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Of mice and men

Human embryonic cells incorporate themselves into rodents' brains

You may remember Pinky and The Brain, the intelligent mice in the cartoon created by Steven Spielberg, following the experiment coordinated by Brazilian geneticist Alysson Muotri at the Salk Institute in the United States. In the midst of a worldwide race, Muotri managed to implant human embryonic cells in the brains of mice. The experiment – one of the first done on animals – worked. The embryonic cells differentiated themselves into a neuron, came into contact with the rodents’ natural neurons and responded to electric impulses, but evidently the animals showed no sign of wanting to dominate the world, like The Brain tries to in each new episode of the cartoon.

“The number of cells incorporated into the brains of the mice is less than 0.1%”, says Muotri, who works under the supervision of Fred Gage, the head of the Salk’s genetics laboratory. His intention was to see if it is possible to implant human embryonic cells into animals – until now, most of the research has been done will cells in a culture, in vitro. This work, published last month in the PNAS, the magazine of the Academy of Sciences of the United States, showed how to produce chimeras – animals that incorporate characteristics from other species and, in this case, turn themselves into a model for testing medicines in a live organism, supplementing the evaluations made in human cells in a culture.

“Our model can serve to evaluate the potential of therapies, taking into account the whole organism, with many variables and interferences”, he says. “Furthermore, for the first time we have a model for studying the first stages of human development, using normal cells or cells carrying mutations responsible for specific diseases of human beings, which still do not have an animal model.” Chimeric mice are now used to study some neurodegenerative diseases, such as amyotrophic lateral sclerosis.

To arrive at these results, Muotri and the team from the Salk, in collaboration with Kinichi Nakashima, from the Nara Institute of Science and Technology, in Japan, first marked the human embryonic cells that they were going to use, adding to each one of them a fluorescent green, which afterwards would allow them to be identified.  Only then did they transplant them into the brains of four mice with only 14 days of gestation, still in their mother’s uterus. The animals survived the surgery and were born healthy of a natural birth.

When in Rome, do as the Romans do
On opening the brains of the mice, months afterwards, the biologists saw that from 50 to 100 of the 100 thousand or so human cells implanted in each animal had differentiated themselves into nerve cells, neural cells, both glia (supportive cells) and neurons, which receive and conduct messages through the central nervous system. They also found that the majority of the transplanted cells migrated from the ventricle, the cavity of the brain into which they were injected, and spread through other regions, such as the cortex, hippocampus, thalamus, cerebellum and corpus callosum.

In each space into which they were incorporated, the human cells adapted themselves to the previous cellular architecture, taking on similar size, shape and spatial orientation to those of the cells that were already there. Normally, the neurons of human beings measure 17 micrometers and are 50% larger than the equivalent ones of mice – or of the human embryonic cells that formed neurons in the brains of these animals. The growth rate of the human cells also accompanied the rate of the neurons of the rodents themselves – this detail suggests a noteworthy similarity between the biochemical signals that govern the maturing of the nerve cells in man and in the mouse, even though the two species separated from a common ancestor some 20 million years ago.

This and other experiments indicate that, at least in the brains of other species, the human embryonic cells do what is expected of them, allowing themselves to be modulated by the embryonic environment and without causing any problems, since no sign of rejection has been seen, even in the brains of the two animals that were sacrificed a year and a half after birth. Other specialists had already demonstrated that human embryonic cells had been incorporated harmoniously into the brains of chicken embryos with 1.5 to 2 days of development. They are demonstrations of the potential of human cells for forming connections – or synapses – with the neurons of other species, although it is not yet known whether they may also differentiate themselves into human neurons and contribute towards the recovery of damaged tissues, should they by applied directly in the human beings themselves.