Celebrating cerebral organoids

Scientists successfully fine-tune pluripotent stem cells to develop into 'mini brains' that present with discrete brain regions and provide hope for producing usable brain models

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Of all the organs that researchers would love to be able tomodel in the lab, the brain is high on the list. Recent advancements in stemcell work have allowed scientists to produce lab-grown organs such as livers inminiature, but brains are a different level of complexity entirely.
Recently, however, scientists from the Institute ofMolecular Biotechnology of the Austrian Academy of Sciences have developed amethod to direct pluripotent stem cells to develop into "mini brains," cerebralorganoids that have discrete brain regions. They were even able to use these"mini brains" to model the progression of a human neuronal disorder andidentify its origin. The paper, "Cerebral organoids model human braindevelopment and microcephaly," appeared online in Nature August 28.
Led by Dr. Jürgen Knoblich, the team began its work withestablished human embryonic stem cell lines and induced pluripotent stem cellsand examined the growth conditions that contributed to the differentiation ofthe stem cells into various types of brain tissue. Rather than use patterninggrowth factor conditions, the team used media for neuronal induction anddifferentiation.
"We modified an established approach to generate so-calledneuroectoderm, a cell layer from which the nervous system derives," explainedKnoblich. "Fragments of this tissue were then maintained in a 3D-culture andembedded in droplets of a specific gel that provided a scaffold for complextissue growth. In order to enhance nutrient absorption, we later transferredthe gel droplets to a spinning bioreactor. Within three to four weeks, definedbrain regions were formed."
The organoids formed after 15 to 20 days, and consisted ofcontinuous tissue surrounding a fluid-filled cavity similar to a cerebralventricle. By 20 to 30 days, the team saw defined brain regions, including acerebral cortex, retina, meninges and choroid plexus. After two months, the"mini brains" reached their maximum size—further growth did not occur, likelybecause of the absence of a circulation system—and were capable of survivingindefinitely (up to 10 months, so far) in a spinning bioreactor.
Using the mini brains, the scientists were also able tomodel microcephaly, a genetic disorder in which brain and skull size aregreatly reduced. Both normal brain function and life expectancy are generallypoor for individuals with microcephaly. The models were generated using RNAinterference and induced pluripotent stem cells generated from the skin tissueof a patient with microcephaly. This provided the team with mini brain modelsthat presented with microcephaly, and allowed them to discover that theneuroepithilial tissue was smaller in affected brains, but increased neuronaloutgrowth was demonstrated, leading to the hypothesis that in microcephalypatients, neural differentiation happens prematurely and at the expense of stemand progenitor cells that would have contributed to more brain growth.
"In addition to the potential for new insights into thedevelopment of human brain disorders, mini brains will also be of greatinterest to the pharmaceutical and chemical industry," Dr. Madeline A.Lancaster, team member and first author of the publication, commented in astatement. "They allow for the testing of therapies against brain defects andother neuronal disorders. Furthermore, they will enable the analysis of theeffects that specific chemicals have on brain development."
So far, a variety of different tissues and even organs havebeen successfully grown in labs from stem cells: trachea, bone, liver buds(tiny but fully functioning mini organs), kidneys and even beating hearttissue. The ability to grow various organs in a lab could have a variety ofbenefits for both the medical and pharmaceutical fields. For those in thepharmaceutical world, fully functioning, lab-grown livers and kidneys offer afantastic way to test toxicity of drug candidates—one of the leading causes oflate-stage development failure—without risking patients. Beyond that, beingable to grow organs in the lab could have a huge impact on the significantbacklog of patients waiting on organ transplant lists. Even better, bydeveloping the organs from stem cells—namely autologous stem cells derived fromthe patients themselves—could minimize or eliminate the risk of rejection.

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