PhD defence M. Masterlaro de Rezende

Non canonical Wnt ligands and cytokine-driven myelopoiesis

The studies of Marina Mastelaro de Rezende identify mechanisms by which Wnt5 regulates hematopoietic ageing and suggests that blocking this pathway reverses some of the ageing-associated changes in myeloid cell production.

Hematopoiesis is the process of blood cell production starting from undifferentiated pluripotent stem cells and finishing with diverse highly specialized cells, such as red (erythrocytes) and white (leukocytes) cells. There are various subtypes of leukocytes and they are accountable for immune, inflammatory and infection responses. For instance, granulocytes recognize and fight invading pathogens. So do monocytes, in addition to producing molecules to initiate inflammatory responses. These cells are produced by a process called myelopoiesis, which must be tightly regulated to fulfil physiological needs throughout life. This process is chiefly dependent upon a class of molecules named cytokines.For granulocyte and monocyte production, the cytokines IL-3 and GM-CSF are the most important. Our study indicates that a molecule called Wnt5b, which is increased in expression with ageing, can skew myeloid cell differentiation. Wnt5b was previously not linked to myelopoiesis. IL-3, in the presence of Wnt5b, induced stem-cell maintenance, whilst GM-CSF unleashed a differentiation program in the presence of Wnt5b. We also investigated whether the differentiation in the presence of GM-CSF and Wnt5b was altered with aging. We provide evidence for a role for Wnt5b in regulating myeloid progenitor senescence and this was reversed by blocking Wnt5 signaling with the antagonist Box5. Blocking Wnt5 might have therapeutic use, although its risks will have to be investigated in future studies. Collectively.

Promotores: Prof.dr. R. Gosens and Prof.dr. E.J. Parendes Gamero