GENERATION OF CELLS OF THE IMMUNE SYSTEM STEM CELLS

EMBRYONIC STEM CELLS BONE MARROW DERIVED STEM CELLS CD34 + HEMATOPOIETICMESENCHYMAL

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

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

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

MYELOID LYMPHOID BONE MARROW CMPCLP CD34+ HSC ERYTHROID BLOOD CELLS Endothelial cells Mesenhymal Stem Cells (MSC) FatBone Cartilage Other Stem Cells Neuronal cellsEpithelial cells of the liver, kidney, skin, myocytes of the heart and muscle, GI tract

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

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

HSC – assymetric cell division self renewal cell differentiation Dendritic cell HSC Stromal cell Central sinus Bone 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/p19 Arf - enhances telomerase function

A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET „NICHE” Osteoblast MSCHSC HSC HSC HSC Mobilized 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 Nestin + MSC

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

BONE MARROW TRANSPLANTATION 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- Gratwohl & Baldomero Curr Opin Hematol 2009 Replacement of complex tissuesReplacement of complex tissues Heterogenous cell populationsHeterogenous cell populations Stem- and progenitor cell reservoire in adultsStem- and progenitor cell reservoire in adults Circulation and migration to tissue through the bloodCirculation and migration to tissue through the blood Reverse migration of peripheral immune cells to the bone marrowReverse migration of peripheral immune cells to the bone marrow Increasing number of bone marrow transplantations

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

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”