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induced pluripotent stem cells emerged, allowing scientists to make rapid progress in the fields of stem cell and developmental biology . One of the very potential applications is organoid . With the help of stem cells' differentiation ability, researchers can make stem cells form aggregation under 3D conditions, and then differentiate in a direction towards a certain organ tissue.
These cells will eventually assemble into miniature, organ-like clumps, and the simulated objects can be the liver, kidneys, or brain. Brain-like organs make the research on neuroscience more convenient. Scientists can directly manipulate the neurons of interest in in petri dish to find the neural mechanisms or potential drug targets behind it.
Image source: 123RF
However, the brain-like organs in the Petri dish are not perfect, and neural tissue is always difficult to mature and differentiate completely correctly, so it also lacks some connections in the real brain, which has also become a major shortcoming in the research of brain-like organs.
Today, the major research of "Natural " finally solved this problem. The study transplanted brain-like organs into the developing brain of rats. As a result, they found that brain-like organs can develop and mature normally, and are partially integrated with the brain's neural circuits, truly becoming part of the brain . In the study, human induced pluripotent stem cells (hiPSCs) were first selected as the basis for culture. HiPSCs can culture neurons, astrocytes and microglia under 2D conditions. Under special 3D culture conditions, hiPSC can also develop into different structures such as striatum and cortex. These tissues can be merged to form assembled organoids, which is also a way to study complex neural circuits.
In the paper, the researchers transplanted the cultured human cortical organoids into the cortex of juvenile rats. The immune systems of these juvenile mice are defective, so the transplanted organoids will not be immune rejected.
The time point of transplantation is also very critical. must complete before the rat brain neural circuit is completely formed, which can provide a development window for organoids. In fact, organoids will also desperately integrate into new soil. Even if organoids originate from humans, they will not resist the living environment of rats.
▲The human cortical organoids can be transplanted into the brain of rats and develop and mature and play their functions (Picture source: Reference [1])
According to observations, organoids can develop and mature together with the brain of rats. These organoids will gradually develop blood vessels and provide nutrition for their own development . Gradually, some cell types that did not exist originally appeared in the organoids, and specific immune cells such as microglia will gradually infiltrate into the organoids. All these show that human brain-like organs have formed functional connections with the rat brain and are integrated.
However, organoids do not develop exactly like the human cerebral cortex and lack some cell types. However, compared with in vitro culture, the transplanted brain-like organ neurons are larger and more closely connected to . The survival status of rats who received transplantation is no different from that of ordinary rats, and the proportion of rats who survived for more than 1 year exceeded 70%.
▲The author transplanted the brain-like organ to a specific part of the rat (Picture source: Reference [3])
In addition to normal brain-like organs, the researchers also tried to culture brain-like organs with stem cells of patients with Timothy syndrome for transplantation. The organoid neurons developed from this are obviously simpler and will also have different synaptic connections and electrical activities.
Of course, researchers also want to know a key question whether these brain-like organs that have successfully gained a place in rats can play a role. They brought special photosensitive proteins to the cells of brain-like organs, and neurons can be activated under the stimulation of blue light .
They found that stimulating brain-like organs can be used to train rats for reward-related behaviors, such as licking water sources. Rats that did not receive transplantation would not have similar reactions, which shows that brain organs participated in the rat reward learning process . These new results also prove that brain-like organs can form suitable and mature tissues in the host, and organoid research has been pushed to a new level.
In the future, a disease research system that can be closer to reality is coming towards us.
Reference:
[1] Human brain organizations influence rat behavior. Nature Vol 610 (2022).
[2] A nomenclature consensus for nervous system organizations and assemblys. Nature (2022). DOI: https://doi.org/10.1038/s41586-022-05219-6
[3] Maturation and circuit integration of translated human cortical organizations. Nature (2022). DOI: https://doi.org/10.1038/s41586-022-05277-w
Disclaimer: WuXi AppTec content team focuses on introducing the progress of global biomedical health research. This article is for information exchange only. The views in the article do not represent the position of WuXi AppTec, nor does it represent that WuXi AppTec supports or opposes the views in the article. This article is not a recommendation for treatment. If you need treatment plan guidance, please go to a regular hospital for treatment.
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