Self-assembling 3D vessel-on-chip model with hiPSC-derived astrocytes

Stem Cell Reports, vol. 19, pp. 946–956

Abstract

Functionality of the blood-brain barrier (BBB) relies on the interaction between endothelial cells (ECs), pericytes, and astrocytes to regulate molecule transport within the central nervous system. Most experimental models for the BBB rely on freshly isolated primary brain cells. Here, we explored human induced pluripotent stem cells (hiPSCs) as a cellular source for astrocytes in a 3D vessel-on-chip (VoC) model. Self-organized microvascular networks were formed by combining hiPSC-derived ECs, human brain vascular pericytes, and hiPSC-derived astrocytes within a fibrin hydrogel. The hiPSC-ECs and pericytes showed close interactions, but, somewhat unexpectedly, addition of astrocytes disrupted microvascular network formation. However, continuous fluid perfusion or activation of cyclic AMP (cAMP) signaling rescued the vascular organization and decreased vascular permeability. Nevertheless, astrocytes did not affect the expression of proteins related to junction formation, transport, or extracellular matrix, indicating that, despite other claims, hiPSC-derived ECs do not entirely acquire a BBB-like identity in the 3D VoC model.

Authors 9

1. Dennis M. Nahon Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

2. Marc Vila Cuenca Aachen Department of Anatomy and Embryology Department of Clinical Genetics

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands; Department of Clinical Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Clinical Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

3. Francijna E. van den Hil Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

4. Michel H. Y. Hu Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Centre

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands; Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

5. Tessa de Korte Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

6. Jean‐Philippe Frimat Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Centre

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands; Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

7. Arn M. J. M. van den Maagdenberg Aachen Department of Human Genetics Department of Neurology, Leiden University Medical Centre

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands; Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Human Genetics, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

   Department of Neurology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

8. Christine L. Mummery Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands

9. Valeria V. Orlova corresponding Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands. Electronic address: v.orlova@lumc.nl

   Department of Anatomy and Embryology, Leiden University Medical Centre, 2333ZA Leiden, the Netherlands