Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells

Lippmann, Ethan S.; Azarin, Samira M.; Kay, Jennifer E.; Neßler, R.; Wilson, Hannah K.; Al‐Ahmad, Abraham; Palecek, Sean P.; Shusta, Eric V.

doi:10.1038/nbt.2247

Cited by 673 publications

(993 citation statements)

References 57 publications

(93 reference statements)

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“…Indeed, the hiPS cell-derived vascular precursor cells have been shown to be excellent models to study disease. For example, hiPS cell-derived vascular precursors have been used to derive blood-brain barrier type endothelial cells (ECs) in culture (14) or to study patientspecific EC and smooth muscle cell defects in a Hutchinson Gilford progeria model (15) and rescue the vascular phenotype of Williams-Beuren syndrome (16).…”

mentioning

confidence: 99%

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

Samuel

Dahéron

Liao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

112

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Fig. 2. Rapid induction of interchromosomal interactions by nuclear hormone signaling. (A) 3D-FISH confirmation of E 2 -induced (60 min) TFF1:GREB1 interchromosomal interactions in HMECs with the distribution of loci distances measured (box plot with scatter plot) and quantification of colocalization (bar graph) before and after E 2 treatment. Cells exhibiting mono-or biallelic interactions were combined for comparison with cells showing no colocalization; statistical significance in the bar graph was determined by χ 2 test (**, P < 0.001). (B) 2D FISH confirmation of the interchromosomal interactions in HMEC cells by combining chromosome paint (aqua) and specific DNA probes (green and red). (Upper) Illustrates two examples of mock-treated cells. (Lower) Shows the biallelic interactions/ nuclear reorganization after E 2 treatment for 60 min, exhibiting kissing events between chromosome 21 and chromosome 2. (C) Similar analysis on HMECs, but in this case using 3D FISH to paint chromosome 2 (red) and chromosome 21 (green), showing E 2 -induced chromosome 2-chromosome 21 interaction. Both assays revealed neither chromosome 21-chromosome 21 nor chromosome 2-chromosome 2 interactions in response to E 2. (D) Temporal kinetics of GREB1:TFF1 interactions by 3D FISH in HMECs (**, P < 0.001 by χ 2 ). (E-G) Nuclear microinjection of siRNA against ERα, CBP/p300, or SRC1/pCIP prevented E 2 -induced interchromosomal interactions, counting both mono-and biallelic interactions (**, P < 0.001 by χ 2 ). The injection of siER and siDLC1 were done in the same experiment, sharing the same control group. (H) Nuclear microinjection of siRNA against LSD1, which was shown to be required for estrogen-induced gene expression (22), did not block E 2 -induced interchromosomal interactions. The injection of siLSD1 and SRC1/pCIP were done in a single experiment, sharing the same control group.

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mentioning

confidence: 99%

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

Samuel

Dahéron

Liao

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

140

112

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“…In this co-culture model of the BBB, a significant tightness and the expression of tight and adherence junction proteins as well as multidrug-resistance proteins were demonstrated. 39,40 …”

Section: -10mentioning

confidence: 99%

An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development

et al. 2016

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The development of therapeutic substances to treat diseases of the central nervous system is hampered by the tightness and selectivity of the blood-brain barrier. Moreover, testing of potential drugs is time-consuming and cost-intensive. Here, we established a new microfluidically supported, biochip-based model of the brain endothelial barrier in combination with brain cortical spheroids suitable to detect effects of neuroinflammation upon disruption of the endothelial layer in response to inflammatory signals. Unilateral perfusion of the endothelial cell layer with a cytokine mix comprising tumor necrosis factor, IL-1b, IFNc, and lipopolysaccharide resulted in a loss of endothelial von Willebrand factor and VE-cadherin expression accompanied with an increased leakage of the endothelial layer and diminished endothelial cell viability. In addition, cytokine treatment caused a loss of neocortex differentiation markers Tbr1, Tbr2, and Pax6 in the cortical spheroids concomitant with reduced cell viability and spheroid integrity. From these observations, we conclude that our endothelial barrier/cortex model is suitable to specifically reflect cytokine-induced effects on barrier integrity and to uncover damage and impairment of cortical tissue development and viability. With all its limitations, the model represents a novel tool to study cross-communication between the brain endothelial barrier and underlying cortical tissue that can be utilized for toxicity and drug screening studies focusing on inflammation and neocortex formation. Published by AIP Publishing. [http://dx

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“…1 The technology could help companies identify drug candidates that readily enter the brain or that decrease blood brain barrier permeability.…”

Section: By Lev Osherovich Senior Writermentioning

confidence: 99%

Blood brain barrier in a dish

Osherovich¹

2012

Science-Business eXchange

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Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells

Cited by 673 publications

References 57 publications

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

Generation of functionally competent and durable engineered blood vessels from human induced pluripotent stem cells

An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development

Blood brain barrier in a dish

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