The human brain in the mouse's head

There is still no treatment for most neuropsychiatric disorders, including autism, schizophrenia, Alzheimer's disease and other forms of dementia. The human brain has a complex organization. Even if an experimental drug shows good results in animal models, it often proves ineffective in studies involving humans.

One of the promising directions is the use of pluripotent stem cells. With the help of special technology, researchers turn human skin cells into neurons and test new drugs on them, as well as evaluate changes over the course of the disease. In addition, these cells can be transplanted to the site of the affected tissues. Biologists have already succeeded in growing some organoids from stem cells in vitro, but these model systems still do not sufficiently simulate complex brain structures.

Researchers from the Salk Institute in San Diego, USA, have developed a new approach to create more complex models of organoids. To maintain vital activity and provide nutrition and respiration, they were transplanted to rodents. This method will help researchers in the development of new drugs for the treatment of brain diseases, it will shorten the testing time of experimental drugs, and in the long term, it may become the basis for the transplantation of laboratory-grown neurons to the place of affected human brain tissues.

Human organoid transplant (green) in mouse brain.
The neurons are marked in red. Source: Salk Institute.

Organoids of the human brain grown in laboratory conditions are functionally limited, since they do not have a network of blood vessels that provide nutrition to cells and supply them with oxygen. This does not allow to achieve a more complex structure – the limited lifetime makes it impossible for organoids to pass a sufficient number of cycles. Growing a network of blood vessels in a test tube partially solves this problem, but still does not recreate the microenvironment characteristic of brain tissue.

The authors of the study transplanted artificial organoids from human pluripotent stem cells into the mouse cerebral cortex, rich in blood vessels. The grafted organoids, after integration into the natural environment, formed neurons and auxiliary cells (astrocytes). It is noteworthy that nutrition was carried out not only from the blood vessels of the host organism. Two weeks later, their own vessels appeared, penetrating the three-dimensional structure of the organoids. After 90 days, axons moved away from the transplanted tissue to different parts of the mice's brain.

In one experiment, the researchers divided the organoids into two parts. One of them was transplanted to mice, and the second was left in culture. This allowed us to evaluate the advantages and disadvantages of both environments. They found that within a few months, the cell culture was full of dead cells, while the transplanted organoids continued to live.

The researchers also assessed the functional state of the graft using calcium imaging tests, in which neurons in an excited state are stained, and optogenetic methods. The organoids functioned fully and interacted with the host cells. This proves that the provision of blood supply allowed the organoids to achieve sufficient complexity of structure.

The results of the study have a huge potential for studying the mechanisms of brain damage in neurological disorders, as well as for developing methods of their treatment.

Article by A. A. Mansour et al. An in vivo model of functional and vascularized human brain organoids is published in the journal Nature Biotechnology.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on Salk News: Grafted brain organoids provide insight into neurological disorders.