SB202190 is a selective, potent, cell-permeable inhibitor of p38 MAP kinases, inhibiting p38α (SAPK2A, MAPK14) and p38β (SAPK2B, MAPK11) with IC₅₀ values of 50 and 100 nM, respectively (Davies et al.; Jiang et al.). As a pyridinyl imidazole inhibitor, SB202190 directly binds p38 MAP kinases in the ATP binding pocket (Fox et al.).
MAINTENANCE AND SELF-RENEWAL
· Improves the self-renewal ability of neural stem cells from NPC1-deficient mice (Yang et al.).
· Blocks adiponectin-mediated proliferation of hematopoietic stem cells (DiMascio et al.).
· Reduces BMP3-mediated proliferation of C3H10T1/2 mesenchymal stem cells (Stewart et al.).
DIFFERENTIATION
· Induces cardiomyocyte differentiation from human embryonic stem cells (Graichen et al.).
MAINTENANCE AND SELF-RENEWAL
· Improves the self-renewal ability of neural stem cells from NPC1-deficient mice (Yang et al.).
· Blocks adiponectin-mediated proliferation of hematopoietic stem cells (DiMascio et al.).
· Reduces BMP3-mediated proliferation of C3H10T1/2 mesenchymal stem cells (Stewart et al.).
DIFFERENTIATION
· Induces cardiomyocyte differentiation from human embryonic stem cells (Graichen et al.).
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Protocols and Documentation
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Applications
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Resources and Publications
Educational Materials (3)
Publications (7)
BMP-3 promotes mesenchymal stem cell proliferation through the TGF-beta/activin signaling pathway. Journal of cellular physiology 2010 JUN
Abstract
Adipogenesis plays a key role in the pathogenesis of obesity. It begins with the commitment of mesenchymal stem cells (MSCs) to the adipocyte lineage, followed by terminal differentiation of preadipocytes to mature adipocytes. A critical, but poorly understood, component of adipogenesis involves proliferation of MSCs and preadipocytes. The present study was undertaken to examine the hypothesis that bone morphogenetic protein-3 (BMP-3) promotes adipogenesis using C3H10T1/2 MSCs and 3T3-L1 preadipocytes as in vitro model systems. We demonstrated that although it did not promote the commitment of MSCs to the adipocyte lineage or the differentiation of preadipocytes to adipocytes, BMP-3-stimulated proliferation by threefold in both cell types. Owing to a lack of information on MSC proliferation, we then delineated the molecular mechanisms underlying BMP-3-stimulated MSC proliferation. We showed that BMP-3 activated the transforming growth factor-beta (TGF-beta)/activin but not ERK1/2, p38 MAPK, or JNK signaling pathways in C3H10T1/2 cells. Furthermore, the TGF-beta/activin receptor kinase inhibitor SB-431542 blocked BMP-3-stimulated proliferation. Importantly, siRNA-mediated knockdown of the key TGF-beta/activin signaling pathway components, ActRIIB, ALK4, or Smad2, abrogated the mitogenic effects of BMP-3 on MSCs. Together, these results demonstrate that BMP-3 stimulates MSC proliferation via the TGF-beta/activin signaling pathway, thus revealing a novel role for this divergent and poorly understood member of the TGF-beta superfamily in regulating MSC proliferation.
Enhanced cardiomyogenesis of human embryonic stem cells by a small molecular inhibitor of p38 MAPK. Differentiation 2008 APR
Abstract
Human embryonic stem cells (hESC) can differentiate to cardiomyocytes in vitro but with generally poor efficiency. Here, we describe a novel method for the efficient generation of cardiomyocytes from hESC in a scalable suspension culture process. Differentiation in serum-free medium conditioned by the cell line END2 (END2-CM) readily resulted in differentiated cell populations with more than 10% cardiomyocytes without further enrichment. By screening candidate molecules, we have identified SB203580, a specific p38 MAP kinase inhibitor, as a potent promoter of hESC-cardiogenesis. SB203580 at concentrations textless10 microM, induced more than 20% of differentiated cells to become cardiomyocytes and increased total cell numbers, so that the overall cardiomyocyte yield was approximately 2.5-fold higher than controls. Gene expression indicated that early mesoderm formation was favored in the presence of SB203580. Accordingly, transient addition of the inhibitor at the onset of differentiation only was sufficient to determine the hESC fate. Patch clamp electrophysiology showed that the distribution of cardiomyocyte phenotypes in the population was unchanged by the compound. Interestingly, cardiomyogenesis was strongly inhibited at SB203580 concentrations textgreater or =15 microM. Thus, modulation of the p38MAP kinase pathway, in combination with factors released by END2 cells, plays an essential role in early lineage determination in hESC and the efficiency of cardiomyogenesis. Our findings contribute to transforming human cardiomyocyte generation from hESC into a robust and scalable process.
Identification of Adiponectin as a Novel Hemopoietic Stem Cell Growth Factor The Journal of Immunology 2007 MAR
Abstract
The hemopoietic microenvironment consists of a diverse repertoire of cells capable of providing signals that influence hemopoietic stem cell function. Although the role of osteoblasts and vascular endothelial cells has recently been characterized, the function of the most abundant cell type in the bone marrow, the adipocyte, is less defined. Given the emergence of a growing number of adipokines, it is possible that these factors may also play a role in regulating hematopoiesis. Here, we investigated the role of adiponectin, a secreted molecule derived from adipocytes, in hemopoietic stem cell (HSC) function. We show that adiponectin is expressed by components of the HSC niche and its receptors AdipoR1 and AdipoR2 are expressed by HSCs. At a functional level, adiponectin influences HSCs by increasing their proliferation, while retaining the cells in a functionally immature state as determined by in vitro and in vivo assays. We also demonstrate that adiponectin signaling is required for optimal HSC proliferation both in vitro and in long term hemopoietic reconstitution in vivo. Finally we show that adiponectin stimulation activates p38 MAPK, and that inhibition of this pathway abrogates adiponectin's proliferative effect on HSCs. These studies collectively identify adiponectin as a novel regulator of HSC function and suggest that it acts through a p38 dependent pathway.
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