
AsianScientist (Jul. 30, 2012) – Researchers at the Stowers Institute for Medical Research have identified an important molecular cue that stops quiescent mouse hematopoietic (or blood-forming) from proliferating when their services are not needed.
In the latest issue of the journal Cell, the team led by Dr. Linheng Li, in collaboration with Fumio Arai and Toshio Suda in the Department of Cell Differentiation at Keio University, Japan, reports that Flamingo and Frizzled 8, a tag team best known for its role in establishing cell polarity, are crucial for maintaining a quiescent reserve pool of hematopoietic stem cells in mouse bone marrow.
The current working model, which grew out of earlier work by Li and others, postulates that HSCs sit quietly and only divide a few times a year in response to wear and tear, injury or disease.
But how quiescent and active hematopoietic stem cell subpopulations are maintained and regulated in vivo is largely unknown.
What is known is that both populations of cells reside in adjacent specialized microenvironments; Frequently cycling HSCs constitute around 90 percent of all HSCs and are found in the central bone marrow, where they engage in a constant molecular dialog with pre-osteoblasts, the precursors of bone-forming osteoblasts.
Trying to decode the nature of this interaction, lead author Ryohichi Sugimura focused on Flamingo (Fmi), a surface-based adhesion molecule, and Frizzled 8 (Fz8), a membrane-based receptor, both of which are part of the non-canonical arm of the Wnt signaling pathway.
After in vitro experiments had revealed that Fmi and Fz8 accumulate at the interface between co-cultured quiescent hematopoietic stem cells and pre-osteoblasts, Sugimura and his colleagues were able to show that Fmi also regulates Fz8 distribution in vivo.
Within quiescent HSC microenvironments, Sugimura showed that the expression levels of canonical Wnt ligands where low; on the other hand, expression levels of non-canonical Wnt ligands and inhibitors of the canonical arm of the Wnt signaling network were high.
Mice that had been genetically engineered to lack either Fmi or Fz8 provided the crucial clue: Not only had the number of quiescent hematopoietic stem cells plummeted in these mice, their hematopoietic stem cell function was reduced by more than 70 percent as well.
“These observations indicated that the osteoblast niche provides a microenvironment in which non-canonical Wnt signaling prevails over canonical Wnt-signaling under normal conditions,” says Sugimura. “It also suggested that Fmi and Fz8 might play a direct role in maintaining the pool of quiescent hematopoietic stem cells.”
Treatment with the cell-cycle specific cytotoxic drug 5-flourouracil, which wipes out actively dividing hematopoietic stem cells, confirmed the role of non-canonical Wnt-family members Fmi and Fz8. Under stress, canonical Wnt-signaling dominated, enabling quiescent HSCs to proliferate and replenish the diminished supply of actively cycling HSCs.
But Li says the team must thread carefully where Wnt signaling is concerned, as he cautioned that if the balance shifts to far in favor of canonical Wnt-signaling, it may instead increase the risk of leukemia.
The article can be found at: Sugimura R et al. (2012) Noncanonical Wnt Signaling Maintains Hematopoietic Stem Cells in the Niche.
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Source: Stowers Institute for Medical Research;
Photo: Ryohichi Sugimura/Stowers Institute for Medical Research
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