Getting Old Neural Stem Cells to Make Young Neurons Again

When the neural stem cells in our brains get older, they create far fewer neurons.  This plays a role in neurodegenerative diseases from Alzheimer’s to Parkinson’s.

It also plays a role in our increasingly deficient ability to simply find those car keys.

New research is changing that paradigm. Among others, a team from Japan’s Keio University, and the Riken national research institute, reports this month in Proceedings of the National Academies of  Science they used embryonic mice to find a micro-RNA (ribonucleic acid) molecule that controls neuron making at that young age. When they applied knowledge they gain from that embryonic stage to older neural stem cells (NSCs) that had stopped making neurons, those cells produced neurons again. The mechanism is believed to exist in humans as well.

Senior Author Hideyuki Okano tells Bioscience Technology: “We observed the neurogenic-to-gliogenic switching in developing NSCs.”  That is, Okano and his team examined embryonic NSCs for the proportion of neurons they produced—versus supporting glial cells. They found, as other have, that the developing embryo creates neurons first, then switches over to making glial cells. The team isolated the microRNA-17/106-p38 axis responsible for that initial switch in embryonic development.

When they turned on and off this embryonic pathway in older, post-natal NSCs in the Petri dish, they persuaded older post-natal NSCs to switch from glial cell-producing to neuron-producing.

Stem cells across the board are still difficult to control. And getting large supplies of neurons out of cell cultures various groups are calling “neural stem cells” is very difficult.

But “there is general agreement that neurogenesis largely precedes gliogenesis during CNS development in vertebrates,” Okano explains. And adult NSCs, he says, clearly can produce neurons in the body, “whereas they exhibit strong gliogenic characteristics under culture conditions in vitro.” Adult NSCs in two regions of the brain—the SVZ and hippocampus—also “make neurons, even though transplant studies have shown us that the adult CNS is a gliogenic environment.”

So there is a lot of evidence that old NSCs can make neurons. But it is hard to pin the exact age that NSCs begin making substantially more glial cells than neurons, he says. “It is difficult to clearly explain the association between total glial cell number and changes in NSC abilities. Moreover, there is less evidence about gliogenic ability of aged NSCs because most of studies about NSCs have mainly focused on the neurogenic ability. “

Still, Okano says: “There are some reports about decline of neurogenesis ability of NSCs with age. These reports indicate that reduction in paracrine Wnt3 factors, and increase of (chemokine) CCL11 concentration in blood, impaired adult neurogenesis in the hippocampus, for example.”

Could the group’s microRNA approach improve memory in humans? Okano believes so, but says more work needs to be done.

“We observed the neurogenic effect by overexpression of miR-17 in primary cultured neurospheres” – spheres of a variety of cells, including NSCs—“derived from the SVZ at postnatal day 30. Similar phenomenon by overexpression of miR-106b-25 cluster has been reported by another group.”

But, he says, his approach has only been tried in the Petri dish. “There is no evidence using knock-out mice. Therefore, the functions of them in adult neurogenesis and learning/memory functions are still unclear.”

The next step for the group?  They will study the influence of his microRNA in NSCs in the adult body. They are hoping to develop “a useful method for precise manipulation of cytogenesis from NSCs. “

However, he says, “we think that further understanding of basic molecular mechanisms underlying the neural development is also an important issue.” He will study the ways in which his microRNA system interacts with other gliogenic genes. He wants to fully understand the mechanisms underlying “the end of neurogenic competence and acquisition of gliogenic competence.”

Finally, the group will “examine the significance of miR-17/p38 pathway in various somatic stem cells other than NSCs,” he says.