Former DMS grad. student finds that Wnt signaling pathways regulate blood formation
The Wnt signaling pathways are crucial regulation pathways in hematopoiesis (blood formation) and may be important for devising future leukemia treatments, former DMS graduate student Michael Nemeth described last Wednesday in Chilcott Auditorium.
Wnt stands for wingless-type MMTV (mouse mammary tumor virus) integration site. The Wnt family of proteins consists of highly conserved secreted signaling molecules that regulate cell-to-cell interactions during embryogenesis.
Nemeth outlined the canonical Wnt signaling pathway, in which a Wnt glycopeptide binds the transmembrane receptor Frizzled. A series of transduction steps stabilizes a transcription factor called β-catenin, which translocates to the nucleus and affects gene expression. In addition, he talked about a second, noncanonical pathway that appears to be β-catenin independent and antagonizes the canonical pathway.
Hematopoietic stem cells (HSCs) are found in adult bone marrow and give rise to all blood cell types. HSCs can either self-renew to maintain their numbers or differentiate into blood cells. In healthy mammals, about 75% of HSCs are self-renewing and the rest are differentiating; in mice, a gene called Hmgb3 regulates this balance.
Nemeth’s recent study, published in Proceedings of the National Academy of Sciences, highlights the role of Wnt5a in inhibiting the canonical signaling pathway. He irradiated mice to disable their native HSCs and transplanted engineered, cultured HSCs.
Nemeth found that the HSCs with Wnt5a have a greater chance of grafting success than the HSCs without Wnt5a. In addition, he observed that mice without a functioning Wnt5a gene die before birth because the HSCs are unable to migrate successfully from the fetal liver to the bone marrow. He concluded that Wnt5a’s antagonism with the canonical pathway causes HSCs to enter a quiescent G0 state and preferentially self-renew, increasing HSC repopulation rates and therefore grafting success rates.
The study is an important step towards understanding HSC signaling and behavior. The study also highlights possible pharmaceutical applications. For example, Wnt5a could be used to accelerate engraftment regeneration in bone marrow transplant patients. Since many types of leukemia stem cells resemble HSCs, small peptides mimicking Wnt5a could also be used to treat leukemia.