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Umbilicalcord
Fetal liverAdult bone marrow
Absolute No. of stem cells and quiescent progenitors
Yolk Sac
Periodo mesoblastico(sacco vitellino)
Periodo epatico (6a settimana)
SpleenPeriodo epato-splenico
(12a settimana)
Periodo midollare (20a settimana)
MICROAMBIENTE MIDOLLARE
Componentecellulare
Componente vascolareCellule reticolariStruttura nervosaAdipociti, fibroblasti, MacrofagiCellule stam. mesenchimali
Matriceextracellulare
Fibre reticolari/collageneProlungamenti cell. reticolariProteine d’adesioneproteoglicani
SANGUE PERIFERICO
ERITROCITIPIASTRINE
GRANULOCITINEUTROFILI
GRANULOCITIEOSINOFILI
GRANULOCITIBASOFILI
EMIVITA DELLE CELLULE DEL SANGUE
ERITROCITI 120 giorni
PIASTRINE 4-5 giorni
GRANULOCITI 6-8 ore
MONOCITI 8 ore
LINFOCITI VARIABILE
HEMATOPOIESIS
Stem cell
SELFRENEWAL
CFU-GEMM
STEM CELL POOL
CFU-GM
CFU-Eo
CFU-Bas
BFU-E
CFU-Mk
CFU-G
CFU-MMonocytes
Erytrocytes
CFU-E
Platelets
PROLIFERATIVEPOOL
MATURATIVEPOOL
MATUREBLOOD CELLS
Megakaryocytes
Neutrophyls
Basophyls
Eosinophyls
LTC-ICELTC-IC
MYELOPOIESIS
Fattori trascrizionali emopoietici
RARs PU.1 C/EBPε
Sp1
C/EBPs
Egr-1 Rb p53
PU.1 C/EBPs
MICSBP
PU.1
GMP
PU.1C/ EBPs
PU.1
GATA-1
CMP
MEP
GATA -1
BasoGATAs
MITF
Meg
GATA-1,GATA-2NF-E2,RUNX1,FLI1
E
GATA-1,LMO2
B
PU.1
Pax 5
T
GATA-3
CLP
Ikaros
HSC
CBFβ,HOXA9,CUTL-1
SCL/LMO2, ID1
GATA-2,Ikaros
G
C/EBPαPU.1
EoP
C/EBPβ
GATA-1
+/-C/EBPs
Sp1GATA-1;PU.1
Hoxa5
PU.1
Hoxa10
TAL-1,LDB1
E2A,E47
Normal hematopoiesis
CFU-GM
CFU-M
CFU-G
CFU-MEG
Limphoid progenitor
Quiescent Staminal cell
Myeloblast
Monoblast
Megakaryoblast
Pro-erythroblast Erythroblast
Granulocyte
Monocyte
Platelets
Red cells
CFU-GEMM
BFU-E / CFU-E
Epo
SCF, TPO, IL3, GM-CSF
SCF, IL6 IL3, GM-CSF
Plasma cellB lymphocyte
Proliferating staminal cell
SCF, IL1, IL3, IL6, Flt3
ligand, IL11
TGFβ, TNFα, INFγ, LIF
SELF RENEWAL COMMITTMENT PRECURSOR EXPANSION TERMINAL DIFFERENTIATION
Normal hematopoiesis
CFU-GM
CFU-M
CFU-G
CFU-MEG
Limphoid progenitor
Quiescent Staminal cell
Myeloblast
Monoblast
Megakaryoblast
Pro-erythroblast Erythroblast
Granulocyte
Monocyte
Platelets
Red cells
CFU-GEMM
BFU-E / CFU-E
Epo
SCF, TPO, IL3, GM-CSF
SCF, IL6 IL3, GM-CSF
Plasma cellB lymphocyte
Proliferating staminal cell
SCF, IL1, IL3, IL6, Flt3
ligand, IL11
TGFβ, TNFα, INFγ, LIF
SELF RENEWAL COMMITTMENT PRECURSOR EXPANSION TERMINAL DIFFERENTIATION
Normal hematopoiesis
CFU-GM
CFU-M
CFU-G
CFU-MEG
Limphoid progenitor
Quiescent Staminal cell
Myeloblast
Monoblast
Megakaryoblast
Pro-erythroblast Erythroblast
Granulocyte
Monocyte
Platelets
Red cells
CFU-GEMM
BFU-E / CFU-E
Epo
SCF, TPO, IL3, GM-CSF
SCF, IL6 IL3, GM-CSF
Plasma cellB lymphocyte
Proliferating staminal cell
SCF, IL1, IL3, IL6, Flt3
ligand, IL11
TGFβ, TNFα, INFγ, LIF
SELF RENEWAL COMMITTMENT PRECURSOR EXPANSION TERMINAL DIFFERENTIATION
Normal hematopoiesis
CFU-GM
CFU-M
CFU-G
CFU-MEG
Limphoid progenitor
Quiescent Staminal cell
Myeloblast
Monoblast
Megakaryoblast
Pro-erythroblast Erythroblast
Granulocyte
Monocyte
Platelets
Red cells
CFU-GEMM
BFU-E / CFU-E
Epo
SCF, TPO, IL3, GM-CSF
SCF, IL6 IL3, GM-CSF
Plasma cellB lymphocyte
Proliferating staminal cell
SCF, IL1, IL3, IL6, Flt3
ligand, IL11
TGFβ, TNFα, INFγ, LIF
SELF RENEWAL COMMITTMENT PRECURSOR EXPANSION TERMINAL DIFFERENTIATION
SOURCES OF HEMATOPOIETICSTEM CELLS FOR TRANSPLANT
Cord Blood 0.5%
Bone Marrow 1%
Mobilized Peripheral Blood 0.1-10%
THE CD34 ANTIGENFor more than a decade, CD34
molecule has been the best-known marker of HSC;Very high academic as commercial interest;
Berenson et al (1988) reported successful hematopoietic
reconstitution in baboons with selected CD34+ bone marrow
cells.
