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GENERATION OF CELLS OF THE IMMUNE SYSTEM STEM CELLS

GENERATION OF CELLS OF THE IMMUNE SYSTEM STEM CELLS. EMBRYONIC STEM CELLS BONE MARROW DERIVED STEM CELLS CD34 + HEMATOPOIETIC MESENCHYMAL. DECISION OF CELL DIFFERENTIATION. Discovery of stem cells Till and McCullogh 1960. Spleen of irradiated mouse Colony forming units (CFU).

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GENERATION OF CELLS OF THE IMMUNE SYSTEM STEM CELLS

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  1. GENERATION OF CELLS OF THE IMMUNE SYSTEM STEM CELLS

  2. EMBRYONIC STEM CELLS BONE MARROW DERIVED STEM CELLS CD34+ HEMATOPOIETIC MESENCHYMAL

  3. DECISION OF CELL DIFFERENTIATION Discovery of stemcells Till and McCullogh 1960 Spleen of irradiated mouse Colony forming units (CFU) MYELOID FERTILIZED EGG Omnipotent EMBRYONAL STEM CELL Pluripotent TISSUE STEM CELL Multipotent LYMPHOID

  4. BONE MARROW TRANSPLANTATION GENERATION OF BLOOD CELLS DURING LIFE SPAN BEFORE BIRTH AFTER BIRTH Yolk sac Flat bones Liver Cell number (%) Spleen Tubular bones years months BIRTH

  5. CELL TYPES OF THE BONE MARROW Stem cells Osteoblasts Osteoclasts Stromal cells BONE B-cell precursors Dendritic cell Progenitors Precursors Blood circulation Central sinus Unspecialized stem cells with unlimited proliferating capacity

  6. CD34+HSC BONE MARROW MYELOID LYMPHOID CMP CLP ERYTHROID BLOOD CELLS Endothelial cells Mesenhymal Stem Cells (MSC) Other Stem Cells Fat Bone Cartilage Neuronal cells Epithelial cells of the liver, kidney, skin, myocytes of the heart and muscle, GI tract

  7. Self renewal + Assimmmetric cell division At least one differentiated cell Progenitor/Precursor More differentiated cell Progenitors/Precursors IMPORTANCE OF TISSUE STEM CELLS • Continuous replenishment of the hematopoietic system • Continuous generation of peripheral immune cells • Circulating progenitors/precursors - BLOOD • Tissue-specific progenitors/precursors - TISSUES • LIMITED TISSUE – SPECIFIC REGENERATIVE POTENTIAL

  8. SOMATIC CELLS Telomer length ARE STEM CELLS EVER - YOUNG CELLS? What about aging? Replicative scenescence is inhibited by telomerase Stromal cells – ‘niche’ is aging as other cell types STEM CELLS The number and the differentiating capacity of pluripotent stem cells is decreasing with age GC, HSC Telomerase +

  9. SELF RENEWAL AND POTENCY • OF DIFFERENTIATION OF STEM CELLS IS REGULATED BY: • The stem cell ‘niche’ • Cytokines (LIF, SCF) • Special signalling molecules • JAK – STAT variants • Transcription factors Oct-4 • Pluripotency maintaining factor Nanog • HSC self renewing factor Bmi-1 • - inhibits the anti-proliferative, apoptosis promoting factors p16/p19Arf • - enhances telomerase function Stromal cell Bone HSC Dendritic cell Central sinus HSC – assymetric cell division self renewal cell differentiation

  10. A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET „NICHE” Osteoblast HSC MSC HSC HSC HSC Nestin+MSC Mobilizedhematopoeticstemcells (HSC) developinclosecontactwithosteoblasts, mesenchymalstemcells (MSC) and endothelialcells Uccelli A et al. NatRevImmunol 2008

  11. AORTA Blood cell Biomechanic stress HSC GENERATION OF HEMATOPOETIC CELLS COUPLED DEVELOPMENT OF ENDOTHELIAL AND HEMATOPOETIC STEM CELLS (HSC) Adamo et al., Nature 2009, North TE, et al. Cell 2009

  12. BONE MARROW TRANSPLANTATION Increasing number of bone marrow transplantations 1990-2007 • Increasing age limit • Increased number of typed donors • Umbilical cord banks • Developing countries • New indications • Autoimmune diseases • Tolerance induction • Regenerative medicine • Non HSC-derived stem cells • adipose tissue-derived MSC- • Replacement of complex tissues • Heterogenous cell populations • Stem- and progenitor cell reservoire in adults • Circulation and migration to tissue through the blood • Reverse migration of peripheral immune cells to the bone marrow Gratwohl & Baldomero Curr Opin Hematol 2009

  13. MULTIPOTENT MESENCHYMAL STEM CELL Uccelli A et al. Nat Rev Immunol 2008 Mesenchymal stem cells (MSC) modulate the functions of other cells through cell – to – cell interactions and through soluble factors produced by them

  14. CHARACTERISTICS AND FUNCTIONS OF MESENCHYMAL STEM CELLS • Regulation of bone marrow HSC • Integrate to the bone • Not immunogenic • Migrate to the site of tissue damage • Traverse vessel wall • Similar action in different tissues • Produce trophic and induced factors • React to inflammatory signals • Immune suppressive - GVHD • Support tumor growth • Integration • Immune suppression • BYSTANDER EFFECTS • Modulation of damaged tissue environment • Inhibition of proliferation • Anti-inflammatory effect • Inhibition of immune cells • Inhibition of apoptosis • Trophic effects – HSC function • WNT signaling • Notch signaling • Similar effects to bone marrow functions • Augmentation of endogenous regenerative mechanisms • Low level of integration • Low level of trans-differentiation • „Touch and go”

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