Wrong organoids
Immature cells found under stress in mini-brains
Svetlana Yastrebova, N+1
Miniature living models of the human brain may not reflect the actual development of this organ, scientists write in Nature (Bhaduri et al., Cell stress in cortical organoids impairs molecular subtype specification). Although mini-brains contain many different types of cells, their development from progenitors is not the same as in the whole body. In addition, the cells of such organoids are more active than in the real brain, producing molecules-markers of cellular stress.
In 2008, neuroscientists discovered that mouse embryonic stem cells in culture are organized into three-dimensional structures that resemble a miniature brain. These structures (they are also called organoids) have the similarity of departments, and some of the cells migrate into them, as in the embryonic development of a real brain. In 2013, another group of researchers obtained such organoids from human cells for the first time, and later researchers learned how to form different types of organoids, each of which mimics some part of the brain.
Scientists from the California Institute in San Francisco and Santa Cruz and The Aga Khan University in Karachi (Pakistan), led by Arnold R. Kriegstein, analyzed transcriptomes (a set of RNA) of 189409 individual cells in the developing cerebral cortex of five human embryos at 7-22 weeks of development (corresponding to the time of neurogenesis) and 235121 cells from 37 organoids that mimic this cortex. This made it possible to compare the activity of neuronal genes and glial elements in the real brain and the mini-brain and see how functionally different cells are distributed in the space of each structure.
The intensity of expression of various genes in the cells of the developing cerebral cortex (a) and the cells of organoids that mimic it (b). A drawing from an article in Nature.
Although all the major cell types were represented in the organoids, their arrangement was different from that observed in the real cortex. Functionally similar neurons in mini-brains rarely formed groups and were scattered randomly across the tissue.
Judging by which genes were most intensively expressed in organoid cells (this was determined by the number of RNA molecules of different types), in general, neurons and glia in mini-brains are less mature than in the developing cortex, and the development of these cells does not reach its logical conclusion. If in the cells of the radial glia of the forming cortex one can notice traces of specialization and understand what types of neurons and glia are formed from it, then with the radial glia of organoids it was much more difficult to do.
In addition, in many cells of mini-brains, there was an increased expression of genes that encode molecules characteristic of cellular stress: activate glycolysis (PGK1) and trigger changes in the endoplasmic network (ARCN1, GORASP2). Intensive work of these genes is not typical for the developing cerebral cortex. In the sections of the cortex that were kept in the nutrient medium for a week, their expression also did not increase, from which the authors concluded that cellular stress may be a characteristic feature of cultures of neurons and glia, as well as their precursors.
Interestingly, when cells from organoids were planted in the cortex of the large hemispheres of a live mouse, they completed maturation, and the intensity of the production of markers of cellular stress in them decreased. Probably, stress is somehow provoked by the environment of brain organoids.
Scientists conclude that it is necessary to study the development of the human brain and, in particular, the cerebral cortex on organoids with caution, taking into account all the differences in the formation of these structures. The same applies to studies of the formation of connections between neurons, and modeling of diseases of the nervous system on brain organoids.
These recommendations will become more and more relevant, given that the number of works on miniature models of the brain is growing. On organoids that mimic various parts of the brain, the effects of mutations characteristic of Neanderthals have already been studied and electrical activity of cells has been achieved as in premature babies.
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