How Blood Stem Cells Renew And Differentiate

Scientists in Japan have revealed how the enzyme ragnase-1 is required for the normal production of blood cells in the body.

AsianScientist (Mar. 26, 2019) – A team of researchers in Japan has identified a molecule called ragnase-1 as a key regulator of the formation of blood cells in the body. Their findings are published in the journal Nature Communications.

The body needs to create a continuous supply of blood cells to enter circulation. Blood cells have a wide variety of functions, ranging from supplying oxygen to tissues, fighting infections and enabling the blood to clot upon injury. A delicate balance must be maintained in avoiding deficiency of these cells while preventing their excessive proliferation.

In the present study, scientists led by Professor Nobuyuki Takakura of Osaka University, Japan, found that an enzyme known as ragnase-1 is key to regulating the renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs), from which all blood cells are derived.

The team first used a computer-based analysis to identify those genes that differed markedly in their expression between adult and embryonic HSPCs. Among these genes, they then selected ragnase-1 for further analyses, given earlier findings of its role in the differentiation of another stem cell type. These further analyses included experiments with the deletion of one or both copies of the ragnase-1 gene in mice, followed by evaluations of stem cell differentiation into other blood cell lineages and the overall health of these mice.

“Our findings showed that the deletion of both or even just one of the copies of ragnase-1 led to abnormalities in the renewal and differentiation of HSPCs from the bone marrow,” Takakura explained. “The ragnase-1 knockout mice also showed physiological abnormalities like weight loss and an enlarged spleen—and they died at a young age.”

The researchers then investigated the mechanism by which ragnase-1 elicits its effects on HSPCs. They found that the protein exerts regulatory activity at the post-transcriptional level by degrading two target mRNAs—Gata2 and Tal1—which are involved in hematopoiesis.

“Our findings showed that this activity of ragnase-1 is key to determining whether stem cells remain in a quiescent state, self-renew to maintain a pool of such cells for future differentiation, or start to differentiate into the various blood cell lineages depending on the current needs of the body,” said lead author Assistant Professor Hiroyasu Kidoya of Osaka University.

These findings could provide a new target for therapeutic strategies aimed at treating diseases such as leukemia, said the authors.

The article can be found at: Kidoya et al. (2019) Regnase-1-mediated Post-transcriptional Regulation Is Essential for Hematopoietic Stem and Progenitor Cell Homeostasis.


Source: Osaka University; Photo: Shutterstock.
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