GENERATION OF CELLS OF THE IMMUNE SYSTEM

STEM CELLS

EMBRYONIC STEM CELLS

BONE MARROW DERIVED

STEM CELLS

CD34+ HEMATOPOIETIC MESENCHYMAL

Spleen of irradiated mouseColony forming units (CFU)

Discovery of stem cellsDiscovery of stem cellsTill and McCullogh 1960Till and McCullogh 1960

FERTILIZED EGGFERTILIZED EGG

OmnipotentOmnipotent

EMBRYONAL STEM CELLEMBRYONAL STEM CELLPluripotentPluripotent

TISSUE STEM CELLTISSUE STEM CELLMultipotentMultipotent

MYELOIDMYELOID

LYMPHOIDLYMPHOID

DECISION OF CELL DIFFERENTIATIONDECISION OF CELL DIFFERENTIATION

00

20

40

60

80

1 2 3 4 5 6 7 8 9 10 20 30 40 50 60 70

GENERATION OF BLOOD CELLS DURING LIFE SPAN

BEFORE BIRTH AFTER BIRTH

Spleen

Liver

Yolk sac

Cel

l num

ber

(%)

BIRTH

months years

Flat bones

Tubular bones

BONE MARROW TRANSPLANTATION

centrálissinus

csont

CELL TYPES OF THE BONE MARROW

Dendritic cell

B-cell precursors

Stem cells

Stromal cellsBONE

Centralsinus

Unspecialized stem cells with unlimited proliferating capacity

Osteoblasts

Osteoclasts

ProgenitorsProgenitors

PrecursorsPrecursors

Blood circulation

MYELOID LYMPHOID

BONE MARROW

CMP CLP

CD34+ HSC

ERYTHROID

BLOOD CELLSEndothelial cells Mesenhymal Stem Cells

(MSC)

Fat Bone CartilageOther Stem Cells

Neuronal cells Epithelial 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 cellsContinuous generation of peripheral immune cells

• Circulating progenitors/precursors - BLOODCirculating progenitors/precursors - BLOOD

• Tissue-specific progenitors/precursors - TISSUESTissue-specific progenitors/precursors - TISSUES

LIMITED TISSUE – SPECIFIC REGENERATIVE POTENTIALLIMITED TISSUE – SPECIFIC REGENERATIVE POTENTIAL

At least one differentiated cellProgenitor/Precursor

More differentiated cellProgenitors/Precursors

Self renewal+

Assimmmetric cell division

IMPORTANCE OF TISSUE IMPORTANCE OF TISSUE STEM CELLSSTEM 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

centrálissinus

csont

Dendritic cell

HSC

Stromal cell

Centralsinus

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/p19Arf

• - enhances telomerase function

A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT A FELNŐTT HEMATOPOETIKUS ŐSSEJTEK KÉPZŐDÉSÉT BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET BIZTOSÍTÓ CSONTVELŐI MIKROKÖRNYEZET „NICHE”„NICHE”

OsteoblastOsteoblast

MSCMSC HSCHSC

HSCHSC

HSCHSC

HSCHSC

Mobilized hematopoetic stem cells (HSC) develop in close contact with Mobilized hematopoetic stem cells (HSC) develop in close contact with osteoblasts, mesenchymal stem cells (MSC) and endothelial cellsosteoblasts, mesenchymal stem cells (MSC) and endothelial cells

Uccelli A et al. Nat Rev Immunol 2008Uccelli A et al. Nat Rev Immunol 2008

NestinNestin++MSCMSC

Biomechanic stressBiomechanic stress

GENERATION OF GENERATION OF HEMATOPOETIC CELLSHEMATOPOETIC CELLS

Blood Blood cellcell

AORTAAORTA

HSCHSC

COUPLED DEVELOPMENT OF COUPLED DEVELOPMENT OF ENDOTHELIAL AND HEMATOPOETIC ENDOTHELIAL AND HEMATOPOETIC

STEM CELLS (HSC)STEM CELLS (HSC)

Adamo et al., Nature 2009, North TE, et al. Cell 2009Adamo et al., Nature 2009, North TE, et al. Cell 2009

BONE MARROW TRANSPLANTATIONBONE 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 2009Gratwohl & Baldomero Curr Opin Hematol 2009

•Replacement of complex tissuesReplacement of complex tissues•Heterogenous cell populationsHeterogenous cell populations•Stem- and progenitor cell reservoire in Stem- and progenitor cell reservoire in adultsadults•Circulation and migration to tissue Circulation and migration to tissue through the blood through the blood •Reverse migration of peripheral immune Reverse migration of peripheral immune cells to the bone marrowcells to the bone marrow

Increasing number of bone marrow Increasing number of bone marrow transplantationstransplantations

1990-20071990-2007

MULTIPOTENT MESENCHYMAL STEM CELL MULTIPOTENT MESENCHYMAL STEM CELL

Mesenchymal stem cells (MSC) modulate the functions of other cells throughMesenchymal 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 2008Uccelli A et al. Nat Rev Immunol 2008

CHARACTERISTICS AND FUNCTIONS OF MESENCHYMAL CHARACTERISTICS AND FUNCTIONS OF MESENCHYMAL STEM CELLSSTEM 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”