Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood–brain barrier

Jin Kim, Kyung Tae Lee, Jong Seung Lee, Jisoo Shin, Baofang Cui, Kisuk Yang, Yi Sun Choi, Nakwon Choi, Soo Hyun Lee, Jae Hyun Lee, Yong Sun Bahn, Seung Woo Cho

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood–brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans—the most common pathogen causing fungal meningitis—and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.

Original languageEnglish
Pages (from-to)830-846
Number of pages17
JournalNature biomedical engineering
Volume5
Issue number8
DOIs
Publication statusPublished - 2021 Aug

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications

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