title: Smad7 promotes self-renewal of hematopoietic stem cells.
abstract: The Smad-signaling pathway downstream of the transforming growth factor-beta superfamily of ligands is an evolutionarily conserved signaling circuitry with critical functions in a wide variety of biologic processes. To investigate the role of this pathway in the regulation of hematopoietic stem cells (HSCs), we have blocked Smad signaling by retroviral gene transfer of the inhibitory Smad7 to murine HSCs. We report here that the self-renewal capacity of HSCs is promoted in vivo upon blocking of the entire Smad pathway, as shown by both primary and secondary bone marrow (BM) transplantations. Importantly, HSCs overexpressing Smad7 have an unperturbed differentiation capacity as evidenced by normal contribution to both lymphoid and myeloid cell lineages, suggesting that the Smad pathway regulates self-renewal independently of differentiation. Moreover, phosphorylation of Smads was inhibited in response to ligand stimulation in BM cells, thus verifying impairment of the Smad-signaling cascade in Smad7-overexpressing cells. Taken together, these data reveal an important and previously unappreciated role for the Smad-signaling pathway in the regulation of self-renewal of HSCs in vivo.
authors.affiliation: Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Blank
authors.forename: Goran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moody
authors.forename: Taiju
authors.initials: T
authors.lastname: Utsugisawa
authors.forename: Mattias
authors.initials: M
authors.lastname: Magnusson
authors.forename: Sofie
authors.initials: S
authors.lastname: Singbrant
authors.forename: Jonas
authors.initials: J
authors.lastname: Larsson
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015870:Gene Expression; D008024:Ligands; D051379:Mice; D023461:Myeloid Progenitor Cells / Q000166:cytology / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051906:Smad7 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D008024:Ligands; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta