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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 és McCullogh 1960. Spleen of irradiated mouse Colony forming units (CFU). MYELOID.

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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 stem cells Till és McCullogh 1960 Spleen of irradiated mouse Colony forming units (CFU) MYELOID FERTILIZED EGG Omnipotent EMBRYONAL STEM CELL Pluripotent TISSUE STEM CELL Multipotent LYPHOID

  4. EARLY MOUSE EMBRYOS Blastocyst stage of differentiation 4.5 DAY 5.5 DAY Ectoplacental part EXTRAEMBRYONAL PARTS Primitive sheet Primitive ectoderm Inner Cell Mass ICM Extraembryonal ectoderm Primitive endoderm Inner endoderm Embryonal ectoderm Blastocoel Trophectoderm Dorsal part Primitive amnion EMBRYONAL PARTS In vitro fertilization – IVF – human embryos

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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 +

  10. 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

  11. PLURIPOTENT BONE MARROW STEM CELLS REGENERATIVE MEDICINE HMB MSC HSC Endothel L M Bone Cartilage, Muscle, Fat Pericyte EPC Osteoclast Osteoblast endothel EctodermalMesodermalEndodermal Skin Neuro Liver Pancreas Gut ADULT VASCULO / ANGIOGENESIS Asahara & Kawamoto 2004 Am J Physiol Cell Physiol

  12. PROPOSED MECHANISMS FOR ADULT STEM CELL PLASTICITY HSC HSC HSC HSC Differentiation of HSC from a more pluripotent SC HYERARCHY Indirect trans-differentiation of HSC through a more pluripotent SC Direct trans-differentiation of HSC Fusion of HSC with tissue cell TRANSDIFFERENTIATION - FLEXIBILITY GET THROUG ECTO-/ENDO-/MEZODERM BARRIERS LYMPHOID/MYELOID BARRIERS

  13. EMBRYONAL DEVELOPMENT OF ENDOTHELIAL CELLS Hemangioblaszt Flk-1+brachury+ Hemogenic endothelium Tie2highc-Kit+CD41- Scl/Tal1 Runx1/AML1 Hematopoesis CD41+CD45- Primitive hematopoesis CD41-CD45- LT-HSC ST-HSC CMP CLP HEMOGENIC ENDOTHELIUM HSC Chen MJ et al. Nature 457:887, Lancrin C et al. Nature 457:892, Eilken HM et al. Nature 457:896, 2009

  14. 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

  15. A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET „NICHE” Osteoblast HSC MSC HSC HSC HSC Nestin+MSC Mobilised hematopoetic stem cells (HSC) develop in close contact with osteoblasts, mesenchymal stem cells (MSC) and endothelial cells Uccelli A et al. Nat Rev Immunol 2008

  16. 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

  17. CHARACTERISTICS AND FUNCTIONS OF MESENCHYMAL STEM CELLS • Regulation of bone marrow HSC • Integrate to the bone • Not immunogenic • Migrate to the site of tissue demage • 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 demaged 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”

  18. HOMEOSTASIS OF HEALTHY ENDOTHELIAL CELLS REQUIRES CONTINUOUS REGENERATION Permeability is increasing Retention and modulation of lipoproteins CRONIC STRESS Age Smoking High cholesterin levels High blood pressure Diabetes PROTECTIVE RESPONSE INFLAMMATION Modified endothelial functions Plaque formation Thrombosis TISSUE ENVIRONMENT Pro-angiogenic Anti-angiogenic EGYENSÚLY Decrease vessel wall demage Restore regenerative mechanisms Differenciated entothelial cells STRESS Physical stress – shear Moreno et al. J Am Coll Cardiol 2009

  19. VESSEL REGENERATION BY BONE MARROW-DERIVED STEM- AND PROGENITOR CELLS Endothelial progenitor cells (EPC) Hemangioblast Circulating EPC number Training Statin therapy Mobilisation Lipid reducing & anti-inflammatory effects COMPETENT BONE MARROW Differentoated endothelial cells STRESS Biomechanic stress Mesenchymal stroma cells EPC Smooth muscle progenitor cells (SMPC) Decrease demage of vessel wall Restore regenerative mechanisms EQUILIBRIUM Removal of cholesterol Generation of new vessels Angiogenesis

  20. A GYULLADÁSOS FOLYAMATOK ELŐSEGÍTIK A CSONT LEBONTÁST INFLAMMATORY T CELL RESPONSE BONE DESORPTION PROTECTIVE MECHANISMS INHIBITION OF BONE FORMATION

  21. Enhancement Inhibition MM RA Gátlás

  22. THE INFLAMMATORY CYTOKINE IL-20 PLAYS A ROLE IN BONE RESORPTION AFTER MENOPAUSE IL-20 citokine-specific anti-body inhibits RANK receptor expression on osteoclast precursors and RANKL expression on osteoblasts Hsu Y-H et al. JEM 2011

  23. 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- Csoport Auto Allo • 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

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