Download Role of Cytokines in Stem Cell Self

Jayanti Tokas1, Puneet Tokas2, Shailini Jain3, Hariom Yadav3
1Department
of Biotechnology, JMIT, Radaur, Haryana, India
2KITM, Kurukshetra, Haryana, India
3NIDDK, National Institute of Health, Bethesda, MD 20892, USA
Stem Cells

Stem cells are master cells with two important
characteristics
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Unspecialized cells capable of their own renewal
Ability to differentiate into different cell types
The stem cells may have various differentiation
potentials


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
Totipotent
Pluripotent
Multipotent
Unipotent
Stem Cells Fate
Stem Cell
Fail to differentiate or
undergo apoptosis Neoplasia
Replenish old/damaged
tissue by proliferation and
maturation
Differentiation senescence and apoptosis
Stem cell niche
Niche signals regulate stem cell

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Self-renewal
Survival
Maintenance
Niche cells adhere to stem cells by cell-cell
adhesion
Stem/niche organization provides cues to
organize spindles and self-renewal signals
Niches
exist
in
many
adult
tissues:
hematopoietic system, neural tissues, skin, gut
epithelium, etc
Cytokines

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Prime molecules modulating cellular
growth
and
differentiation
of
embryonic, hematopoietic and other
stem cell types
Act in low concentrations (10-4 -10-5 M)
Complex molecules
Two important characteristics
Redundancy
 Pleiotropism

STAT signaling



Principal mediator of the biological responses to
ligands that activate gp130
Post-translationally regulated by tyrosine and
serine phosphorylation
Structure:
1.
2.
3.
4.
5.
Tetramer, a leucine zipper like domain located at the
amino terminus
DNA binding domain
Src homology domain 3- like region
Src homology domain 2 (SH2), a critical site of
tyrosine phosphorylation
Carboxy-terminal transactivation domain
Two alternate pathways SHP-2 signaling
Active
Inactive
+PO4
BP
Activation by External
phosphotyrosines
P Y
NSH2
PTPase
SH 2
Activation through binding of SH2
domains to C-terminal
phosphotyrosines of SH2
Abbreviations :
S, substrate
BP, bisphosphorylated SH2 domain binding
protein
pY
N-SH2
NSH2
p
Y542
pY
C-SH2
Y
PTPase
C-SH2
pY580
+PO4
Cytokine Receptor Signaling
Cytokin
e
Cell membrane
P
Cytokine R
JAK
SH
2
Gene
expression
P
STA
T
JAK
P
P
P
P
SH
2
STA
T
Nucleus
P
SH
2
STA
T
P
P
P
Cytoplasm
STA
T
P
SH
2
(Constantinescu, 2000)
Oct 3/4

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Marker for undifferentiated cells
Master regulator of initiation, maintenance and
differentiation of pluripotent cells
Exerts effects via certain target genes like
genes encoding, the transcriptional co-factor
UTf-1, Zfp42/Rex-1, PDGF, otx-2, etc
Requires several cofactors to execute its
functions of maintaining pluripotency
Relationship between Oct-3/4 expression and
stem cell fate
Embryonic Stem cells self renewal
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LIF maintains ES cells self renewal
Signal transduction by LIF and other IL-6 family
members occurs via a common signal transducer gp130
Dimerization of the receptor associated subunit
activates receptor associated kinases like Src and the
Janus family of kinases e.g. Jak1, Jak2 and Tyk2
Homo-dimerization (IL-6/IL-6R and IL-11/IL-11R) or
hetero-dimerization (LIF/LIFR)
Embryonic stem cell renewal factor (ESRF) : a LIF
independent signaling factor
Signaling pathways induced by IL-6 family
cytokines
IL-6 family cytokines
Jak1/2/Tyk2
-phosphorylation
-dimerization
P-Y126
P-Y173
P-Y265
P-Y 275
Gab1
Box2
gp130
STAT3
Box1
SHP2
Y118-P
Ras
-GTP
-P
Raf
Grb2
Box3
MEK
-P
STAT3-P
STAT3-P
Self-renewal
ERK1/2
-P
Differentiation
Essentials of Stem Cell Biology, pg no. 32
Hematopoietic stem cells (HSC) self
renewal
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Expression of cell surface molecules
TpoR+Flk2+KIT
HOXB4
EpoR and t EpoR (tEpoR
EpoR )
SCF and IL-6 : expression of receptor CXCR4
of stromal derived factor
Self renewal blockade : IL-3 and TNF
Hematopoietic stem cells (HSC) self renewal
Keratinocyte Stem Cells
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Present in hair follicle bulge area
Cell adhesion, cell migration, and clonogenicity
Stem cells express more β1 integrin and
adhere more rapidly to collagen IV
Misu :
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Direct target gene of Myc
Up-regulated in many cancers
Depletion might result in increased self renewal
capacity
Role of Myc in regulating epidermal stem cell
fate
Adhesion and cytoskeleton
Growth promoting target genes
New Players in Stem cell self renewal and
Future directions
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Nanog – marker for pluripotent cell lines
Induced pluripotent stem cells from human fibroblasts
Maintenance of self renewal property in ES via Nanog
is independent of LIF/STAT3, and also Oct-3/4
Understanding the molecular mechanism of stem cell
renewal and commitment - unparalleled progress for
tissue replacement, transplantation and other stem cell
based therapies
Expression of genes AML1 or RUNX1 (human cord stem
cells)
Stem cell research in livestock a long way to go……