"Nature" blockbuster: "mouse body and human brain" chimeric model is born! Will neuroscience take a new leap?

*For medical professionals only

Based on human stem cell culture technology, scientists have built brain organoids in vitro to study human brain development and neurological diseases
.
However, in vitro culture cannot restore the real development environment of the brain in the body, which greatly limits the progress of
organoid-related research.

On the one hand, brain organoids cultured in vitro do not develop to produce blood vessels, so they cannot obtain nutrients on their own, which means that it is difficult for them to thrive in the long term
.
On the other hand, in contrast to the brains of human infants, where sensory stimulation is required for the normal development of neurons and their connections, brain organoids lack the regulation of sensory stimulation to support their maturation in vitro culture [1].

To solve this problem, Sergiu P.
Pașca of Stanford University and his colleagues borrowed the brains and bodies
of rats.

They successfully transplanted human stem cell-derived brain organoids into the somatosensory cortex of neonatal rats, demonstrating that brain organoids can develop and mature normally under such circumstances, and can also integrate with rat neural tissue and participate in regulating rat behavior [2]
.

The article was published yesterday in the top journal Nature
.

Screenshot of the front page of the paper

The somatosensory cortex is the area
of the brain responsible for receiving and integrating sensory signals.
In this study, Sergiu P.
Pașca et al.
directed transplantation of intact human brain organoids into the somatosensory cortex of neonatal rats without thymus (3-7 days of birth) and performed magnetic resonance scans (MRIs) at multiple time points to continuously monitor the development of human brain organoids
.

The results showed that after the human brain organoids were transplanted into the rat brain, the volume increased by 9 times
at 3 months.
For rats, survival was still high (74%) 12 months after transplantation, while no central nervous system abnormalities such as motor or memory deficits and glial hyperplasia were detected
.

Give rats a "human brain"

According to the results of neuronal transcription level, morphology and function analysis, rats can indeed better support the development and maturation
of human brain organoids than in vitro culture.
The most obvious difference is neuronal morphology, the human brain organoid neurons that thrive in rats are quite large, the cell body is 1.
5 times more than in vitro culture, the total length of dendrites is increased by 6 times, and the density of dendritic spines is also significantly higher than that of neurons
cultured in vitro.
The analysis of neuronal electrophysiological characteristics also confirmed this conclusion
.

The difference is quite large

After transplantation into rats, the human brain organoids
finally look a little "human-like".
Compared with in vitro culture, transplanted human brain organoids have a more refined cortical structure, and the electrophysiological characteristics of vertebral body neurons are similar
to human L2/3 vertebral body neurons.
Of course, there is still a gap between the real human brain, in which no hierarchical structure in the human cerebral cortex is observed in these brain organoids, and certain cell types
are missing.

Not only that, the researchers also recruited 3 patients with Timothy syndrome and 3 healthy volunteers to obtain brain organoids
using human stem cell culture technology.

In vitro culture, the brain organoid structure was similar
between the patient and control groups.
However, when transplanted into rat brains, it was observed that human brain organoids derived from patients with Timothy syndrome had significant differences in neurons, with smaller neurons and different firing frequencies
, compared to controls.
This shows that the "mouse body and human brain" has the potential to become a research model
for neurological diseases in the future.

Rats help us more accurately observe the disease versus healthy human brain

What's even more amazing is that the human brain organoid and its host rat have a very "tacit understanding" to achieve the realm
of "mouse body and human brain".

The researchers found that transplanted human neurons can project axons into rat brain tissue and form synapses with rat neurons (here the brain supplement E.
T.
touches fingers).

If you touch the rat's whiskers, you can detect that part of its "human brain" neurons are activated
.
If rats are trained for several days of reward in combination with optogenetic methods, it can be observed that by stimulating the "human brain", the mice can be driven to perform corresponding behaviors
to obtain rewards.

The transplanted "human brain" successfully dominated the rats and mice

All in all, Sergiu P.
Pașca et al.
provided a new research model for the study of human neurological diseases, successfully transplanted human brain organoids into rat brains, and broke through the bottleneck encountered in the current in
vitro culture of brain organoids.

Due to the difference in the development rate of neurons between different species, the rejection of xenografts between humans and rodents such as rats leads to the rejection of xenografts, and it is difficult for the "mouse body human brain" to completely replicate the structure and function of the normal human brain [2,3].

Nevertheless, Sergiu P.
Pașca et al.
observed that the "human brain" is not only able to mature in the rat brain, but can even adapt to its new body—integrating with rats' neural networks to drive rat behavior
.
This discovery may lead to new platforms for related research, helping us decipher the mysteries
of human brain and neurological diseases.

The researchers say that in the future, other parts of the human brain (such as human microglia, endothelial cells, GABAergic interneurons) may be integrated into rats to build and observe more complex human neural circuits
.

Of course, such research cannot avoid ethical controversy
.
In the contemporaneous comments, Scientists such as J.
Gray Camp and Barbara Treutlein expressed their views that in this context, it is necessary to promote a more active dialogue between researchers, ethicists, regulatory agencies, and the public, and to develop reasonable frameworks and boundaries for human brain organoid-related research [3].

It is worth mentioning that just last year, a group jointly organized by the National Academy of Sciences, the National Academy of Engineering, and the Academy of Medicine issued a report that said The human brain organoids are too primitive and do not have the ability
to require legal supervision such as human consciousness and intelligence.
In response to the results of this study, the team members believe that "we need to weigh the ethical issues caused by human organoids and the needs of patients with neurological diseases and mental diseases" [4].