GENERATION OF CELLS OF THE IMMUNE SYSTEM
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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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Generation of cells of the immune system stem cells

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+ HEMATOPOIETICMESENCHYMAL


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

CD34+HSC

BONE MARROW

MYELOID

LYMPHOID

CMP

CLP

ERYTHROID

BLOOD CELLS

Endothelial cells

Mesenhymal Stem Cells (MSC)

Other Stem Cells

FatBone Cartilage

Neuronal cells

Epithelial cells of the liver, kidney, skin, myocytes of the heart and muscle, GI tract


Generation of cells of the immune system stem cells

TISSUE STEM CELLS IN THE BONE MARROW

REGENERATIVE MEDICINE

Asahara & Kawamoto 2004 Am J Physiol Cell Physiol


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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 +


Generation of cells of the immune system stem cells

  • 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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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


Generation of cells of the immune system stem cells

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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