emopoiesi e staminali
TRANSCRIPT
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Il SangueIl Sangue
• Globuli rossi (eritrociti)
• Globuli bianchi (leucociti)
• Piastrine
• Plasma
• Globuli rossi, globuli bianchi e piastrine sono prodotti nel midollo osseo
• In un adulto approssimativamente 5L di sangue (peso corporeo x 70)
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Componenti del sangue: cellule e funzioni
Componenti del sangue: cellule e funzioni
• Eritrociti
• Trasporto di O2 & CO2
• Leucociti
• Risposta immune
• Fagocitosi
• Piastrine
• Emostasi
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Componenti del sangueComponenti del sangue
Figure 16-2: The blood count
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EmatocritoEmatocrito• Percentuale del
volume ematico che comprende i globuli rossi
• 40-52% (M)
• 35-47% (F)
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Globuli rossiGlobuli rossi
• Trasporto di O2 ai tessuti
• Dischi biconcavi contenenti emoglobina
• Vita media di 120 giorni
• 4.4-5.9 x 1012
RBCs/L (M)
• 3.8-5.2 x 1012
RBCs/L (F)
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Componenti del sangueComponenti del sangue
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Ematopoiesi: il processo di formazione del sangue
Ematopoiesi: il processo di formazione del sangue
• Avviene principalmente nel midollo oseo, a partire dalle cellule staminali.
• I tempi ed i ritmi dell’emopoiesi sono regolati da citochine e fattori di crescita
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Globuli rossi
Globuli bianchi Piastrine
Cellule staminali
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EmatopoiesiEmatopoiesi
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stem
cell
HEMATOPOIESIS
GranulocyteLymphocyte
MonocytePlateletsRBC
Lymphopoiesis
Granulopoiesis
Monocytopoiesis
Erythropoiesis
Thrombopoiesis
Lymphoblast Monoblast Myeloblast
Myelocyte
Metamylelocyte
Band granulocyte
Pro-Myelocyte
Reticulocyte
Pro-erythroblast
Basophilic erythroblast
Orthocromatic erythroblast
Polychromatic erythroblast
Megakaryoblast
Megakaryocyte
Pluripotent stem cell (Hemocytoblast)
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Megakaryopoiesis
Neu
Bas
Lym
Mon
Eos
Pla
RBC
Granulopoiesis
Monocytopoiesis
Erythropoiesis
{ Similar precursor produces Mast cells
Monocyte or a related precursor gives rise to many specialized phagocytes & antigen-presenting cells
Macrophages Kupffer cells Langerhans cells Dendritic cells Microglia Osteoclasts etc
FURTHER DIFFERENTIATIONS
Similar precursor produces Natural killer cells
B lymphocytes become Plasma cells
Thrombopoiesis
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Midollo osseo normale
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MACROFAGO
FIBROBLASTO
CELLULA STAMINALE
OSSO
OSSO OSSO
OSSO
CELLULA ADIPOSA
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•IL6
•G-CSF
•GM-CSF
•M-CSF
•SCF
•Flk-2VCAM-1 ICAM-1
E-selectin
P-selectin
CD105 endogli
n
VEGF2R
Ruolo dei vasi
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Macrophage
Sinusoid
Stromal
cellFat cell Megakaryocyte
Platelets
Midollo osseo
Reticular Fibers
4
3
2Stromal cell
1
1-4 Developing cells
Endothelial cell
M
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Macrophage
Sinusoid
Stromal cellFat cell
Midollo rosso
Reticular Fibers
Stromal cell
Endothelial cell
STROMAL ELEMENTS
M
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Sinusoid
Platelets
Midollo rosso
4
3
2
1
1-4 Developing & stored cells
HEMATOPOIETIC CELLS
Megakaryocyte
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Compartimenti midollari
EMATOPOIETICO
VASCOLARE
STROMALEFIBROBLASTI
COLLAGENE
MATRICE
CELLULE ADIPOSE
MACROFAGI
s i nuso i d i
Endotelio
sinusoidi
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MOBILIZZAZIONE
Lapidot, 2002
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Che cosa è mieloide
Macrophage
Sinusoid
Stromal cell
Fat cellFat cell Megakaryocyte
Platelets
RED BONE MARROW
Reticular Fibers
4
3
2Stromal cell
1
1-4 Developing cells
Endothelial cell
M
Il midollo rosso è mieloide, in contrasto al midollo giallo, che è pieno di grasso e povero di cellule ematopoietiche
Il tessuto mieloide può esistere al di fuori del midolo osseo, ad esempio nel fegato fetale
Il tessuto mieloide è il sito dell’ematopoiesi, che include anche la linfopoiesi. Tuttavia ciò che il midollo produce sono essenzialmente i precursori linfocitari. I linfociti completano la loro formazione negli organi linfoidi. Così, la mielopoiesi (intesa come produzione di cellule non-linfoidi) occupa la maggioranza degli spazi midollari.
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Le cellule staminali devono rimpiazzare se stesse,
mediante il processo di divisione mitotica, e nello
stesso tempo fornire all’organismo cellule mature
stem
cell
Divisione simmetrica
stem
cell
Divisione asimmetrica
Le cellule staminali e le divisioni “asimmetriche”
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Le cellule mature derivano, dopo molte divisioni e molti passaggi differenziativi, dalle stem cells.
stem
cell
I fattori di crescita regolano la proliferazione, differenziazione & rilascio di cellule allo scopo di controllare il numero di cellule necessarie a
fronteggiare la perdita (es.emorragie), o l’incrementato bisogno (es. infezioni o condizioni di bassa pressione di ossigeno dovuta
all’altitudine).
