Stem Cells and Cell Signaling
Cheng-En Lai
BIOE 506: Molecular and Cellular
Bioengineering
4/25/2011
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
Background: Stem Cells
• Self Renewal
• Pluripotency
• Source for tissue engineering
and cell replacement
therapies
• Similar to cancer cells; stem
cells thought to be derived
Adapted from System
Biosciences (systembio.com)
from cancer stem cells
• Understanding stem cells is important for
understanding cancer
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
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
SMAD Signaling Pathway
OCT3
OCT4
Nanog
Adapted from Blank
et al. (2008)
Stem Cell Differentiation Overview
Adapted from Watabe et al. (2009)
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
TGF-β in Neural Stem Cells
• BMP inhibits
neural
differentiation
• TGF-β promotes
differentiation in
committed
progenitors
• Inactivation of
TGF-β growthinhibitory
functions result in
tumor
progression Adapted from Mishra et
al. (2005).
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
WNT Signaling Pathway
Adapted from Katoh et al.
(2007).
WNT Signaling Pathway
• Cell fate determination
• Transformation of cancer stem cells due to
disregulation
Notch Signaling Pathway
Adapted from Bray et al.
(2009).
Notch Signaling Pathway
• Promotion of neural cell differentiation
• Involved in self-renewal of hematopoietic
stem cells
Hedgehog Signaling Pathway
Adapted from Altaba et
al. (2002).
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
FGF Signaling Pathway
Adapted from Katoh et al.
(2006)
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
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.
TGF-β1 /WNT Pathway Cross-talk
WNT/FGF/Notch/SMAD/Hedgehog
Cross-talk
• Balance of all signaling pathways is important
for homeostasis and prevention of cancer and
congenital diseases
Hedgehog pathway
SMAD pathway
Notch
family
receptor
Notch
family
receptor
Hedgehog pathway
induced
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
References
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•
•
•
•
•
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).