Science/Tech

3-D Model Brain Built With Stem Cells: Organoids' Architecture Mirrors The Real Thing

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A magnified image of a cerebral organoid — a brain-like structure built from human stem cells — showing cerebral tissue adjacent to developing retinal tissue (brown pigmented region). Madeline A. Lancaster | Nature

Scientists in Europe have used stem cells to build a model organ comprised of the 3-D architecture of a young brain, according to report published today in Nature.

Over the past five years, it has become apparent that embryonic stem (ES) cells, which can become any cell from any organ in the body, don’t need much coaxing to do so, especially in regards to the brain.

Mouse ES cells tossed onto a petri dish, with the right brain-related growth factors, will begin building concentric layers of neurons — with one curved sheet on top of the next. This process is surprisingly similar to the assembly of the young brain, which led researchers at the Institute of Molecular Biotechnology in Austria to ask if human ES cells could build a 3-D brain on their own.

The researchers created an environment that turned on intrinsic cues within the human embryronic stem cells to simulate normal development. The cells were seeded on gel scaffold in the shape of ball, which promoted their growth into three dimensions. This gel-cell ball was then incubated with growth factors in a spinning bioreactor, which promoted nutrient absorption.

After a month of self-assembly in an incubator, miniature human brain-like structures, which they dubbed “cerebral organoids," began to bloom.

The organoids included brain regions that resembled the human cerebral cortex — the most complex tissue in the animal kingdom — and the ventricles, which are liquid-filled tubes that course through the brain and provide nourishment.

“The cerebral cortical regions display an organization similar to the developing human brain at early stages,” wrote the international team of scientists who were led by Drs. Madeline Lancaster and Juergen Knoblich of the Institute of Molecular Biotechnology.

Image3 Comparison of the organoid (right) to the developing brain (left, section of a mouse brain shown). Both show neural stem cells in red and neurons in green. Credit: Marko Repic and Madeline A. Lancaster | Nature Credit: Marko Repic and Madeline A. Lancaster | Nature

In a second experiment, the team used this system to model a neurodevelopmental disease called microcephaly. This inherited disease occurs when an newborn’s brain doesn’t fully grow while in the womb or after birth, leading to a shrunken head and intellectual disability. The study of this disease has been hampered by the lack of a strong animal model, such as with mice, that recapitulates the severely reduced brain size.

The researchers took a few skin cells from a microcephaly patient and reprogrammed them into induced pluripotent stem cells, which, like ES cells, can convert into any type of organ tissure.

Cerebral organoids developed from this patient’s cells exhibited the stunted growth seen with the disease, which suggests these artificial “brains” could be useful for studying developmental disease.

“What made the observations so particularly exciting is that cells from a patient with a severe disorder of brain development developed into an abnormal organoid with features analogous to many of those in the patient,” said professor Paul Matthews, a clinical neuroscientist at Imperial College London who was not involved with the work. “The investigators then showed that these abnormal features could be “cured” by replacing the defective gene.” 

However, the new organoids are not a perfect “brain in a dish," according to neuroscienitst Dr. Oliver Brüstle of the University of Bonn, who wrote an accompanying commentary for Nature.

For one thing, they didn’t have blood vessels, restricting the “metabolic supply” of the organioids as well as their size, which topped out at four millimeters. In addition, their human-like neural regions “are randomly distributed and lack the shape and overall spatial organization seen in the brain,” wrote Brüstle, who still feels the technique is an excellent and innovative research tool for biomedicine.

 

Sources: Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013.

Brüstle O. Miniature human brains. Nature. 2013.

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