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A Synergistic Engineering Approach to Build Human Brain Spheroids

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Programmed Morphogenesis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2258))

Abstract

Self-assembling brain spheroids derived from human stem cells closely emulate the tangled connectivity of the human brain, recapitulate aspects of organized tissue structure, and are relatively easy to manipulate compared to other existing three-dimensional (3D) cellular models. However, current platforms generate heterogeneously sized and short-lived spheroids, which do not robustly and reproducibly model human brain development and diseases. Here, we present a method to generate large-scale arrays of homogeneously sized 3D brain spheroids derived from human-induced pluripotent stem cells (hiPSCs) or immortalized neural progenitor cells to recapitulate Alzheimer’s disease (AD) pathology in vitro. When embedded in extracellular matrix, these brain spheroids develop extensive outward projection of neurites and form networks, which are mediated by thick bundles of dendrites. This array facilitates cost-effective, high-throughput drug screening and mechanistic studies to better understand human brain development and neurodegenerative conditions, such as AD .

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References

  1. Paşca SP (2018) The rise of three-dimensional human brain cultures. Nature 553:437–445

    Article  Google Scholar 

  2. Frega M, Tedesco M, Massobrio P et al (2014) Network dynamics of 3D engineered neuronal cultures: a new experimental model for in-vitro electrophysiology. Sci Rep 4:5489

    Article  CAS  Google Scholar 

  3. Choi S, Kim Y, Quinti L et al (2016) 3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”. Mol Neurodegener 11:75

    Article  Google Scholar 

  4. Zhang B, Korolj A, Lai B et al (2018) Advances in organ-on-a-chip engineering. Nat Rev Mater 3:257–278

    Article  Google Scholar 

  5. Kim Y, Choi S, D’Avanzo C et al (2015) A 3D human neural cell culture system for modeling Alzheimer’s disease. Nat Protoc 10:985–1006

    Article  CAS  Google Scholar 

  6. Jorfi M, D’Avanzo C, Tanzi RE et al (2018) Human neurospheroid arrays for in vitro studies of Alzheimer’s disease. Sci Rep 8:2450

    Article  Google Scholar 

  7. Jorfi M, D’Avanzo C, Kim D et al (2018) Three-dimensional models of the human brain development and diseases. Adv Healthc Mater 7:1700723

    Article  Google Scholar 

  8. Kim S, Cho A, Min S et al (2019) Organoids for advanced therapeutics and disease models. Adv Ther 2:1800087

    Article  Google Scholar 

  9. Raja WK, Mungenast AE, Lin Y-T et al (2016) Self-organizing 3D human neural tissue derived from induced pluripotent stem cells recapitulate Alzheimer’s disease phenotypes. PLoS One 11:e0161969

    Article  Google Scholar 

  10. Joseph JV, van Roosmalen IA, Busschers E et al (2015) Serum-induced differentiation of glioblastoma neurospheres leads to enhanced migration/invasion capacity that is associated with increased MMP9. PLoS One 10:e0145393

    Article  Google Scholar 

  11. Choi S, Kim Y, Hebisch M et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515:274–278

    Article  CAS  Google Scholar 

  12. Dawson TM, Golde TE, Lagier-Tourenne C (2018) Animal models of neurodegenerative diseases. Nat Neurosci 21:1370–1379

    Article  CAS  Google Scholar 

  13. Duval K, Grover H, Han L-H et al (2017) Modeling physiological events in 2D vs. 3D cell culture. Physiology 32:266–277

    Article  CAS  Google Scholar 

  14. Lee H-K, Sanchez C, Chen M et al (2016) Three dimensional human neuro-spheroid model of Alzheimer’s disease based on differentiated induced pluripotent stem cells. PLoS One 11:e0163072

    Article  Google Scholar 

  15. Meyer K, Feldman HM, Lu T et al (2019) REST and neural gene network dysregulation in iPSC models of Alzheimer’s disease. Cell Rep 26:1112–1127

    Article  CAS  Google Scholar 

  16. Lin Y-T, Seo J, Gao F et al (2018) APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types. Neuron 98:1141–1154

    Article  CAS  Google Scholar 

  17. Wang H (2018) Modeling neurological diseases with human brain organoids. Front Synapt Neurosci 10:15

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Institutes of Health (P30 NS045776). All microfabrication procedures of the brain spheroids array were performed at the BioMEMS Resource center (EB00002503). Scanning Electron Microscopy was performed at the Center for Nanoscale Systems (CNS) at Harvard University, supported by the National Science Foundation (Award No. 1541959). The authors acknowledge Anika Marand for her help with the brain spheroids extraction.

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Authors and Affiliations

  1. Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Djuna von Maydell & Mehdi Jorfi

Authors
  1. Djuna von Maydell
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  2. Mehdi Jorfi
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Corresponding author

Correspondence to Mehdi Jorfi .

Editor information

Editors and Affiliations

  1. Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh Liver Research Center, University of Pittsburgh, Department of Bioengineering Swanson School of Engineering, University of Pittsburgh, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Mo R. Ebrahimkhani

  2. Department of Bioengineering Swanson School of Engineering, Pittsburgh Liver Research Center, Department of Pathology, Division of Experimental Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Joshua Hislop

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© 2021 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

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von Maydell, D., Jorfi, M. (2021). A Synergistic Engineering Approach to Build Human Brain Spheroids. In: Ebrahimkhani, M.R., Hislop, J. (eds) Programmed Morphogenesis. Methods in Molecular Biology, vol 2258. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1174-6_11

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  • DOI: https://doi.org/10.1007/978-1-0716-1174-6_11

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1173-9

  • Online ISBN: 978-1-0716-1174-6

  • eBook Packages: Springer Protocols

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