They are the size of a grain of rice, but they open new paths in research on the last frontier, the human brain. Dutch researchers have managed to create mini brains capable of continuing to grow and they have done so using portions of tissue from a human fetus. The research showed how these organoids included various types of cells and expanded following a scaffold formed by proteins, also generated internally. This work offers a new way to study brain function and, above all, pathologies such as tumors that attack the organ that houses the human mind.
Traditionally, scientists have used different ways to model the biology of tissues, studying both their functioning and that of the organs they form and the associated pathologies. And they did it by cultivating cell lines, blood, liver, neurons, etc., or with laboratory animals as a model. For a few years they have also done it with organoids, a kind of 3D mini-organs with many of the morphological, developmental and even functional characteristics of the organ. This breakthrough occurred thanks to the use of stem cells. Organoids can be formed directly from cells of a given tissue, but researchers are also using pluripotent (adult) or embryonic stem cells to develop into the organ to be studied.
What researchers from the Hubrecht Institute and the Princess Máxima Center for Pediatric Oncology (both in the Netherlands) have done now has been to develop a line of organoids starting not from individual stem cells, but from tissues from a human fetus donated for research after an abortion. To grow mini-organs, other approaches broke down the original tissue into individual cells. In this work, published in the scientific magazine cellinstead of working with portions of fetal brain tissue, the team discovered that they could self-organize by raising structures in three dimensions.
They can multiply in vitro, which means that from a small portion of fetal tissue we can generate multiple organoids
Delilah Hendriks, co-author of the achievement
Dr. Delilah Hendriks, co-author of this research, explains in an email what they have achieved: “The fact that these organoids are derived from tissues means that we can study the developing human brain.” in vitro”. The work verified how proteins created by these cerebroids were organized to form extracellular matrices, structures on which the rest of the brain cells multiplied until they reached the size of a grain of rice. “In addition, compared to existing models, they can multiply in vitrowhich means that from a small portion of fetal tissue we can generate multiple organoids and these in turn can generate more, which is not only advantageous for reproducibility, but also becomes a powerful tool for genetic engineering, especially in the context of brain cancer modeling,” adds Hendriks.
That was the second part of his work. Using the CRISPR gene-gluing technique, they introduced defects in TP53, a known cancer-causing gene, into several organoid cells. After three months, the cells with defective TP53 had completely outcompeted the healthy cells. This greater ability to replicate is a typical characteristic of cancer cells. They then used the same gene editing technique for the opposite, that is, to deactivate three genes linked to glioblastoma, the most aggressive of brain tumors. “We managed to deactivate all three genes at the same time. This means that we were able to introduce complete knockout mutations in TP53, PTEN and NF1 using CRISPR to engineer mutant organoids,” concludes Hendriks.
The organoids derived from the fetal tissues continued to grow for more than six months, allowing the scientists to continue creating many similar organoids from a single tissue sample. Meanwhile, minitumors with changes in the glioblastoma gene were also able to multiply, maintaining the same combination of mutations. This could be used to perform repetitions of experiments with the same organoids, increasing the reliability and reproducibility of their results in future research.
“Brain organoids from fetal tissue are a valuable new tool for studying human brain development. “Now we can more easily study how the developing brain expands and observe the role of different cell types and their environment,” explains Benedetta Artegiani, group leader at the Princess Máxima Center, in a statement. “Our new tissue-derived brain model allows us to better understand how the developing brain regulates cell identity. “It could also help understand how errors in this process can lead to neurodevelopmental diseases such as microcephaly, as well as other diseases that can result from derailed development, including childhood brain cancer,” adds the researcher.
Professor Jacob Hanna, from the Laboratory for the Study of Pluripotent Cells and Ex Utero Embryogenesis at the Weizmann Institute of Sciences (Israel), values the results of this research: “It is important because it can offer clues about what happens in brain development during authentic formation.” of the brain, instead of being based on tissues derived from embryonic stem cells,” he told the SMC Spain news service. For his part, the researcher at the National Center for Biotechnology (CNB-CSIC), Lluís Montoliu, calls for caution: “Organoids are not equivalent to the organs they model. Neither in complexity nor in diversity of cell types. “That is why we should remain cautious when interpreting the results that we may derive from the use of organoids in research.”
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