Researchers have used stem cells to grow tiny structures that resemble the developing human brain. Although these structures are far from representing an actual brain, they hold promise to be useful for exam brain abnormalities that are otherwise hard to study. The research could lead to treatment and preventive measures for a wide range of neurological disorders including Alzheimer’s disease and microcephaly (mental retardation due to an unusually small brain). The results of the study, conducted by researchers in Austria and the United Kingdom, was published online on August 28 in the journal Nature.
The human brain is an extremely complex structure and the “mini-brains” grown by the researchers are tiny the structures, which are about four millimeters in diameter. However, they share some of the crucial three-dimensional architecture of a developing human brain. The researchers expect that their findings will allow them to investigate human brain disease in the laboratory. At present, brain disorders such as Alzheimer’s disease are studied in animals such as mice and rats; the brains of these animals are far different from the human brain.
The investigators have used their technique to study brain tissue created from a patient suffering from microcephaly. The research builds on several experiments published by other researchers since 2008, which showed how stem cells could be manipulated to create not just nerve cells, but more elaborate neuron-based structures as well. Lead researcher Jürgen Knoblich’s laboratory is housed at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences. At the laboratory, Dr. Knoblich conducted experiments with human embryonic stem cells, which are derived from an embryo. He experimented with stem cells that were obtained by reprogramming mature tissue (i.e., human skin cells) into an embryonic-like state. Both types of stem cells are “pluripotent,” meaning that they can develop into all other cell types in the body.
The researchers added chemicals known as growth factors to the stem cells; this resulted in the creation of tissues that would go on to form the central nervous system. The tissues were put in a gel-like substance resembling the environment of a developing human embryo. This material was then put into a spinning bioreactor, which is a container that promotes cell development. After 20 to 30 days, the neural cells organized themselves into tiny structures, called cerebral organoids. These structures had defined brain regions, including a dorsal cortex, which is the largest component of the human brain, and the choroid plexus, where cerebrospinal fluid is produced. The neurons were active and fired; however, within the structures, the various portions were not well organized; thus the shape and overall spatial organization did not fully match that of a real brain. In addition, key brain components, such as the cerebellum, an area involved in motor control, were missing.
After the organoids attained a size of four millimeters in diameter, they stopped growing. The researchers suspected that this was because they lacked a circulatory system. At that stage, they resembled the developing brain of a nine-week-old human embryo. Despite their imperfections, the organoids have tremendous research potential. For example, the researchers used their technique on a patient with microcephaly. They first reprogrammed the patient’s skin cells into stem cells, then grew those into mini brains. As expected, the mini brains grew to a lesser-than-normal size. By examining the mini-brains in the laboratory, the researchers were able to pinpoint some ways in which the disease develops. It appears that in microcephalics, stem cells get transformed into neurons prematurely; this process occurs at the expense of a proper buildup of stem cells. The investigators theorized that that is why the brains of such patients end up being smaller than normal.