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A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke

Nature Biomedical Engineering volume 5, pages 847–863 (2021)Cite this article

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Abstract

The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood–brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.

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Fig. 1: Characterization of the BBB reconstructed in a microfluidic chip.
Fig. 2: Establishing ischaemia.
Fig. 3: Behaviours of neurons, BMECs and pericytes.
Fig. 4: Behaviours of astrocytes and microglia.
Fig. 5: Characterization of the neurorestorative potential of stem cells.
Fig. 6: Tracking the therapeutic stem cells.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request.

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Acknowledgements

We thank H. Suh for editing the manuscript; and T. Klein, J. Saunders and S. Saunders for their support. W.L. was supported by NIH National Center for Advancing Translational Science Clinical and Translational Science Award at the Stanford Child Health Research Institute (UL1 TR001085) and NIH National Cancer Institute career development award (K25CA201545).

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Author notes

  1. These authors contributed equally: Zhonglin Lyu, Jon Park, Kwang-Min Kim.

Authors and Affiliations

  1. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    Zhonglin Lyu, Jon Park, Kwang-Min Kim, Hye-Jin Jin, Gary K. Steinberg & Wonjae Lee

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Kwang-Min Kim, Haodi Wu & Jayakumar Rajadas

  3. Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Deok-Ho Kim

  4. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Deok-Ho Kim

  5. Stanford Stroke Center, Stanford University School of Medicine, Stanford, CA, USA

    Gary K. Steinberg & Wonjae Lee

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Contributions

Z.L. and K.-M.K. designed and performed the experiments, and analysed and interpreted the data; J.P. designed experiment; H.-J.J. and H.W. performed the experiments; W.L. conceived and supervised the project, designed and performed experiments, and analysed and interpreted the data. The manuscript was mainly written by W.L. with contributions from all of the authors.

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Correspondence to Wonjae Lee.

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Lyu, Z., Park, J., Kim, KM. et al. A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke. Nat Biomed Eng 5, 847–863 (2021). https://doi.org/10.1038/s41551-021-00744-7

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