Group members: Ulrika Blank, Göran Karlsson, Ronan Quéré, Matilda Nifelt Hägerström, Emma Larsson and Stefan Karlsson
To study the role of Smad signaling for regulation of hematopoietic stem cell (HSC) fate options in murine and human hematopoietic cells. The regulation of stem cell self-renewal, differentiation and transformation to malignancy is studied in model systems that lack or over-express components of the Transforming Growth Factor-beta (TGF-beta) superfamily-signaling pathway.
The TGF-beta superfamily of ligands include TGF-betas, Activins, and BMPs (see figure). These growth factors play key roles both during embryogenesis and through adulthood, and have proven to be involved in the regulation of fate decisions of hematopoietic progenitors and stem cells. TGF-beta and related factors bind and signal through membrane serine/threonine kinase receptors, which upon activation phosphorylate intracellular Smad proteins that subsequently form a complex with the common Smad4, and move into the nucleus where target gene transcription is modified. Generally, Smad2 and Smad3 mediate intracellular signaling from TGF-beta and Activin ligands, while Smad1, Smad5 and Smad8 are involved in the BMP signaling pathways. Conversely, there are inhibitory Smads, Smad6 and Smad7, that negatively regulate the response to TGF-beta superfamily ligands.
We are asking how each component in this complex network of signaling pathways specifically influence HSC self-renewal, differentiation and malignant transformation.
The canonical Smad-signailing pathway showing signals through the TGF-beta, activin and BMP-receptors. Smad7 in an inhibitory Smad. Smad8 is not expressed in hematopoietic stem cells. The curved lines indicate the cell membrane and the nuclear membrane.
TGF-beta is the strongest known negative regulator for proliferation of primitive hematopoietic cells in vitro. However, we have demonstrated a lack of HSC phenotype in vivo in TGF-beta receptor deficient mice. Instead lack of TGF-beta signaling resulted in disrupted T-cell homeostasis and a multifocal inflammatory disease. We have recently clarified the role of BMP signaling in hematopoiesis in vivo, demonstrating a limited role for signaling through Smad1 and Smad5 in the regulation of HSC in the fetal liver and postnatally. Additionally, we have demonstrated that different ways of completely disrupting the Smad signaling pathway result in divergent effects on HSC self-renewal without causing the expected inflammatory disease. Enforced expression of the inhibitory Smad7 caused an in vivo expansion of HSCs, while Smad4 deletion on the contrary resulted in impaired HSC self-renewal. Not only do these studies demonstrate critical roles for the TGF-beta superfamily and Smads in the regulation of HSCs in vivo, but also that the level of disruption of Smad signaling is of importance. Currently, we are focusing on the role of canonical Smad signaling in preventing transformation of normal HSC to a malignant fate. We have also started to explore whether non-canonical signals mediated through the TGF- family of receptors regulate HSC and how Smad pathways interact with other signaling pathways to regulate hematopoiesis. Integrative signaling between Smad pathways and other pathways is also being investigated.
Larsson J, Goumans M-J, Jansson-Sjöstrand L, van Rooijen M, Ward D, Levéen P, Xu X, ten Dijke P, Mummery CL, Karlsson S. (2001). Abnormal vascular development, but intact hematopoietic potential in transforming growth factor- receptor I deficient mice. EMBO J 20:1663-1673.
Larsson J, Blank U, Helgadottir H, Björnsson JM, Ehinger M, Goumans M-J, Fan X, Levéen P, Karlsson S. (2003). TGF-?-signaling-deficient hematopoietic stem cells have normal self-renewal and regenerative ability in vivo despite increased proliferative capacity in vitro. Blood 102: 3129 – 3135.
Levéen P, Larsson J, Ehinger M, Cilio CM, Sundler M, Jansson Sjöstrand M, Holmdahl R, Karlsson S. (2002). Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100: 560 - 568.
Larsson J, Karlsson S. (2005). The role of Smad signaling in hematopoiesis. Oncogene 24(37):5676-92)
Singbrant S, Moody J, Blank U, Karlsson G, Zwijsen A, Karlsson S (2006). Smad5 is dispenable for adult murine hematopoiesis. Blood 108: 3700-3706.
Blank U, Karlsson G, Moody J, Utsugisawa T, Magnusson M, Singbrant S, Larsson J, Karlsson S (2006). Smad7 promotes self-renewal of hematopoietic stem cells in vivo. Blood 108: 4246-4254.
Karlsson G, Blank U, Moody JL, Ehinger M, Singbrant S, Deng C-X, Karlsson S (2007). Smad4 is critical for self-renewal of hematopoietic stem cells. Journal of Experimental Medicine 204:467-474.
Blank U, Karlsson G, Karlsson S (2008). Signaling pathways governing stem cell fate. Blood 111: 492-503.
Singbrant Söderberg S, Karlsson G, Karlsson S (2009). Complex and context dependent regulation of hematopoiesis by TGF- superfamily signaling. Annals of the New York Academy of Sciences 1176: 55-69.
Singbrant Söderberg S, Karlsson G, Ehinger M, Jaako P, Stadtfeld M, Graf T, Karlsson S (2010). Canonical BMP signaling is dispensable for hematopoietic stem cell function in both adult and fetal liver hematopoiesis, but essential to preserve colon architecture. Blood 115: 4689-4698.
• Prof. Hiromitsu Nakauchi, Tokyo , Japan (HSC molecular biology)
• Prof. Tariq Enver, University College London
• Prof. Leif Oxburgh, Maine Medical Center, Portland, Maine
Page Manager: Jens Forsberg
Last modified: 2010-07-30
