Self-organization of brain organoids from fetal tissue
summary: Scientists have created 3D brain organoids from self-organizing human fetal tissue, providing a new way to study brain development and disease. These tiny brains contain different types of brain cells and extracellular matrix, very similar to the human brain. They also show the potential for cancer research and drug testing.
- Brain organoids develop from fetal brain tissue, self-organizing themselves into complex three-dimensional structures.
- These organoids mimic brain regions and respond to signaling molecules involved in brain development.
- Organoids are valuable for studying brain development, neurodevelopmental diseases, childhood brain cancer, and responses to drugs.
source: Princess Máxima Pediatric Oncology Centre
Scientists have developed tiny 3D organoids from human fetal brain tissue that self-regulate in the laboratory. These lab-grown organoids open up a whole new way to study how the brain develops. They also provide a valuable means of studying the development and treatment of diseases related to brain development, including brain tumors.
Scientists use different methods to model the biology of healthy tissues and diseases in the laboratory. These include cell lines, laboratory animals, and 3D mini-organs from a few years ago. These so-called organoids have characteristics and a level of complexity that allow scientists to accurately model organ functions in the laboratory.
Organelles can form directly from tissue cells. Scientists can also “direct” stem cells – found in embryos or in some adult tissue – to develop into the organ they aim to study.
Until now, brain organoids have been grown in the laboratory by stimulating embryonic or pluripotent stem cells to grow into structures representing different regions of the brain. Using a specific mixture of molecules, they will try to mimic the natural development of the brain, with the “recipe” for each cocktail requiring a lot of research to develop.
Now, scientists at the Princess Máxima Children’s Oncology Center and the Hubrecht Institute, based in Utrecht, the Netherlands, have developed brain organoids directly from human fetal brain tissue.
The study was published in a prestigious journal cell Today (Monday), and partly funded by the Dutch Research Council.
The researchers, led by Dr Delilah Hendricks, Professor Dr Hans Clevers and Dr Benedetta Artigiani, were surprised to find that using small pieces of fetal brain tissue rather than individual cells was vital in the development of small brains. To grow other small organs such as the intestine, scientists typically break down the original tissue into single cells. Instead of working with small pieces of fetal brain tissue, the team found that these pieces could self-organize to form organoids.
The cerebral organs were approximately the size of a grain of rice. The three-dimensional structure of the tissue was complex, containing a number of different types of brain cells. Importantly, brain organoids contain many so-called extrinsic radial glial cells, a type of cell found in humans and our evolutionary ancestors. This confirms the close similarity between the organisms and the human brain and their use in study.
Whole sections of brain tissue also produced proteins that form the extracellular matrix, a kind of “scaffolding” around cells. The team believes these proteins could be the reason why pieces of brain tissue are able to self-organize into 3D brain structures. The presence of extracellular matrix in the organoids will allow further study of the environment of brain cells, and what happens when things go wrong.
The researchers found that the tissue-derived organoids retained different properties of the specific region of the brain from which they were derived. They responded to signaling molecules known to play an important role in brain development. This finding suggests that tissue-derived organelles could play an important role in untangling the complex network of molecules involved in directing brain development.
Given the ability of tissue-derived organoids to expand rapidly, the team next studied their potential in brain cancer modeling. The researchers used the CRISPR-Cas9 gene editing technology to introduce defects in the known cancer gene TP53 into a small number of cells in the organoids.
After three months, the cells with the defective TP53 outgrew healthy cells in the organoid, meaning they gained a growth advantage, a typical feature of cancer cells.
They then used CRISPR-Cas9 to turn off three genes associated with the brain tumor, glioblastoma: TP53, PTEN, and NF1. Researchers have also used these mutant organelles to look at their response to existing cancer drugs. These experiments demonstrated the potential for organoids to be used in cancer drug research to bind certain drugs to specific genetic mutations.
The tissue-derived organoids continued to grow in a dish for more than six months. Importantly, the scientists were able to replicate them, allowing them to grow many similar organelles from a single tissue sample.
Small tumors containing the genetic changes in glioblastoma were also able to replicate, maintaining the same combination of mutations. This advantage means that scientists can perform repeated experiments on tissue-derived organoids, increasing the reliability of their findings.
