TY - JOUR
KW - astrogliosis
KW - barrier resilience
KW - fluid shear stress
KW - human BBB-on-a-chip
AU - Kaihua Chen
AU - Isabelle M. Linares
AU - Michelle A. Trempel
AU - Alexis M. Feidler
AU - Dinindu De Silva
AU - Sami Farajollahi
AU - Jordan Jones
AU - Julia Kuebel
AU - Pelin Kasap
AU - Britta Engelhardt
AU - Jonathan Flax
AU - Vinay V. Abhyankar
AU - Richard E. Waugh
AU - Harris A. Gelbard
AU - Niccolo Terrando
AU - James L. McGrath
AB - The blood–brain barrier (BBB) maintains cerebral homeostasis and protects the central nervous system (CNS) during systemic inflammation. Advanced in vitro models integrating circulation, a functional BBB, and reactive glial cells are essential for studying the link between peripheral inflammation and neuroinflammation. Fluid shear stress, a key hemodynamic parameter, strengthens microvascular barriers. This study examines endothelial shear conditioning on barrier function in a fluidic µSiM-BBB (Microphysiological System featuring a Silicon Membrane –BBB). hiPSC-derived brain microvascular endothelial cell monocultures are conditioned with 0.5 Pa shear stress for 48 h. Shear conditioning lowers baseline permeability, increases glycocalyx production, and reduces responses to inflammatory challenges, including barrier breakdown, ICAM-1 upregulation, and neutrophil transmigration. Shear conditioning produces a resilient barrier function against a low-dose inflammatory challenge (10 pg mL−1 TNF-α/IL1-β/INF-γ) but a high-dose challenge (50 pg mL−1) disrupts the barrier. Adding astrocytes as neuroinflammatory “sensors” reveals that a high-dose inflammatory challenge activates astrocytes but only in combination with fibrinogen—a plasma protein known to trigger astrogliosis in multiple neurological conditions. This study highlights the utility of fluidic-enabled µSiM-BBB for investigating acute peripheral inflammation and brain injury relationships, serving as a foundation for more advanced models, including more cells of the neurovascular unit and brain parenchyma.
BT - Advanced Science
DO - 10.1002/advs.202508271
IS - n/a
LA - en
N2 - The blood–brain barrier (BBB) maintains cerebral homeostasis and protects the central nervous system (CNS) during systemic inflammation. Advanced in vitro models integrating circulation, a functional BBB, and reactive glial cells are essential for studying the link between peripheral inflammation and neuroinflammation. Fluid shear stress, a key hemodynamic parameter, strengthens microvascular barriers. This study examines endothelial shear conditioning on barrier function in a fluidic µSiM-BBB (Microphysiological System featuring a Silicon Membrane –BBB). hiPSC-derived brain microvascular endothelial cell monocultures are conditioned with 0.5 Pa shear stress for 48 h. Shear conditioning lowers baseline permeability, increases glycocalyx production, and reduces responses to inflammatory challenges, including barrier breakdown, ICAM-1 upregulation, and neutrophil transmigration. Shear conditioning produces a resilient barrier function against a low-dose inflammatory challenge (10 pg mL−1 TNF-α/IL1-β/INF-γ) but a high-dose challenge (50 pg mL−1) disrupts the barrier. Adding astrocytes as neuroinflammatory “sensors” reveals that a high-dose inflammatory challenge activates astrocytes but only in combination with fibrinogen—a plasma protein known to trigger astrogliosis in multiple neurological conditions. This study highlights the utility of fluidic-enabled µSiM-BBB for investigating acute peripheral inflammation and brain injury relationships, serving as a foundation for more advanced models, including more cells of the neurovascular unit and brain parenchyma.
EP - e08271
T2 - Advanced Science
TI - Shear Conditioning Promotes Microvascular Endothelial Barrier Resilience in a Human BBB-on-a-Chip Model of Systemic Inflammation Leading to Astrogliosis
UR - https://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202508271
VL - n/a
Y2 - 2025-09-19
SN - 2198-3844
ER -