An in vivo model of functional and vascularized human brain organoids

Abed Alfatah Mansour, J. Tiago Gonçalves, Cooper W. Bloyd, Hao Li, Sarah Fernandes, Daphne Quang, Stephen Johnston, Sarah L. Parylak, Xin Jin, Fred H. Gage*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

646 Scopus citations


Differentiation of human pluripotent stem cells to small brain-like structures known as brain organoids offers an unprecedented opportunity to model human brain development and disease. To provide a vascularized and functional in vivo model of brain organoids, we established a method for transplanting human brain organoids into the adult mouse brain. Organoid grafts showed progressive neuronal differentiation and maturation, gliogenesis, integration of microglia, and growth of axons to multiple regions of the host brain. In vivo two-photon imaging demonstrated functional neuronal networks and blood vessels in the grafts. Finally, in vivo extracellular recording combined with optogenetics revealed intragraft neuronal activity and suggested graft-to-host functional synaptic connectivity. This combination of human neural organoids and an in vivo physiological environment in the animal brain may facilitate disease modeling under physiological conditions.

Original languageAmerican English
Pages (from-to)432-441
Number of pages10
JournalNature Biotechnology
Issue number5
StatePublished - 1 Jun 2018
Externally publishedYes

Bibliographical note

Funding Information:
We thank members of the Gage laboratory for helpful discussions; S. Schafer for the pCSC-CAG-GFP lentivirus and I. Verma for the pBOB-CAG-Td-Tomato construct. We also thank M. Shtrahman for assistance and two-photon imaging expertise, L. Moore, S. Baktvar, S. Kim, B. Miller, C. Lim, and I. Guimont for their technical assistance, M.L. Gage for editorial comments, V. Mertens for illustrations, I. Farhy-Tselnicker and J. Klug for technical advice, and M. Shtrahman, and T. Toda for critical reading and comments on the manuscripts. We thank U. Manor and the Waitt Advanced Biophotonics Core, K. Diffenderfer and the Salk Stem Cell Core, C. O’Connor and C. Fitzpatrick and the FACS Core, and the Salk Institute for generously providing critical infrastructural and financial support. We apologize to those whose work was not cited owing to space limitations. This work was supported by the NIH (U19 MH106434, U01 MH106882), The Paul G, Allen Family Foundation, Bob and Mary Jane Engman, The Leona M, and Harry B, Helmsley Charitable Trust Grant (2012-PG-MED), Annette C, Merle-Smith, The G, Harold and Leila Y, Mathers Foundation, JPB Foundation, Dolby Family Ventures for F.H.G. and NIH grants (R01NS083815, R01AG047669) for X.J. S.F. was funded by CIRM Bridges to Stem Cell Research Internship Program. A.A.M. received funding from the EMBO Postdoctoral Long-term Fellowship (ALTF 1214-2014, EMBO fellowship is co-funded also by the European Commission FP7-Marie Curie Actions, LTFCOFUND2013, GA-2013-609409), and is currently supported by the Human Frontiers Science Program (HFSP Long-Term Fellowship-LT001074/2015).

Publisher Copyright:
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.


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