Next, the researchers aim to further explore the potential of their new tissue-derived brain organoids. They also plan to continue their work with bioethicists—who have already been involved in shaping this research—to guide the development and future applications of the new brain organoids.
Dr. Benedetta Artigiani, research group leader at the Princess Máxima Children’s Oncology Center who co-led the research, says:
Brain organoids derived from fetal tissue are an invaluable new tool for studying human brain development. We can now study how the developing brain expands more easily, and consider the role of different cell types and their environment.
“Our new tissue-derived brain model allows us to gain a better understanding of 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 stem from Derailed growth, including brain cancer in children.
Dr. Delilah Hendricks, affiliate group leader at the Princess Máxima Children’s Oncology Centre, postdoctoral researcher at the Hubrecht Institute and Oncode researcher, who co-led the research, says:
“These new organoids derived from embryonic tissue could provide new insights into what shapes different regions of the brain, and what creates cellular diversity. Our organoids are an important addition to the field of brain organoids, as they can complement existing organoids made from pluripotent stem cells. We hope We can learn from both models to decipher the complexity of the human brain.
“The ability to continue to grow and use brain organoids from embryonic tissue also means that we can learn as much as possible from these precious materials. We are excited to explore the use of these new tissue organoids to make new discoveries about the human brain.”
Professor Dr. The research was co-led by Hans Clevers, a pioneer in organoid research and former research group leader at the Hubrecht Institute and the Princess Máxima Children’s Oncology Center and an Oncode investigator. He says:
“With our study, we are making an important contribution to the fields of organ and brain research. Since we developed the first human gut organoids in 2011, it has been great to see that this technology has really taken off. Since then, organoids have been developed for all tissues of the human body Almost, both healthy and diseased – including a growing number of pediatric tumors.
“Until now, we have been able to extract organoids from most human organs, but not from the brain – and it is really exciting that we are now able to overcome this hurdle as well.”
The study was conducted in collaboration with Leiden University Medical Centre, Utrecht University, Maastricht University, Erasmus University Rotterdam, and the National University of Singapore.
NB: Human fetal tissue was obtained from healthy abortion subjects, between gestational weeks 12-15, from completely anonymous donors. Anonymous women donated tissue voluntarily and based on informed consent.
They were informed that the material would be used for research purposes only, and that the research would include understanding how organs develop naturally, including the possibility of transplanting cells derived from the donated material.
About neurodevelopmental research and neurotechnology news
author: Sarah Wells
source: Princess Máxima Pediatric Oncology Centre
communication: Sarah Wells – Princess Máxima Pediatric Oncology Centre
picture: The image is the property of the Princess Máxima Centre, the Hubrecht Institute/B Artegiani, D Hendriks, and H Clevers.
Original search: Open access.
“The human fetal brain self-organizes into long-term expanding organoids” by Delilah Hendricks et al. cell
The human fetal brain organizes itself into long-term expanding organoids
- Human fetal brain organoids (FeBOs) display cellular heterogeneity and can be expanded
- FeBOs produce a tissue-like ECM niche and enable ECM disruption studies
- Derivation of regional FeBOs allows the study of regional morphological effects
- CRISPR-engineered FeBOs are a scalable bottom-up tumor modeling platform
Human brain development involves a coordinated and massive expansion of neural progenitors during the establishment of a multicellular tissue structure. Continuously expanding organoids can be grown directly from multiple somatic tissues, but until now, brain organoids can only be generated from pluripotent stem cells.
Here, we show the brain of a healthy human fetus in the laboratory It organizes itself into organelles (FeBOs), and aspects of virtual transcription Alive Cellular heterogeneity and complex organization.
FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, ensuring the production of tissue-like extracellular matrix (ECM), which ultimately leads to FeBO expansion. FeBO lines derived from different regions of the central nervous system (CNS), including the dorsal and ventral forebrain, maintain their regional identity and allow aspects of positional identity to be explored.
Using CRISPR-Cas9, we demonstrate the generation of mutant FeBO lines to study brain cancer. Taken together, FeBOs form a complementary organic platform for the central nervous system.