Engineering the human blood-brain barrier in vitro

Jamieson, John J.; Searson, Peter C.; Gerecht, Sharon

doi:10.1186/s13036-017-0076-1

Cited by 65 publications

(54 citation statements)

References 125 publications

(155 reference statements)

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“…Binding of Ang2-Liposomes to brain ECs was efficient in static fluid or at low FSS (1 dyne/cm 2 ), but was inhibited at higher FSS of 6 dyne/cm 2 ( Fig 2E ). This bears consideration for the design of Ang2-functionalized nanoparticles, as physiological FSS in brain capillaries ranges from approximately 5–23 dyne/cm 2 [ 24 , 94 ]. Designing Ang2-nanoparticles with higher avidity via the multivalent effect could help withstand nanoparticle detachment forces imparted by the presence of flow.…”

Section: Discussionmentioning

confidence: 99%

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier

et al. 2018

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The blood-brain barrier (BBB) limits transport of nanoparticles from the circulation to the brain parenchyma. Angiopep-2, a peptide which functions as a brain transport vector, can be coupled to nanoparticles in order to facilitate binding and internalization by brain endothelial cells (ECs), and subsequent BBB penetration. This multi-step process may be affected by blood flow over brain ECs, as flow influences endothelial cell phenotype as well as interactions of nanoparticles with ECs. In the present study a microfluidic BBB model was constructed to evaluate binding and internalization by brain ECs, as well as BBB penetration of Angiopep-2 coupled liposomes (Ang2-Liposomes) in static and flow conditions. Ang2 conjugation to liposomes markedly improved binding relative to unconjugated liposomes. Ang2-Liposomes bound and were internalized efficiently by brain endothelial cells after static incubation or with 1 dyne/cm2 of fluid shear stress (FSS), while binding was reduced at a FSS of 6 dyne/cm2. Penetration of the model microfluidic BBB by Ang2-Liposomes was higher at a FSS of 1 dyne/cm2 and 6 dyne/cm2 than with static incubation. Analysis of barrier function and control experiments for receptor-mediated penetration provided insight into the magnitude of transcellular versus paracellular transport at each tested FSS. Overall, the results demonstrate that flow impacted the binding and BBB penetration of Ang2-functionalized nanoparticles. This highlights the relevance of the local flow environment for in vitro modeling of the performance of nanoparticles functionalized with BBB penetrating ligands.

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Section: Discussionmentioning

confidence: 99%

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier

et al. 2018

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“…organoids, human iPSCs, etc.) that model blood vessels with specific focus on PC contributions to vascular development and barrier function (Jamieson et al, 2017;Stebbins et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Pericytes Directly Communicate with Emerging Endothelial Cells During Vasculogenesis

Payne

Tewari

Dunkenberger

et al. 2020

Preprint

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SummaryPericytes (PCs), cells that extend along capillaries to contribute stability and other critical functions to established vasculature, are attracting attention from various fields involving vascular-related pathologies. Here, we demonstrate primary evidence of PC communication with endothelial cells (ECs) prior to tube coalescence. Observations of apparent PCs during early embryogenesis urged development of a mouse embryonic stem cell line (DR-ESCs), enabling unique dual-reporter investigations into earliest PC-EC interactions. Live imaging of differentiating DR-ESCs corroborated emergence of a PC lineage, which preceded EC differentiation, and further revealed highly dynamic PC-EC interactions during coordinated vessel formation. We show direct PC-EC communication via cell microinjection and dye-transfer, and RNA-seq analysis indicates a PC-EC coupling mechanism via gap junction Connexin43 (Cx43), exclusively up-regulated throughout DR-ESC differentiation. High resolution imaging of embryonic and postnatal mouse vasculature substantiates Cx43 plaques at PC-EC borders. These findings indicate a new role for PCs during vasculogenesis via Cx43-mediated communication with ECs.

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“…Adapted with permission. [ 382 ] Copyright 2017, Springer Nature. B) Schematic of the BBB‐on‐a‐chip and confocal image of self‐assembled iPSC‐ECs (green: CD31), pericytes (red: F‐actin), astrocytes (magenta: GFAP) (blue: nuclei) (SB = 100 µm).…”

Section: Modeling Vascular Mechanopathology In Vascularized Microphysmentioning

confidence: 99%

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

Pradhan

Banda

Farino

et al. 2020

Adv Healthcare Materials

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The vascular system is integral for maintaining organ‐specific functions and homeostasis. Dysregulation in vascular architecture and function can lead to various chronic or acute disorders. Investigation of the role of the vascular system in health and disease has been accelerated through the development of tissue‐engineered constructs and microphysiological on‐chip platforms. These in vitro systems permit studies of biochemical regulation of vascular networks and parenchymal tissue and provide mechanistic insights into the biophysical and hemodynamic forces acting in organ‐specific niches. Detailed understanding of these forces and the mechanotransductory pathways involved is necessary to develop preventative and therapeutic strategies targeting the vascular system. This review describes vascular structure and function, the role of hemodynamic forces in maintaining vascular homeostasis, and measurement approaches for cell and tissue level mechanical properties influencing vascular phenomena. State‐of‐the‐art techniques for fabricating in vitro microvascular systems, with varying degrees of biological and engineering complexity, are summarized. Finally, the role of vascular mechanobiology in organ‐specific niches and pathophysiological states, and efforts to recapitulate these events using in vitro microphysiological systems, are explored. It is hoped that this review will help readers appreciate the important, but understudied, role of vascular‐parenchymal mechanotransduction in health and disease toward developing mechanotherapeutics for treatment strategies.

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Engineering the human blood-brain barrier in vitro

Cited by 65 publications

References 125 publications

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier

Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier

Pericytes Directly Communicate with Emerging Endothelial Cells During Vasculogenesis

Biofabrication Strategies and Engineered In Vitro Systems for Vascular Mechanobiology

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