Using miniature brain implants in rodents for novel drug discovery

ABSTRACT

Introduction: There continues to be a need to create an artificial human blood-brain barrier for pharmacological testing and modeling of diseases. Our group has recently vascularized human brain organoids with human iPSC-derived endothelial cells. Other groups have achieved brain organoid perfusion after vascularization with murine endothelial cells.

Areas covered: This review article discusses the remaining hurdles, advantages, and limitations of creating a human organoid blood-brain barrier in rodents for novel drug discovery.

Expert opinion: The creation of a human organoid blood-brain barrier in rodents will be feasible with appropriate molecular and cellular cues. An artificial human blood-brain barrier model may be used for pharmacological testing or for the study of the human blood-brain barrier in development or disease. Potential limitations of the model include an inferior competence of the blood-brain organoid barrier, the immunodeficient environment and low reproducibility due to variations in organoid morphology and vascularization. Despite its limitations, an artificial human blood-brain barrier model in rodents will further our understanding of blood-brain barrier pharmacology, and the field is expected to see significant advances in the next years.

KEYWORDS:

• Human brain organoid
• blood-brain barrier
• vascularization
• perfusion
• human endothelial cells
• induced pluripotent stem cells

Article highlights

• Human brain organoids have been vascularized in vivo with human endothelial cells, and perfusion of human brain organoids has been achieved with murine endothelial cells.

• Despite evolutionary conservation among vertebrate species, there are profound molecular differences between the human and rodent blood-brain barrier.

• All available capillary endothelial cell lines lack sufficiently high transepithelial electrical resistance values and sufficiently low paracellular permeability.

• Endothelial cells and VEGF alone are not sufficient to achieve perfusion of human vascularized brain organoids.

• An artificial human blood-brain organoid model will allow for pharmacological testing and study of the human blood-brain barrier during development and disease.

• Potential limitations of the new human blood-brain organoid model may include an inferior competence of the blood-brain barrier, the immunodeficient environment and low reproducibility due to variations in organoid morphology and vascularization.

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Acknowledgments

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of interest

B Waldau has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee owns shares in Flocel Inc, a Blood-Brain Barrier company. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

B Waldau is funded by a intramural UC Davis Cellular Therapy grant which was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR001860.