The Journal of Experimental Medicine
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Published online March 12, 2007
doi:10.1084/jem.20060465
The Journal of Experimental Medicine, Vol. 204, No. 3, 467-474
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Karlsson et al.
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BRIEF DEFINITIVE REPORT

 Smad4 is critical for self-renewal of hematopoietic stem cells

Göran Karlsson1, Ulrika Blank1, Jennifer L. Moody1, Mats Ehinger2, Sofie Singbrant1, Chu-Xia Deng3, and Stefan Karlsson1

1 Department of Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital and Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, 22184 Lund, Sweden
2 Department of Pathology, Helsingborgs Lasarett, 251 87 Helsingborg, Sweden
3 National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892

CORRESPONDENCE Stefan Karlsson: Stefan.Karlsson{at}med.lu.se

Members of the transforming growth factor ß (TGF-ß) superfamily 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-ß superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4–/– primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal.


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