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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. BONE MARROW TRANSPLANTATION. GENERATION OF BLOOD CELLS DURING LIFE SPAN. BEFORE BIRTH. AFTER BIRTH. Yolk sac. Flat bones. Liver.

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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. 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

  4. 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

  5. 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

  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. TISSUE STEM CELLS IN THE BONE MARROW REGENERATIVE MEDICINE Asahara & Kawamoto 2004 Am J Physiol Cell Physiol

  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. 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

  10. SOMATIC CELLS Telomere 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 Gametocytes, HSC Telomerase +

  11. 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

  12. 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

  13. 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

  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. Immature B cells Pre-B Progenitors Centralsinus Endoosteum Stromal cell Macrophage B CELL DEVELOPMENT IN THE BONE MARROW X X X

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