Rat cells help restore the sense of smell
Brain ‘Oroids’ in mice shed light on cancer and other diseases: Mice and rats with mutated calcium channel can recreate the cancer of the gut
The Swiss Federal Institute of Technology in Lausanne and their colleagues used mouse stem cells to model a part of the body that isn’t usually studied: the gut. The researchers had grown cells on a scaffold, so they could replicate the tube structures seen in real gut tissue.
Paca says that there aren not good animal models for Timothy syndrome because the underlying Mutation doesn’t always cause the same symptoms in rodents. “It became very clear to us we’d need to find a way of testing in vivo,” he says.
The researchers turned to brain organoids to recreate the disorder. Stem cells from three people with the same case of Timothy syndrome were cultured for 250 days and treated with signalling molecule that encouraged the cells to turn into brain organoids. The team injected structures into rats brains that formed connections with their own cells, to create a more realistic environment for organoids. This made a system in which the researchers could test potential treatments for the disorder.
Humans have different forms of the calcium channel, and only one is deficient in Timothy syndrome. Getting rid of the mutated channel, the researchers suggest, would allow the other, healthy channels to take over.
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It is his hope that the therapy will eventually be tested in clinical trials, but he will need to prove the therapy is safe before doing so. The researchers think that the treatment would be effective for about three months, so people would need to receive frequent injections. The advantage, Pașca says, is that the biological effects of the treatment would be reversible and any side effects would be short-lived.
The cells were engineered to have light-sensitive genes and be a model for colon cancer. This allowed them to use a blue laser to switch on the genes and trigger the growth of tumours at specific sites in the organoid, then watch how the tumours changed over the course of weeks.
When the researchers injected the cancerous cells into mice, the tumours looked similar to those seen in human colorectal cancer. The organoids accumulated fewer tumours when the researchers restricted calories in their medium, which also happens in people with colorectal cancer.
It would be difficult to establish this according to a stem cell scientist at the university. The lab tried to make mice smarter by giving them rat brain cells but they realized that the differences between rodents with and without the cells were too insignificant to be assessed statistically. Nakauchi says the new papers are very detailed and he is excited about it. This is what I was waiting for, he says.
How neurons connect with one another, and fire, makes integrating cells from two species complicated, says Kristin Baldwin, a neuroscientist at Columbia University in New York City. “Neurons are not just Legos,” she says.
In a paper published by one of the teams on 25 April in Cell1, Baldwin, molecular biologist Jun Wu, and their colleagues attempted to test this by mixing rat and mouse neuronal cells very early in the mice’s development.
The genes were engineered in a group of mice so that they would not produce the same amount of olfactory cells. This disrupted the circuits linking olfactory neurons in the nose with higher brain regions, leaving the mice unable to use their sense of smell to find mini-cookies that the researchers had buried in various places throughout the animals’ cages.
In a Cell paper published by the second team, also on 25 April2, Wu and his colleagues developed a more aggressive strategy for getting rat cells into a mouse’s brain. Using C-CRISPR, a genetic-editing tool that cuts genes in multiple places to ensure that they are fully inactivated, the researchers wiped out every trace of a gene called Hesx1 in a group of mouse blastocysts. The forebrain is a large region in the brain that coordinates much of an animal’s behavior.
“There’s lots of fascinating biology to be learnt from this [rat–mouse] chimaera,” says Jian Feng, a physiologist at the University of Buffalo in New York. He’s not surprised that the rat cells followed the pace of the mouse’s developmental ‘clock’. The mouse embryo paper was published in 2020 and contained up to 4% human cells. Human cells can follow their host’s directions, if the embryo began developing red blood cells 17 days into its life.
A mismatch in the development rates of the species is a concern. However, the teams found that the mouse brains developed at the same rate as they would normally, rather than at the slower pace at which a rat usually develops.
