Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

Anna Herland, Andries Dirk van der Meer, Edward A. Fitzgerald, Tae-Eun Park, Jelle J.F. Sleeboom, Donald E. Ingber

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Abstract

Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types.
Original languageEnglish
Article numbere0150360
Pages (from-to)-
JournalPLoS ONE
Volume11
Issue number3
DOIs
Publication statusPublished - 2016

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Pericytes
blood-brain barrier
astrocytes
Blood-Brain Barrier
Astrocytes
Brain
granulocyte colony-stimulating factor
Gels
Granulocyte Colony-Stimulating Factor
gels
Interleukin-6
endothelium
brain
interleukin-6
Collagen
Endothelium
collagen
inflammation
cells
Inflammation

Keywords

  • IR-100920
  • METIS-317465

Cite this

Herland, Anna ; van der Meer, Andries Dirk ; Fitzgerald, Edward A. ; Park, Tae-Eun ; Sleeboom, Jelle J.F. ; Ingber, Donald E. / Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip. In: PLoS ONE. 2016 ; Vol. 11, No. 3. pp. -.
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Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip. / Herland, Anna; van der Meer, Andries Dirk; Fitzgerald, Edward A.; Park, Tae-Eun; Sleeboom, Jelle J.F.; Ingber, Donald E.

In: PLoS ONE, Vol. 11, No. 3, e0150360, 2016, p. -.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

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AU - van der Meer, Andries Dirk

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AU - Ingber, Donald E.

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AB - Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types.

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