Human Stem Cells Give Rise to Brain-Like Organs in Culture

Ricki Lewis, PhD

August 28, 2013

Human "cerebral organoids" grown in culture from stem cells are revealing the steps of early normal neurogenesis and the origins of microcephaly, according to a report published online August 28 in Nature.

The cerebral organoids join a growing list of human body parts modeled in cell culture, including the human retina, intestines, pituitary gland, and liver.

Madeline Lancaster, PhD, a postdoctoral researcher from the Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, and colleagues used human induced pluripotent stem cells to form embryoid bodies, which have a variety of specialized cell types.

The researchers then used several techniques, including specific culture conditions, scaffolding rich in extracellular matrix components, and a spinning bioreactor to distribute nutrients, to encourage development of neuroectoderm at the expense of other tissues. The results were organized collections, 4 mm in diameter, of neural stem cells, progenitor cells, and neurons.

The cerebral organoids have discrete but interdependent regions that resemble different areas of the early developing human brain, including the dorsal cortex, ventral forebrain, choroid plexus, and retina. Interneurons indicate connectivity, and calcium signaling indicates action potentials. The organoids appear to reflect up to the ninth week of gestation and have been maintained in the laboratory for 10 months to date.

To explore the value of the organoids as a model for brain disease, the researchers induced pluripotent stem cells derived from skin fibroblasts from a patient with microcephaly. The patient-derived organoids look markedly different than those from normal controls.

At a point in embryonic development when a normal neural stem cell population self-renews, the patient's stem cells instead start yielding neurons too early. The stem cell depletion ultimately limits head size, causing intellectual disability. The accelerated stem cells are in the outer layer of the subventricular zone. (Mice lack a subventricular zone, which explains why mice cannot model human microcephaly.)

Although the researchers stated in a news conference that they would like to use the organoids to study the underlying defects in brain development that lead to such conditions as autism and schizophrenia, they cautioned that the work was never intended to provide replacement body parts.

Cerebral organoids may be used to complement model organisms and isolated human cells in culture in drug testing. Said coauthor Juergen A. Knoblich, PhD, also from the Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, "We hope our organoids will contribute to the transfer of knowledge from model organisms to cure disease in humans."

The authors have disclosed no relevant financial relationships.

Nature. Published online August 28, 2013.

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