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October 16, 2022 / eMedClub News /-- On October 12, 2022, Nature published an article titled " Maturation and circuit integration of transplanted human cortical organoids", researchers transplanted brain-organoids into rats' developing brains and found that brain-like organs can develop and mature normally.
And with the neural circuits of the rat brain partially integrated, truly become part of
the brain.
Human brain development is a self-organizing process in which cells proliferate, differentiate, migrate and connect to form functioning neural circuits, which are subsequently optimized
through sensory experience.
A key challenge in understanding human brain development and related diseases is the lack of access
to brain tissue.
Human induced pluripotent stem cells (hiPSCs) can generate self-organizing organs similar to specific regions of the nervous system, including human cortical organs (hCOs), but hCOs lack neural pathway connections in vitro and therefore have a very limited
role in mimicking genetic as well as neurological diseases.
Previous studies have shown that human neurons transplanted into the rodent cortex can survive, project and make connections with
rodent cells.
In this study, the researchers selected hiPSCs as the culture basis, induced the culture of hCO, and transplanted it into the cortex of immune system deficient young mice to reduce the immune rejection
of the graft.
These young mice are still in the stage of early plastic development, and the brain neural circuits are not fully formed, providing a window for the development of the organoids, and the organoids will gradually integrate into the surrounding environment
.
▲ hCO is transferred into the mouse brain Image source: Reference 1
In the experiment, 12 months after transplantation, the survival rate of transplanted animals was as high as 74%, the transplanted hCO (t-hCO) developed and matured with the brains of rats, and the volume increased by 9 times within three months, and the transplanted rats did not detect obvious motor or memory deficits, gliopathy or EEG abnormalities, and survived well
.
▲ Comparison of hCO with other hCO Image source: Reference 1
The results of the study showed that t-hCO gradually developed blood vessels to provide nutrition for its development, and some cell types that did not exist in the later organoids appeared, and specific immune cells gradually infiltrated the
organoids.
The researchers compared t-hCO with human fetal and adult cortical cell types, as well as cortical gene expression data, and found that t-hCO roughly matched the development time in vivo, but it was not exactly the same, and some cell types
were lacking.
Compared to in vitro cultured hCO, t-hCO neurons are larger and more closely
linked.
Subsequently, the researchers began to investigate
whether t-hCO could play a role.
By constructing disease models, it was found that t-hCO was anatomically integrated into the host's brain and could be activated by rat tissue; By applying special photosensitive proteins to t-hCO cells, the results showed that t-hCO can not only receive input signals, but can also be activated
by environmental stimuli.
In addition, t-hCO can also use rat circuits to drive behavior, and stimulation of t-hCO can be used to train rats in reward-related behavior, while rats that have not received transplantation will not have similar responses, indicating that t-hCO is involved in the reward learning process of rats, and t-hCO can regulate the activity of rat neurons to drive behavior
.
These data suggest that transplanted human cortical neurons mature and participate in host circuits that control behavior, with functional connections forming functional connections
between human brain-like organs and rat brains.
brief summary
Neural organoids can explore human development and disease principles in vitro, but in vitro organoids are limitedby the lack of neural connections.
The researchers developed a platform that can transplant hCOs into rats and be used to study the development and function
of human cells in vivo.
T-hCO can cultur mature cell types and is anatomically and functionally integrated into the rodent brain, where graft position and growth can be checked by MRI monitoring
.
However, this organoid transplantation still has time-space and cross-species limitations, even if transplanted in the early stages of development, it is impossible to form high-fidelity human neural circuits for high-fidelity reading in rats, and it is impossible to judge whether the spontaneous activities observed in t-hCO represent the developmental phenotype, and more cell types need to be included in the future, including microglia and human endothelial cells, etc.
, and understand the role of t-hCO in transcription, How synapses and behavioral levels affect the host
.
In general, brain organoids can form suitable and mature tissues in the host body and participate in host behavior, which means that organoid research has taken a higher level, providing a new, clearer and more effective research system
for studying human nerve and brain development and the formation of related diseases.
Resources:
1.
Revah, O.
, Gore, F.
, Kelley, K.
W.
et al.
Maturation and circuit integration of transplanted human cortical organoids.
Nature 610, 319–326 (2022).
https://doi.
org/10.
1038/s41586-022-05277-w
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