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21.03.19 Neural stem cell activation speed depends on position in brain

last modified Mar 21, 2019 03:48 PM
Otsuki and Brand show that in the Drosophila brain, the speed at which stem cells can be activated to start diving depends on their dorsal-ventral location, an important consideration in designing regeneration therapies

Dorsal-ventral differences in neural stem cell quiescence are induced by p57KIP2/Dacapo

Leo Otsuki and Andrea H Brand (2019) Developmental Cell (22 April) 49: 1–8. DOI: 10.1016/j.devcel.2019.02.015.



Image: Spatial differences in stem cell quiescence. Stem cells (green) in the late Drosophila embryo. Red: dorsal stem cells, which undergo G0 quiescence. Blue: ventral stem cells, which undergo G2 quiescence.


Media release, 21 March 2019

A need for speed: stem cell activation for regenerative therapy

One strategy for treating brain injury or neurodegenerative disease is to activate stem cells residing in patient brains, inducing them to replace lost or damaged cells. However, the extent to which individual stem cells are responsive or refractory to activation has not been clear. Otsuki and Brand (The Gurdon Institute, University of Cambridge) reveal that stem cells activate rapidly or slowly depending on where they reside in the brain, an important consideration when designing regenerative therapies. The study is published today in the journal Developmental Cell

Many organs harbour cells with regenerative potential, known as stem cells. Stem cells divide rapidly in the embryo to generate specialised cells that carry out the functions of each organ – for example, electrically excitable neurons in the brain. However, most stem cells cease activity in the late embryo and become quiescent before birth. The ability to re-awaken quiescent stem cells in adult organs might have significant implications for tissue repair, as activated stem cells could divide and replenish any cells lost to injury or disease. 

Before they can awaken and generate new cells, quiescent stem cells must transit through a series of preparatory steps known as the cell cycle. It has been thought for a long time that quiescent stem cells are arrested in G0, the earliest and most refractory step in the cell cycle. However, Otsuki and Brand discovered last year that there exists a second type of quiescent stem cell residing in G2, one of the last steps in the cell cycle, with high preparedness to divide. Excitingly, G2 quiescent stem cells activate and produce new cells faster than G0 quiescent stem cells. This property makes G2 stem cells ideal targets for regenerative therapies, as a rapid response is essential in treating injury or disease. 

The high regenerative potential of G2 stem cells makes it important to understand how stem cells become allocated to G2 or G0 quiescence, and whether it is possible to alter this balance. Now, Otsuki and Brand address some of these questions using the genetic model Drosophila. They show that G2 and G0 stem cells are distributed unequally across the brain. More G0 stem cells reside in dorsal regions of the brain, while more G2 stem cells reside in ventral regions. The authors demonstrate that the gene msh, a dorsal patterning factor, helps to put dorsal stem cells into G0 quiescence in the late embryo. Ventral stem cells, which do not express msh, instead enter G2 quiescence. Normally, ventral (G2) stem cells activate and generate new neurons faster than dorsal (G0) stem cells. Remarkably, the authors were able to accelerate the activation of dorsal stem cells by manipulating them to undergo G2 quiescence.

These findings highlight location in the brain as the genetic basis for different types of stem cell quiescence. “Together with our previous finding that the pseudokinase Tribbles regulates G2 stem cells, we have elucidated the mechanisms that allocate and regulate stem cells entering G0 or G2 quiescence”, say Otsuki and Brand. The next step will be to identify whether the same spatial mechanisms also control stem cell quiescence in the human brain.

This study was funded by the Royal Society and Wellcome Trust, and core funding to the Gurdon Institute from the Wellcome Trust and Cancer Research UK.



Read more about research in the Brand lab.

Watch Andrea Brand describe her research on neural stem cell activation on our YouTube video.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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