Researchers from the Institute of Molecular Biotechnology (IMBA) at the Austrian Academy of Sciences (OeAW) say the newly created tissue could be the start of developing model systems for the human brain.
The scientists began the research by using established human embryonic stem cell lines and induced pluripotent stem (iPS) cells from mouse embryonic fibroblasts. They identified growth conditions that helped the stem cells differentiate into a variety of brain tissues.
The researchers used “media” for neuronal induction and differentiation, which allowed them to avoid “patterning growth factor conditions.” They say that these conditions are usually applied to generate particular cell identities from stem cells.
Dr. Jürgen Knoblich from the IMBA and lead study author explains the process:
“We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. 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 3 to 4 weeks, defined brain regions were formed.”
‘Mini-brains’ grown after 2 months
“Cerebral organoids” formed after 15-20 days. These organoids had continuous tissue (neuroepithelia) around a fluid-filled cavity similar to a cerebral ventricle – a cavity in the brain that is continuous with the central canal of the spinal cord.
Defined regions of the brain – including a cerebral cortex, retina, meninges and a choroid plexus – developed after 20-30 days.
After 2 months, full size “mini-brains” had been created that have continued to survive in a spinning bioreactor, and they are currently surviving at 10 months.
The study authors say:
“We have established a novel approach to studying human neurodevelopmental processes through in vitro culture of cerebral organoids from human pluripotent stem cells. This method recapitulates not only fundamental mechanisms of mammalian neurodevelopment, but also displays characteristics of human brain development. We are hopeful that this method will allow for the study of a variety of neurodevelopmental processes specific to human brain development.”
Potential for ‘model brains’
The researchers say that this method could potentially be used to create “model systems” for human brain disorders.
They have already used the “mini-brains” in order to analyze the onset of microcephaly – a genetic neurological condition where the brain is significantly reduced in size.
The team created induced pluripotent stem cells from a patient with microcephaly. In doing so, they were able to create “mini-brains” that were all affected with the disorder.
The brains grew to a smaller size, just as the researchers expected. However, they were interested to find that although the neuropithilial tissue grew to a smaller size in the microcephaly mini-brains compared with those that did not have the disorder, there was increased neuronal outgrowth.
From this, the study authors believe that during the brain development of microcephaly patients, the differentiation in neuronal development begins “prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size.”
Additionally, they discovered that another cause of the disorder could be due to a change in direction when the stem cells divide.
Dr. Madeline Lancaster, first author of the study, says that 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.
“They allow for the testing of therapies against brain defects and other neuronal disorders,” Dr. Lancaster adds. “Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development.”