stem cells and cell signaling cheng-en lai bioe 506: molecular and cellular bioengineering 4/25/2011
TRANSCRIPT
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Stem Cells and Cell Signaling
Cheng-En LaiBIOE 506: Molecular and Cellular
Bioengineering4/25/2011
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Overview• Background
– Stem Cells– Signaling Pathways
• Transforming Growth Factor-β (TGF-β)– SMAD Signaling Pathway– Stem Cell Differentiation Overview– Signaling Examples– TGF-β in various cell types
• Other Signaling Pathways– WNT– Notch– Hedgehog– Fibroblast Growth Factor (FGF)
• Cross-talk– SMAD/WNT– WNT/FGF/Notch/SMAD/Hedgehog
• Conclusions
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• Self Renewal• Pluripotency• Source for tissue engineering
and cell replacement therapies
• Similar to cancer cells; stem cells thought to be derived from cancer stem cells
• Understanding stem cells is important for understanding cancer
Adapted from System Biosciences (systembio.com)
Background: Stem Cells
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Background: Signaling Pathways
• Abnormalities in pathways may give rise to cancer stem cells and tumors
• Understanding the signaling pathways and identifying important factors helps to understand cancer transformation as well stem cell differentiation for tissue engineering and regenerative medicine applications
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Transforming Growth Factor β
• TGF-β proteins and TGF-β related bone morphogenetic proteins (BMPs) are important regulators of stem cell differentiation, maintenance, and self-renewal, as well as carcinogenesis suppression.
• Comprised of 30 related proteins in the SMAD pathway
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SMAD Signaling Pathway
OCT3OCT4Nanog
Adapted from Blank et al. (2008)
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Stem Cell Differentiation Overview
Adapted from Watabe et al. (2009)
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SMAD Signaling Examples
• Nodal and activin cooperate with the WNT pathway to maintain ES cells and keep them undifferentiated and pluripotent.
• Activin and TGF-β confers mesodermal differentiation depending on amount.
• BMP signaling results in mesodermal and ectodermal differentiation in human ES cells.
• Nodal signals are important for OCT3/4 expression and maintenance of ES cells.
• Activin is important for maintenance of pluripotency, which is possibly done through induction of Nanog and OCT-4
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TGF-β in Neural Stem Cells
• BMP inhibits neural differentiation
• TGF-β promotes differentiation in committed progenitors
• Inactivation of TGF-β growth-inhibitory functions result in tumor progression
Adapted from Mishra et al. (2005).
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TGF-β in other Cell Types
• Hematopoietic Stem cells– Inhibits early progenitors, while enhances differentiation of
committed stem cells• Mesenchymal Stem Cells– Inhibits differentiation and maturation into myoblasts,
osteoblasts, and adipocytes, while stimulating MSC proliferation
– Basis for efficient wound repair in mesenchymal tissue• Gastrointestinal Epithelial Stem Cells– Inactivation with one TGF-β component (Receptor, SMAD
protein) is present in all gastrointestinal cancer
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WNT Signaling Pathway
Adapted from Katoh et al. (2007).
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WNT Signaling Pathway
• Cell fate determination• Transformation of cancer stem cells due to
disregulation
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Notch Signaling Pathway
Adapted from Bray et al. (2009).
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Notch Signaling Pathway
• Promotion of neural cell differentiation• Involved in self-renewal of hematopoietic
stem cells
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Hedgehog Signaling Pathway
Adapted from Altaba et al. (2002).
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Hedgehog Signaling Pathway
• Induces differentiation of hematopoietic progenitors and neural stem cells
• Skin, muscle, and brain cancers develop when pathway is maintained improperly in stem cells
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FGF Signaling Pathway
Adapted from Katoh et al. (2006)
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FGF Signaling Pathway
• EMT• Cell survival• Proliferation/differentiation• Cross-talk is seen between WNT and FGF via
down-regulation of GSK3β, resulting in tumors with more malignant phenotypes of mammary carcinogenesis
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TGF-β1 /WNT Pathway Cross-talk
• SMAD and TCF/LEF associate to cooperatively regulate genes
• Series of experiment by Jian et. al. (2006) show that TGF-β1 addition results in rapid nuclear accumulation of β-catenin in MSCs in a new form of cross-talk.
• β-catenin nuclear accumulation is not due to phosphorylation as from canonical WNT pathway
• Mediated by SMAD3/GSK3β disruption through TGF-β mediated phosphorylation.
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TGF-β1 /WNT Pathway Cross-talk
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WNT/FGF/Notch/SMAD/Hedgehog Cross-talk
• Balance of all signaling pathways is important for homeostasis and prevention of cancer and congenital diseases
Notch family receptor
Hedgehog pathway induced
SMAD pathway
Notch family receptor
Hedgehog pathway
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Conclusions
• Many signaling pathways with cross talk involved in stem cell proliferation, maintenance, and differentiation
• Dependent on differentiation stage, type of cell, local environment, and the identity and amount of particular ligand
• Identification of key regulators has potential for generation of iPS cells and cell replacement therapies
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References• Mishra L, Derynck R, & Mishra B. Transforming growth factor-beta signaling in stem cells and
cancer. Science 310, 68-71 (2005).• Blank U, Karlsson G, & Karlsson S. Signaling pathways governing stem-cell fate. Blood. 111(2),
492-503 (2008)• Jian H, et al. Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-
induced proliferation of bone marrow-derived adult human mesenchymal stem cells. Genes Dev 20, 666-674 (2006).
• Katoh M & Katoh M. WNT Signaling Pathway and Stem Cell Signaling Network. Clin. Cancer Res. 13, 4042 (2007).
• Watabe T & Miyazono K. Roles of TGF-beta family signaling in stem cell renewal and differentiation. Cell Research 19, 103-115 (2009).
• Bray S. Notch Signaling: a simple pathway becomes complex. Nature Rev. Mol. Cell Bio. 7, 678-689 (2006).
• Altaba AR, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nature Rev. Cancer, 2, 361-372 (2002).
• Katoh M & Katoh M. Cross-talk of WNT and FGF signaling pathways at GSK3-beta to regulate beta-catenin and SNAIL signaling cascades
• Katoh M. Networking of WNT, FGF, Notch, BMP, hedgehog signaling apthways during carcinogenesis. Stem Cell Reviews. 3(1), 30-38 (2007).