Neural progenitor cells exist in adult human hippocampus all the way to old age, a new transcriptome study published today Science I'll suggest it.
The results reinforce the claim that adults can form new neurons, according to the team behind the work. However, not everyone is convinced that this study shows that ancestors are truly important in adulthood.
“Look, there might be something,” says Juan Arerano, a research scientist in neuroscience at Yale University who was not involved in the research. However, cells appear to be rare because the teams were unable to identify them without the help of machine learning algorithms. “Are they really very relevant in the circuit?”
Although researchers did not quantify the number of cells in the study, neonatal neurons are highly excitatory and plastic, so even a small number can contribute functionally, says research investigator Ionats Demitre, a research expert in the lab of Jonas Frisen at Karolinska's Institute.
Adult proliferation neurons were first recorded in a 1998 study that used synthetic nucleosides to track newly synthesized DNA in neonatal cells. Subsequent work, including carbon dating, lineage tracking and tissue staining techniques, reinforced the idea that new neurons could continue to be produced after childhood.
However, other studies staining cellular markers of neurogenesis suggest that there are few neurons born in adults, and the rate of neurogenesis decreases dramatically in the first few years of life. These results raise questions about the scope and role of neurogenesis in the adult brain, Sean Sorrells, an assistant professor of neuroscience at the University of Pittsburgh, says that he has conducted some of these cell marker studies but has not been involved in the new ones.
Still, the techniques used to track cell markers identified primarily in rodents may not be sensitive enough to detect human progenitor cells, a 2023 study argued. Paul Lucassen, professor of brain plasticity at the University of Amsterdam, who was not involved in the new study, presented an unbiased way of capturing rare cell populations without relying on these markers. By combining this approach with machine learning, researchers have previously identified immature granule cells in adult brains.
The researchers behind the new study added another step: they separate the cells that have grown from the brain, making it easier to spot progenitor cells if they are present.
They profiled neural progenitor cells from six hippocampus under 5 years of age using a single nuclei RNA sequence. Machine learning algorithms trained with transcriptome signatures for these cells sequenced data from nine dentate gyrus ages 20 to 78 to identify signatures of progenitor cells predicted to be a mixture of neural stem cells, immature neural progenitor cells, and neuroblasts.
“I think we all can all agree that in the adult human brain there are cells with these characteristics,” said Evgenia Salta, group leader at the Dutch Institute of Neuroscience, who was not involved in the study.
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Hen Frisen and his team compared their data with published data sets, but found that the adult neural progenitor cells they identified had similar expression profiles to corresponding cells from other species, including rhesus monkeys, pigs and mice. Neural progenitor cells levels vary from person to person, with five additional adults not having detectable cells.
Three types of neural progenitor cells were enriched for a variety of markers. Researchers discovered using a transcriptome platform called Xenium, which allows for 300 marker staining, and helped map the spatial distribution of cells. Progenitor cells localized to the dentate gyrus did not express markers of non-neurogenic cell types, such as microglia and astrocytes.
Doublecortin, frequently used to distinguish neuroblasts and immature neurons, is widely expressed in cell types within samples and is not sufficient to identify these cells, suggesting that many markers are needed to define progenitor cells.
These techniques allow you to “find the complete molecular profile of these cells,” says Salta. “Now, for the first time, we seem to have a perfect trajectory in the adult human brain.”
And the results “we never confirm that we cannot find this one cell type-specific marker of the human neurogenic population, as we know from the brains of mice. This is very ok,” adds Salta. “Of course, it makes our lives as researchers much easier. But the human brain is a complex organ, and it's a good time to acknowledge complexity.”
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The HE expression profiles of adult progenitor cells identified in the study partially overlap with other cell types, such as astrocytes and immune cells, so Arellano says he wonders whether they are in fact neural progenitor cells. If they are progenitor cells, it remains unclear whether this reflects authentic adult neurogenesis, as this can occur during embryo development and may mature later, Salta says. “This is something we don't know for sure yet, but the cell is there.”
According to Sorrells, if neurogenesis occurs in adults, it is likely to be very rare and sparse, so it is brain-independent. And it shows that the team had to use machine learning to find the progenitor cells, and that in two of the four adolescents studied they did not detect them, or that in five of the 14 adults, the neurogenic process is variable and limited. Additionally, many brain donors suffer from severe mental illness or neurological damage, which can affect the level of split cells, says Sorrells.
However, that variability reflects actual biological variability and may be worthy of further research, Salta says. For example, one of the people with the highest levels of immature neural progenitor cells suffers from epilepsy, which is associated with abnormal neurogenesis. “Maybe there is something that we should teach about the phenomenon of neurogenesis in the adult brain,” says Salta. “It's a very sensitive process and can be really sensitive to many exogenous and endogenous factors.”
