subsets in Blood-Brain Barrier Homeostasis and Neurological Diseases

Cited by 5 publications

References 55 publications

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

A sporadic Alzheimer's blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

A sporadic Alzheimer’s blood-brain barrier model for developing ultrasound-mediated delivery of Aducanumab and anti-Tau antibodies

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