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Nature Methods | VOL 15 | JUNE 2018 | 403–409 | www.nature.com/naturemethods
© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
A home for brain organoids
Inside a mouse brain, human cerebral organoids can show their potential.
flurry of excitement has surrounded
organoids as models of human
disease and development. The stem-
cell-derived three-dimensional structures
reconstitute many of the properties found
in native tissue. But investigators are also
acutely aware of their limitations. Rusty
Gage at the Salk Institute and his group have
found that a location in the mouse brain
supports human organoid development
and can overcome some constraints imposed
by cell culture.
Organoids tend to mimic young,
developing tissues. Both their size and the
extent of their development are limited by
the absence of blood vessels, which leads
to cell death during prolonged culture. The
Gage team, led by postdoc Abed Mansour,
asked whether organoids would be healthier
in the context of a living animal.
Long ago, Gage showed that it was
possible to transplant human tissue to
the superior colliculus of the rat brain.
“I remembered this methodology that
I developed and worked on in Sweden
35 years ago,” he says, and this prompted
him to try organoid tissue. Where other
efforts at organoid transplantation failed,
Gage’s team found that 50-day-old cerebral
organoids generated from GFP-expressing
human embryonic stem cells could thrive in
The superior colliculus is a special
environment that sits atop a rich bed of
blood vessels. It takes a steady hand, but
anyone can be trained to do the surgery.
The key, says Gage, is to “really clean it up
so there’s no bleeding at all and you haven’t
nicked the surfaces of the colliculus.”
Transplanted organoids were healthy;
they showed progressive differentiation
of neural and glial cell types, were devoid
of cell death, accepted blood vessels and
sent axonal projections into host tissue.
Organoids imaged through cranial windows
showed regular blood flow and calcium
spiking. Electrophysiology suggested
the maturation of neural networks, and
inroducing an optogenetic construct enabled
the stimulation of electrical activity in
grafted neurons by laser light, with effects
in host tissue.
Organoids remained healthy for up to
283 days after transplantation, and were in
fact limited only by the short life span of the
NOD SCID mouse hosts. Gage is looking to
push the current limits of cell maturation by
exploring the use of longer-lived strains. The
system can also be used to study immune
activity, a component that is missing in brain
and other organoid studies. The researchers
detected scavenging cells called microglia
in the graft, though Gage cautions that their
origins have not been confirmed.
Transplanted organoids have the
potential to provide better disease modeling,
but the approach is limited by the need
for surgery and organoids of high
quality, and by the fact that each animal
accommodates only a single organoid.
The researchers are now examining the
analogous cavity in rat brains, which
can accept four or five organoids and
thus potentially allow the study of cell
interactions across organoids representing
different brain regions. They have yet to find
any evidence of modulated mouse behavior
but are proceeding with caution, given the
high degree of functional integration.
Published online: 31 May 2018
Mansour, A. A. et al. An in vivo model of functional
and vascularized human brain organoids.
Nat. Biotechnol. 36, 432–441 (2018).
A mouse brain section with GFP-expressing
organoid cells 90 days after grafting (nuclei are
DAPI-stained). Reproduced with permission from
Mansour et al. (2018), Springer Nature.