Jayanti Tokas 1, Puneet Tokas 2, Shailini Jain 3, Hariom Yadav 3 1 Department of Biotechnology,...
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Transcript of Jayanti Tokas 1, Puneet Tokas 2, Shailini Jain 3, Hariom Yadav 3 1 Department of Biotechnology,...
Jayanti Tokas1, Puneet Tokas2, Shailini Jain3, Hariom Yadav3
1Department of Biotechnology, JMIT, Radaur, Haryana, India2KITM, Kurukshetra, Haryana, India
3NIDDK, National Institute of Health, Bethesda, MD 20892, USA
Stem Cells
Stem cells are master cells with two important characteristics Unspecialized cells capable of their own renewal Ability to differentiate into different cell types
The stem cells may have various differentiation potentials Totipotent Pluripotent Multipotent Unipotent
Stem Cells Fate
Replenish old/damaged Replenish old/damaged tissue by proliferation tissue by proliferation
and maturationand maturation
Differentiation - Differentiation - senescence and senescence and
apoptosisapoptosis
Fail to differentiate or undergo apoptosis -
Neoplasia
Stem Cell
Stem cell niche
Niche signals regulate stem cell 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
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. Tetramer, a leucine zipper like domain located at
the amino terminus2. DNA binding domain3. Src homology domain 3- like region 4. Src homology domain 2 (SH2), a critical site of
tyrosine phosphorylation5. Carboxy-terminal transactivation domain
Y58
0
P Y
N-SH2
PTPase
C-
SH2
Y542
PTPaseN-SH2 C-SH2
BP
pY pYY
+PO4
PTPa
se
S
Y
+PO4
p Y542
pY580
C-SH2N-
SH2
Activation by External phosphotyrosines
Activation through binding of SH2 domains to C-terminal phosphotyrosines of SH2
Inactive Active
Abbreviations : S, substrate BP, bisphosphorylated SH2 domain binding protein
SH 2
Two alternate pathways SHP-2 signaling
PCytokine R
JAK
Cytokine
JAK PP
PP
STAT
SH2
P
P PSTAT
SH2
P
STAT
SH2 STAT
SH2P
P
Nucleus
Cell membrane
Cytoplasm
Gene expression
STATSTAT
SH2
P
PSH2
Cytokine Receptor Signaling
(Constantinescu, 2000)
Oct 3/4
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
Embryonic Stem cells self renewal
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
IL-6 family cytokines
STAT3
Jak1/2/Tyk2
Self-renewal
- PERK1/2
-GTP
-PRaf
Ras
SHP2
Gab1
Grb2
-PMEK
Differentiation
-phosphorylation-dimerization
gp
130
Box3
Box2
Box1
P-Y126P-Y173P-Y265P-Y 275
Y118-P
STAT3-P
STAT3-P
Signaling pathways induced by IL-6 family cytokines
Essentials of Stem Cell Biology, pg no. 32
Hematopoietic stem cells (HSC) self renewal
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
Keratinocyte Stem Cells
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 :
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
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……