Regulation of hematopoietic stem cells by Smad signaling

Members of the TGF-β family of growth factors have been shown to regulate the in vitro　proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common　level of convergence for all TGF-β family signals, Smad4 is key in orchestrating these　effects. The role of Smad4 in hematopoietic stem cell function has remained elusive due　to early embryonic lethality of the conventional knockout. Here we clarify its role　utilizing an inducible model of Smad4 deletion together with transplantation experiments. Remarkably, induced Smad4-/- mice succumbed to disease, characterized by anemia and histopathological changes in the colonic mucosa, already four weeks following induction. Importantly, upon bone marrow transplantation Smad4 deficiency resulted in impaired repopulative capacity accompanied with decreased self-renewal of HSCs. Gene expression analysis further revealed a decrease in notch1 and c-myc expression providing mechanistic insight to the self-renewal defect. Notably, lineage distribution and cell viability was intact in Smad4-/- BM. Taken together, our data demonstrate an important role for Smad4 in HSC fate decisions.
These findings have implications for the development of stem　cell expansion and advanced cell therapy in the future.