M.W. 110-120 kDaChromosome localization:1q32
E F M
TNF-alphaMIP-1 alphaTGF-beta
IL’sSCFLIFFlt3
LFA-1CD34
CD44
Thy1
L-selectinFlt3
c-kit
P-selectin
α5β1
α4β1
+ +- -
ICAM Collagen Fibronectin Laminin Proteoglycan VCAM-1Thrombospondin
Kit Rec Selectin RecFlt3 Rec
INTERACTIONS OF STEM CELLS WITH MICROENVRONMENT
HSC
HEMATOPOIETIC PROGENITOR CELLS
1950: MURINE MODELSCLINICAL INVESTIGATION
1970: COLONY ASSAYSTILL/ Mc CULLOGH
1975: BONE MARROW TRANSPLANTATION INHUMAN
1995: PHERIPHERAL BLOOD STEM CELLS
- Found throughout the body in all tissues in specific stromal niches
- Multipotent
- Partially committed with a key role in damaged tissues repair
The adult stem cell
- Derives from inner cell mass of blastocyst
- Pluripotent
- Give rise to endoderm, ectoderm, mesoderm tissues
The embryonic stem cell (ES)
Copyright Mike Jones
Diane S. Krause, Neil D. Theise, Michael I. Collector, Octavian Henegariu, Sonya Hwang, Rebekah Gardner, Sara Neutzel, and Saul J. Sharkis
Fluorescence microscopic imagesof (A) lung,(B) esophagus, (C) stomach, (D)colon, (E) bile duct cyst, (F) skin.
Donald Orlic, Jan Kajstura, Stefano Chimenti, Federica Limana, Igor Jakoniuk, FedericoQuaini, Bernardo Nadal-Ginard, David M. Bodine, Annarosa Leri, and Piero Anversa.
Mobilized bone marrow cells repair the infarcted heart, improving function and survival.
La cellula staminale emopoietica
PROPRIETA’ DELLA CELLULA STAMINALE
EMOPOIETICA:
• capacità di “self-renewal”
• capacità di dare origine a progenitori multipotenti
• capacità di dare origine a precursori “committed”
(differentiation plasticity)
• Capacità di engraftment
• Plasticità (developmental plasticity)
EVIDENZE SPERIMENTALI DELLA PLASTICITA’ DELLE CSE: UOMO
CUOREBELTRAMI (2001): I CARDIOMIOCITI POSSONO REPLICARE DOPO IMA
QUAINI (2002): MIGRAZIONE DI HSC DEL RICEVENTE NEL CUORE TRAPIANTATO
FEGATOALISON (2000) E THIESE (2000): STUDIO SU BIOPSIE EPATICHE DI DONNE TRAPIANTATE CON HSC DA UOMINI E BIOPSIE EPATICHE DI UOMINI TRAPIANTATI
CON FEGATI DI DONNE: CELLULE DI ORIGINE MIDOLLARE (CROMOSOMA Y) TROVATE NELL’1-40% DEI CASI.
RENEPOULSOM (2001): BIOPSIE RENALI DI DONNE CHE RICEVONO MIDOLLO OSSEO DA
UOMINI E DI UOMINI CHE RICEVONO RENI DA DONNE: RISCONTRO DI CELLULE DI ORIGINE MIDOLLARE NEL 34% DEI CASI.
GUPTA (2002): UOMINI CON IRA RICEVONO RENI DA DONNE: LE CELLULE DEL RICEVENTE SI TROVANO NEL RENE TRAPIANTATO.
- Derives from a genetic reprogramming of adult somatic cell
- Pluripotent artificial stem cell
- Different growth conditions lead to the differentiation into all possible types of specialized cells
The iPS: induced Pluripotent Stem cell
Skin fibroblasts (KeratinocyteBMSC, PBC)
Retroviral infection with Oct4, Sox2, c-Myc and Klf4 genes
iPS
Epithelium Cartilage Muscle CNS Adipose
(Reprogramming of human somatic cells to pluripotency with defined factors. Daley GQ et al., Nature, 2008)