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Role of Cytokines in Stem Cell Self-Renewal

Role of Cytokines in Stem Cell Self-Renewal. Jayanti Tokas 1 , Puneet Tokas 2 , Shailini Jain 3 , Hariom Yadav 3 1 Department of Biotechnology, JMIT, Radaur, Haryana, India 2 KITM, Kurukshetra, Haryana, India 3 NIDDK, National Institute of Health, Bethesda, MD 20892, USA. Stem Cells.

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Role of Cytokines in Stem Cell Self-Renewal

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  1. Role of Cytokines in Stem Cell Self-Renewal 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

  2. 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

  3. Stem Cells Fate Stem Cell Fail to differentiate or undergo apoptosis - Neoplasia Replenish old/damaged tissue by proliferation and maturation Differentiation - senescence and apoptosis

  4. 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

  5. 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

  6. STAT signaling • Principal mediator of the biological responses to ligands that activate gp130 • Post-translationally regulated by tyrosine and serine phosphorylation • Structure: • 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

  7. Two alternate pathways SHP-2 signaling Active Inactive S +PO4 BP pY pY Y PTPase N-SH2 C-SH2 Activation by External phosphotyrosines S C-SH2 N-SH2 Y542 Y580 PTPase Y C-SH2 N-SH2 P Activation through binding of SH2 domains to C-terminal phosphotyrosines of SH2 SH 2 pY580 p Y542 PTPase Y +PO4 Abbreviations : S, substrate BP, bisphosphorylated SH2 domain binding protein S

  8. Cytokine Receptor Signaling Cytokine Cytokine R Cell membrane P JAK JAK P P P P P P Gene expression SH2 SH2 SH2 SH2 SH2 STAT STAT STAT STAT SH2 P P P STAT Cytoplasm STAT GAS like site P P P Nucleus (Constantinescu, 2000)

  9. 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

  10. Relationship between Oct-3/4 expression and stem cell fate

  11. 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

  12. gp130 Box1 Box2 Y118-P P-Y126 P-Y173 P-Y265 P-Y 275 Box3 Signaling pathways induced by IL-6 family cytokines IL-6 family cytokines -GTP Gab1 Ras SHP2 Raf -P Grb2 Jak1/2/Tyk2 MEK -P -phosphorylation -dimerization STAT3 STAT3-P STAT3-P ERK1/2 - P Self-renewal Differentiation Essentials of Stem Cell Biology, pg no. 32

  13. 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

  14. Hematopoietic stem cells (HSC) self renewal

  15. 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

  16. Role of Myc in regulating epidermal stem cell fate Adhesion and cytoskeleton Growth promoting target genes

  17. 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……

  18. Thank You

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