At birth, a baby's brain has the largest number of neurons in its lifetime.How this complex brain develops in the womb is difficult to study in humans.But a new, potentially controversial method of cultivating tiny brain-like structures called organoids from human fetal brain tissue could provide a realistic model and be used in research into developmental disorders or brain cancer.The team that achieved this for the first time also showed that it can genetically engineer tissue spots, which can help fetal brain organoids (FeBOs) mimic certain diseases.
Researchers have "demonstrated some interesting and creative uses," said Arnold Kriegstein, a neuroscientist at the University of California, San Francisco.He believes FeBO could help researchers solve previously unexplored problems, such as how neurons have specific identities in mature brains.
Images of whole fetal brain organoids
Researchers have created organoids that mimic multiple parts of the brain and nervous system, and these stem cells are capable of translating into many or all known cell types with the right stimulation and environment.To study genetic conditions that affect brain development, scientists can also "reprogram" mature cells from affected patients into stem cells to make organoids.Some stem cell-derived brain organoids, usually about the size of a grain of rice, even produce electrical activity reminiscent of fetal brains.
But while these organoids can be useful representatives of the brain, starting stem cells must be "pushed" to a brain-like state by introducing a mixture of signaling molecules — a complex process that may not fully replicate normal development, says stem cell biologist Benedetta Artegiani.Using natural fetal brain tissue may reveal more about what the human brain really looks like at this stage of development.(Previous studies have made organoids from the gut, liver, and lung tissues of human fetuses, but not the brain.)
So Artegiani, along with stem cell biologist Delilah Hendriks at the Hubrecht Institute and colleagues, collected brain tissue from human fetuses between 12 and 15 weeks after conception.At this stage of development, the human brain is expanding rapidly: many stem cells have become progenitors of nerve cells, but not all have differentiated into various types of neurons, support cells called glial cells, and other cells found in the brain.
This work on abortion organizations is ethically sensitive and politically worrisome in some countries, such as the United States.The European team obtained informed consent from pregnant women who donated fetal tissue and did not pay for the tissue.
Using tissues from different brain regions, including the cortex, forebrain, and spinal cord, the researchers cut the samples into layers and placed each sample in a separate dish containing molecules that told the cells to grow.The researchers reported in the journal Cell on Jan. 7 that each resulting fetal brain organoid grows into a 3D structure similar to its original tissue.The spheres formed by FeBOs contain neurons in their center and progenitor cells outside of them, which allows them to grow without maturing into older brains.
Next, to test whether stable FeBOs could become more mature, the team altered the signaling molecules in the liquid medium around the organoids.This triggers progenitor cells to stop replicating and instead become neurons.These cells form connections and fire as if they were in a complete brain.The researchers worked with bioethicists to make sure FeBO didn't feel pain or become conscious: neither, they said, was likely because organoids lacked sensory input or interactions between mature brain regions.
Artegiani and Hendriks also altered organoid DNA, using genome editor CRISPR to mutate genes involved in brain cancer, including glioblastoma.They found that these cells grew out of control as expected and responded to cancer drugs in the same way as a whole brain.The authors say the model could help test new drugs for brain cancer, which until recently was a daunting task because brain cells usually don't grow well in the lab.They also plan to use FeBOs to study neurodevelopmental disorders such as Down syndrome.Hendrix said the experiments conducted so far were only the "tip of the iceberg."
Alyssson Muotri, a neuroscientist at the University of California, San Diego, said the work was well done, but given previous research into stem cell-derived organoids, the findings about FeBO growth and differentiation are not surprising. "This validates that [stem cell-derived] organoids are indeed mimicking fetal brains," he said.He said the new model has the potential to eventually reveal unknown roles of different signaling molecules in brain development, although this has not yet been proven.
Kriegstein notes that FeBOs apparently produce their own networks of supporting proteins called extracellular matrices, which could allow researchers to better study how these structures develop and specialize.(Researchers must introduce an extracellular matrix for stem cell-derived organoids.)
Artegiani believes FeBO and stem cell-derived organoids each have advantages.Stem cell-derived organoids can reveal the earliest stages of brain development, including how stem cells develop into different cell types.She believes FeBOs can show how individual brain regions grow and form specific structures.
Still, stem cell-derived organoids may be easier to obtain and use for many scientists.In the United States, a 2019 law prohibits most studies of tissue from aborted fetuses.U.S. President Joe Biden lifted the ban in 2021, but regulations still require pregnant women's informed consent and prohibit researchers from paying for it.National Institutes of Health (U.S.)The S. National Institutes of Health asked researchers seeking federal funding to justify the use of fetal tissue.
Restrictions in the United States may also be extended.Bills introduced by the U.S. Senate and multiple state legislatures either completely prohibit research into fetal tissue or require it to be buried or cremated, making it unavailable to researchers.