19 March

PI3K-pathway controls survival of blood stem cells

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Researchers from the group of Jeroen den Hertog discovered that the PI3K pathway controls the survival of blood stem cells in zebrafish embryos. Overactivity of this pathway leads to the death of a part of the blood stem cells, while inhibition of the pathway prevents this effect. Furthermore, based on their experiments, the researchers suspect that early in the development of zebrafish embryos there are subtle differences in the degree to which the blood stem cells possess stem cell-like properties. These differences seem to arise under the influence of PI3K. The PTEN-gene influences the activity of the PI3K pathway; many cancer patients have mutations in the PTEN-gene. The results were published in Oncogene on the 15th of March.

The PTEN-gene is a so-called tumor suppressor gene. It prevents unrestricted cell division, a process that underlies cancer. PTEN controls various signaling pathways that stimulate cell division, including the Phosphatidylinositol-3 kinase (PI3K) pathway. When mutations in PTEN occur, the PI3K pathway goes in overdrive, thereby increasing cell division. Many cancer patients have mutations in the PTEN-gene.

Exploding cells

In this new study, published in Oncogene, the researchers from Den Hertog’s group investigated the effect of (mutations in) pten on the survival of blood stem cells in zebrafish embryos. They noticed that, in the zebrafish with mutations in pten, part of the blood stem cells exploded. This happened during the process of the formation of blood stem cells from the aorta; a phase in the forming of blood, also called hematopoiesis. The death of the stem cells was prevented when the researchers inhibited the activity of the PI3K pathway in the zebrafish mutants. “To our surprise, however, inhibition of the PI3K pathway in zebrafish without mutations also killed a part of the stem cells,” says Sasja Blokzijl-Franke, first author on the paper.

 

Video 1. Some blood stem cells in zebrafish embryos with mutations in the pten-gene explode during their formation. The video shows part of the aorta of a mutant zebrafish embryo of 35-48 hours old. The blood vessel cells make GFP and are fluorescent. The cell on the left in the video is a blood stem cell that separates from the aorta, divides and moves around a bit. The cell on the right also detaches from the aorta and then explodes. Such exploding blood stem cells are almost never observed in wildtype embryos. The movement of the cells has been tracked and the gradient is shown in color. Credit: Suma Choorapoikayil Copyright: Hubrecht Institute.

Surviving blood stem cells

Based on these results, the researchers conclude that the degree of activity of the PI3K pathway controls whether the blood stem cells survive. Over- as well as underactivity of this pathway leads to the death of part of the stem cells. “Over time, we then see that reduced PI3K activity eventually leads to more blood stem cells, while increased activity has the opposite effect,” says Blokzijl-Franke. “It also seems that subtle differences between blood stem cells exist early in the development of the zebrafish embryos. Some cells have slightly more stem cell-like properties than others.”

Stem cell therapies

In summary, the PI3K pathway is responsible for the tight regulation of blood stem cell survival. The pathway also influences the extent to which blood stem cells have specific stem cell-like properties. The results provide insight into the molecular processes that underlie cancer and contribute to the development of stem cell therapies in the long term.

Publication

Blokzijl-Franke, S., Ponsioen, B., Schulte-Merker, S., Philippe Herbomel, Karima Kissa, Suma Choorapoikayil & Jeroen den Hertog.  Phosphatidylinositol-3 kinase signaling controls survival and stemness of hematopoietic stem and progenitor cells. Oncogene (2021).

 

 

Jeroen den Hertog is group leader at the Hubrecht Institute and professor of Molecular Developmental Zoology at Leiden University.