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Celebrating cerebral organoids
Of all the organs that researchers would love to be able to model in the lab, the brain is high on the list. Recent advancements in stem cell work have allowed scientists to produce lab-grown organs such as livers in miniature, but brains are a different level of complexity entirely.
Recently, however, scientists from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences have developed a method to direct pluripotent stem cells to develop into "mini brains," cerebral organoids that have discrete brain regions. They were even able to use these "mini brains" to model the progression of a human neuronal disorder and identify its origin. The paper, "Cerebral organoids model human brain development and microcephaly," appeared online in Nature August 28.
Led by Dr. Jürgen Knoblich, the team began its work with established human embryonic stem cell lines and induced pluripotent stem cells and examined the growth conditions that contributed to the differentiation of the stem cells into various types of brain tissue. Rather than use patterning growth factor conditions, the team used media for neuronal induction and differentiation.
"We modified an established approach to generate so- called neuroectoderm, a cell layer from which the nervous system derives," explained Knoblich. "Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks, defined brain regions were formed."
The organoids formed after 15 to 20 days, and consisted of continuous tissue surrounding a fluid-filled cavity similar to a cerebral ventricle. By 20 to 30 days, the team saw defined brain regions, including a cerebral cortex, retina, meninges and choroid plexus. After two months, the "mini brains" reached their maximum size—further growth did not occur, likely because of the absence of a circulation system—and were capable of surviving indefinitely (up to 10 months, so far) in a spinning bioreactor.
Using the mini brains, the scientists were also able to model microcephaly, a genetic disorder in which brain and skull size are greatly reduced. Both normal brain function and life expectancy are generally poor for individuals with microcephaly. The models were generated using RNA interference and induced pluripotent stem cells generated from the skin tissue of a patient with microcephaly. This provided the team with mini brain models that presented with microcephaly, and allowed them to discover that the neuroepithilial tissue was smaller in affected brains, but increased neuronal outgrowth was demonstrated, leading to the hypothesis that in microcephaly patients, neural differentiation happens prematurely and at the expense of stem and progenitor cells that would have contributed to more brain growth.
"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," Dr. Madeline A. Lancaster, team member and first author of the publication, commented in a statement. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development."
So far, a variety of different tissues and even organs have been successfully grown in labs from stem cells: trachea, bone, liver buds (tiny but fully functioning mini organs), kidneys and even beating heart tissue. The ability to grow various organs in a lab could have a variety of benefits for both the medical and pharmaceutical fields. For those in the pharmaceutical world, fully functioning, lab-grown livers and kidneys offer a fantastic way to test toxicity of drug candidates—one of the leading causes of late-stage development failure—without risking patients. Beyond that, being able to grow organs in the lab could have a huge impact on the significant backlog of patients waiting on organ transplant lists. Even better, by developing the organs from stem cells—namely autologous stem cells derived from the patients themselves—could minimize or eliminate the risk of rejection.