An in vivo model of functional and vascularized human brain organoids

Human cerebral organoids undergo vascularization and maturation in the mouse brain. 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...

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Bibliographic Details
Published in:	Nature biotechnology Vol. 36; no. 5; pp. 432 - 441
Main Authors:	Mansour, Abed AlFatah, Gonçalves, J Tiago, Bloyd, Cooper W, Li, Hao, Fernandes, Sarah, Quang, Daphne, Johnston, Stephen, Parylak, Sarah L, Jin, Xin, Gage, Fred H
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-06-2018 Nature Publishing Group
Subjects:	13/1 13/100 13/106 13/107 13/109 13/2 13/51 14/1 14/19 14/63 631/378 631/532/1360 631/532/2182 64 64/60 Agriculture Animal diseases Animals Axonogenesis Axons Bioinformatics Biomedical Engineering/Biotechnology Biomedicine Biotechnology Blood vessels Blood Vessels - diagnostic imaging Blood Vessels - growth & development Brain Brain - diagnostic imaging Brain - growth & development Brain stem Cell differentiation Cell Differentiation - genetics Differentiation Genetics Gliogenesis Grafting Grafts Humans In vivo methods and tests Information processing Life Sciences Mice Microglia Neural circuitry Neural networks Neurogenesis - genetics Neuroimaging Neurons - cytology Observations Optics Organoids Organoids - growth & development Physiological aspects Physiology Pluripotency Pluripotent Stem Cells - cytology Pluripotent Stem Cells - physiology Stem cell transplantation Stem cells Transplants - diagnostic imaging Transplants - growth & development
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Summary:	Human cerebral organoids undergo vascularization and maturation in the mouse brain. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS A.A.M. and F.H.G. conceived the idea for the project and wrote the manuscript. A.A.M. designed and performed the experiments and analyzed the data. A.A.M. generated hESC lines and organoids culture, performed cellular, molecularand histological assays and analyzed the data. S.F. and D.Q. performed cell culture and histological experiments under the supervision of A.A.M. A.A.M., C.W.B., F.H.G., J.T.G., and S.J. performed surgeries. T.G. and C.W.B. performed two-photon imaging and analyzed the data. S.L.P. performed behavioral experiments. H.L. performed electrophysiological microelectrode and optogenetic experiments under the supervision of X.J. F.H.G. supervised the project and provided funding.
ISSN:	1087-0156 1546-1696
DOI:	10.1038/nbt.4127