Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications

  • Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6. doi: 10.1016/j.stem.2019.05.011.
Gad D Vatine  1 ,  Riccardo Barrile  2 ,  Michael J Workman  3 ,  Samuel Sances  3 ,  Bianca K Barriga  3 ,  Matthew Rahnama  3 ,  Sonalee Barthakur  4 ,  Magdalena Kasendra  4 ,  Carolina Lucchesi  4 ,  Jordan Kerns  4 ,  Norman Wen  4 ,  Weston R Spivia  5 ,  Zhaohui Chen  5 ,  Jennifer Van Eyk  5 ,  Clive N Svendsen  6
Affiliations
  • 1. The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; The Department of Physiology and Cell Biology and the Regenerative Medicine and Stem Cell (RMSC) Research Center, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel. Electronic address: [email protected].
  • 2. The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Emulate, Inc., 27 Drydock Avenue, Boston, MA 02210, USA.
  • 3. The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 4. Emulate, Inc., 27 Drydock Avenue, Boston, MA 02210, USA.
  • 5. Advanced Clinical Biosystems Research Institute, Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 6. The Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: [email protected].
PMID: 31173718 DOI: 10.1016/j.stem.2019.05.011
Abstract

The blood-brain barrier (BBB) tightly regulates the entry of solutes from blood into the brain and is disrupted in several neurological diseases. Using Organ-Chip technology, we created an entirely human BBB-Chip with induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (iBMECs), astrocytes, and neurons. The iBMECs formed a tight monolayer that expressed markers specific to brain vasculature. The BBB-Chip exhibited physiologically relevant transendothelial electrical resistance and accurately predicted blood-to-brain permeability of pharmacologics. Upon perfusing the vascular lumen with whole blood, the microengineered capillary wall protected neural cells from plasma-induced toxicity. Patient-derived iPSCs from individuals with neurological diseases predicted disease-specific lack of transporters and disruption of barrier integrity. By combining Organ-Chip technology and human iPSC-derived tissue, we have created a neurovascular unit that recapitulates complex BBB functions, provides a platform for modeling inheritable neurological disorders, and advances drug screening, as well as personalized medicine.

Keywords
BBB; MCT8; blood-brain barrier; disease model; iPSCs; neural; neurological disease; organ-on-chip; personalized medicine; thyroid.