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Unità formanti colonie
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Donald Metcalf
La scoperta delle “colonie” e dei fattori
di crescita
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L’idea del saggio a colonie
Metcalf & Bradley, 1965
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Le prime colonie ematopoietiche
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Cellule staminali come unità (CFU)Perché i precursori si definiscono “unità”?
Il topo normale possiede tessuto ematopoietico nell’osso e nella milza.
L’irradiazione distrugge il tessuto ematopoietico
Vengono inettate cellule ematopoietiche da un ratto
giovane contenenti un marker cromosomico
Nella milza appaiono isole ematopoietiche contenenti cellule marcate
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Perché i precursori vengono definiti “unità”?
Le cellule ematopoietiche iniettate capaci di formare “isole” o “colonie” ricevono il nome di “Unità formanti colonie - nella milza” (COLONY-
FORMING UNIT, SPLEEN or CFU-S)
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Basophil
Eosinophil
RBC
Neutrophil
T Lymphocyte
Monocyte
Platelets
B Lymphocyte
Pluripotent Stem Cell
CommittedStem Cell
CFU-MegMegakaryocyte
Lymphoid Progenitor Cell
CSCPSC
LPC
MPCMyeloid Progenitor Cell
BFU-E
CFU-E Colony-forming
Unit - ErythroidCFU-M Colony-forming
Unit -Monocyte
Colony-forming Unit - Monocyte.Granulocyte
CFU-GM
CFU-G
CFU-Eo
CFU-Mast
Linee ematopoietiche
CFU-GEMM
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Fattori di crescita
Influenzano la proliferazione e differenziazione di cellule ematopoietiche i diversi modi:
•Fattori di crescita - divisione e proliferazione
•Fattori di sopravvivenza - prevengono l’apoptosi
•Fattori di differenziazione - maturazione cellulare
•Fattori di attivazione - favoriscono l’attivaz. cellulare
Un dato fattore può agire in diversi modi e su più tipi cellulari.
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Basophil
Eosinophil
RBC
Neutrophil
T Lymphocyte
Monocyte
Platelets
B Lymphocyte
Pluripotent Stem Cell
CommittedStem Cell
CFU-MegMegakaryocyte
Lymphoid Progenitor Cell
CSCPSC
LPC
MPCMyeloid Progenitor Cell
BFU-E
CFU-E
CFU-M
Colony-forming Unit - Monocyte.Granulocyte
CFU-GM
CFU-G
CFU-Eo
CFU-Mast
HEMATOPOIESISGrowth factors
M-CSFIL-3, GM-CSF
G-CSF
IL-6
IL-3
SCF IL-1
**
EPO
TPO
*
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Da cellule staminali pluripotenti a cellule mature, differenziate, effettrici di funzioni
specifiche
Da cellule staminali pluripotenti a cellule mature, differenziate, effettrici di funzioni
specifiche
Ematopoiesi
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CURT CIVIN
Nel 1984 scopre
l’antigene CD34
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CD34+
Curt Civin, 1984
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R2
CD
34
Osservare “elettronicamente” le CS
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R4
ANALISI ELETTRONICA A QUATTRO COLORI
G. Scalia & P. Morabito, 2003
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Margaret Goodell
Verso una cellula staminale ancora piu’
“primitiva”
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Le cellule staminali CD34- (side population)
Margaret Goodell
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(Lin)- Sca-1+
c-kit+CD34-
Capaci di ricostituzione emopoietica a lungo termine
Osawa, 1996
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L’espressione di CD34 è inducibile
(Lin)- Sca-1+
c-kit+
CD34-
(Lin)- Sca-1+
c-kit+
CD34+
1 settimana con IL-11 o SCF
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DIVERSI TESSUTI, DIVERSA ORIGINE
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CSE
SANGUE EPATOCITA
TRANS-differenziazione
CONCETTO DI TRANS-DIFFERENZIAZIONE
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James Thomson
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LINEE CELLULARI EMBRIONALI
JA Thomson
MASSA INTERNA COLONIA
C. INDIFFERENZIATE C. DIFFERENZIATE
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intestino epitelio neurale
osso cartilagine
muscolo striato glomeruli
TOTIPOTENZA DELLE ES
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LINEE CELLULARI EMBRIONALI DIVENTANO CELLULE EMATOPOIETICHE
CFU-GEMM BFU-E
CFU-GM CFU-M
CFU-MK GRANULOCYTESJA
Thomson
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CELLULE STAMINALI
ADULTE
CELLULE STAMINALI
EMBRIONALI DA BLASTOCISTI
DONATE
CELLULE STAMINALI
EMBRIONALI DA BLASTOCISTI
CLONATE
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MIDOLLO NORMALE
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AGRANULOCITOSI
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MIELOBLASTI
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PROMIELOCITI
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PROMIELOCITI 2
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MIELOCITI
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MIELOCITI E METAMIELOCITI
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FORME BAND
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neutroGRANULOCITI
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EOSINOFILI
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BASOFILI
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MASTOCITI
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MONOCITI
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MACROFAGI
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MEGACARIOCITI
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PROERITROBLASTI - ERITROBLASTI BASOFILI
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ERITROBLASTI POLICROMATOFILI
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ERITROBLASTI ORTOCROMATICI