Reacción a "Reactions: scientists regenerate neural pathways in mice with rat cells"

In October 2022, Sergiu Pasca's lab from Stanford University, surprised the world by injecting neurons originated from human brain organoids (simplified mini-brains developed from stem cells in a culture medium) into a developing rat brain, using athymic newborn rats (and therefore unable to reject human cells). Those chimeric rat brains, with human neurons, grew normally as the animal continued to develop, and the human cells interconnected with the rat neurons to the extent of establishing functional somatosensory circuits. The authors demonstrated that excitation of the rat whiskers activated the human neurons, confirming that these cells were fully embedded and intercommunicated within the rat brain. Logically, this study raised ethical dilemmas associated with the creation of chimeras, limited originally to the brain, but in which human neurons and rat neurons were mixed. According to the authors, the potential use (and therefore the ethical justification) of this experiment was that it might offer a way to validate, functionally, the state of human neurons from both healthy people and, more importantly, from patients with neurological disorders. As, in these patients, it is usually very difficult to identify what may be wrong in their neuronal function. That paper, from less than two years ago, surely opened the door to the two papers being published today, in which two teams of scientists, working independently, demonstrate that rat stem cells can complement and restore genetically disabled brain regions in mouse embryos.  

First, Jun Wu's lab, from the University of Texas Southwestern at Dallas, reports a surprising experiment in which he inactivates a gene (Hesx1) in mouse embryos using CRISPR gene-editing technology. This gene is necessary for forebrain development and, therefore, the mice derived from these embryos would lack the frontal brain region. However, at the blastocyst stage, the researchers inject the mice with pluripotent embryonic stem cells from rats, and these eventually supplement the neuronal deficit and replenish the mouse forebrain, which is now formed from rat neurons (from the injected stem cells). The head and brain of a rat is larger than that of a mouse. However, the rat neurons grow at a mouse pace and fill the space that is expected in a mouse head, just as if they were mouse neurons. The mice, as far as the researchers can confirm, behave normally.     

The second experiment, developed by Kristin Baldwin's lab at the Scripps Institution in La Jolla and Columbia University in New York, has a similar structure. This time the researchers used two different strategies to eliminate or genetically silence (using a conditional mutation strategy with the Cre/loxP system) the mouse neurons that grow into the olfactory bulb, which is located in the most anterior part of the brain. And these mouse embryos without olfactory bulb or with an inactivated olfactory bulb (and therefore anosmic, unable to perceive any odor) are injected with pluripotent rat stem cells that end up colonizing or complementing with rat neurons the non-existent or non-functional olfactory bulb of the mouse, thus recovering the mice's olfactory capacity. This experiment demonstrates, beyond the previous one, that this complementation isn’t only structural (the rat neurons fill or complement the space or function that should be performed by the olfactory neurons of the mouse) but totally functional. Mice recover their sense of smell due to the rat’s olfactory neurons, even if the recovered sense of smell is not yet equivalent to that of the control mice.   

These are undoubtedly very remarkable advances in neuroscience that allow many other complementation experiments to be tackled. It doesn’t seem like all regions of the developing brain of one species could be complemented with neurons from another species with the same level of success. However, the fact that two laboratories working independently reached similar conclusions is noteworthy. It endorses the robustness and credibility of their findings, and confirms the utility and applicability of this novel form of neuronal complementation via different species.   

Additionally, since both teams use brain chimeras between mice and rats, the ethical issues associated with these experiments are much more limited than the ones that would arise if human cells were used instead. I applaud the decision of these two laboratories to do these complementation experiments using two rodent species, such as the rat and the mouse, which, from an evolutionary perspective, are separated by about 20 million years. The conclusions that result from this series of experiments in rodents enable the development of future applications in humans. With this research, they will already be approached with a basic understanding of the neural processes associated with these complementation experiments.