Stem Cells and Cell Signaling

Stem Cells and Cell Signaling
Cheng-En Lai
BIOE 506: Molecular and Cellular
• 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
Fibroblast Growth Factor (FGF)
• Cross-talk
– WNT/FGF/Notch/SMAD/Hedgehog
• Conclusions
Background: Stem Cells
• Self Renewal
• Pluripotency
• Source for tissue engineering
and cell replacement
• Similar to cancer cells; stem
cells thought to be derived
Adapted from System
Biosciences (
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
SMAD Signaling Pathway
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
• 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
TGF-β in Neural Stem Cells
• BMP inhibits
• TGF-β promotes
differentiation in
• Inactivation of
TGF-β growthinhibitory
functions result in
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
– 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.
WNT Signaling Pathway
• Cell fate determination
• Transformation of cancer stem cells due to
Notch Signaling Pathway
Adapted from Bray et al.
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
FGF Signaling Pathway
Adapted from Katoh et al.
FGF Signaling Pathway
Cell survival
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
• Balance of all signaling pathways is important
for homeostasis and prevention of cancer and
congenital diseases
Hedgehog pathway
SMAD pathway
Hedgehog pathway
• 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
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).

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