Smad4 is critical for self-renewal of hematopoietic stem cells.
Members of the transforming growth factor beta (TGF-beta) 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-beta 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.
Karlsson
Göran
G
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.
Blank
Ulrika
U
Moody
Jennifer L
JL
Ehinger
Mats
M
Singbrant
Sofie
S
Deng
Chu-Xia
CX
Karlsson
Stefan
S
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation / Q000235:genetics; D005804:Genes, Lethal; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D016130:Immunophenotyping; D007249:Inflammation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics
D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta