I Wilmut CCLRC1 End-cap Engineering 8 September 2004 Ian Wilmut, RAL.
Corso di Laurea in Medicina e Chirurgia A.D.E.€¦ · In 1997, Sir Ian Wilmut and his team...
Transcript of Corso di Laurea in Medicina e Chirurgia A.D.E.€¦ · In 1997, Sir Ian Wilmut and his team...
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Corso di Laurea in Medicina e Chirurgia A.D.E.
Le CelluleStaminali 17 maggio 2016
Cinzia Di Pietro
Dipartimento di Scienze Biomediche e Biotecnologiche Sezione di Biologia e Genetica G Sichel
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La Cellula Staminale Cellula capace di dare origine a tutte le popolazioni cellulari di uno o più tessuti
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Le cellule staminali possiedono la capacità di rinnovarsi e di differenziarsi
• sono in grado di generare cellule figlie identiche alla cellula madre (capacità di rinnovo)
• sono in grado di produrre una progenie di cellule con potenziale differenziativo (capacità di differenziamento)
La Cellula Staminale
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La Cellula Staminale
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Totipotente Pluripotente Multipotente Unipotente Cellule Staminali Pluripotenti indotte iPSC Cellule Staminali del cancro
Classificazione
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hESCs
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Classificazione
• Cellule Staminali Embrionali (ESCs)
• Cellule Staminali dell’Adulto
• Cellule Staminali Riprogrammate
Cellule staminali Pluripotenti indotte (iPSCs)
Trasferimento di nuclei di cellule somatiche differenziate in ovociti (SCNTs)
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Le cellule embrionali staminali (in sigla ES da
Embryonic Stem cell), hanno come caratteristica
principale l'elevata capacità di differenziarsi in
qualsiasi altro tipo cellulare.
Inoltre è possibile mantenerle in coltura per un
lungo periodo di tempo.
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hESCs
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neurons
Embryonic stem (ES) cells: Challenges
embryonic stem cells
skin
blood
liver ?
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Capacità di divisione quasi illimitata senza andare in contro a processi di differenziamento
hESCs
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Adult Stem Cells
• Adult stem cells have been identified in most mammalian tissues of the adult body and are known to support the continuous repair and regeneration of tissues.
• Adult stem cells are clonogenic, self-renewing with a plasticity to differentiate into cell types of the particular tissue in which they reside
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Stem cell niches
Direct contact Soluble factors Intermediate cell
stem cell
niche
Niche Microenvironment around stem cells that provides support and signals regulating self-renewal and differentiation
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Adult stem cells are usually located in a specific cellular niche, and niche
microenvironment determine the status of stem cell activation, thus ensuring a balance between maintenance of the stem cell pool
and production of progenitor cells engaged in tissue differentiation
Adult Stem Cells
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Stem cell microenvironment or niche, which can modulate how stem cells participate in tissue regeneration, maintenance and repair .
Stem cell niches are diverse and comprise a variety of cells, extracellular matrices and paracrine hormonal and endocrine signals, which all interact with each other.
Adult Stem Cells
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Adult Stem Cells
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Le cellule staminali adulte sono purtroppo di difficile
reperibilità, poiché numericamente molto scarse;
non possono essere coltivate a lungo poiché, dopo alcune
divisioni cellulari, tendono a perdere le caratteristiche di
pluripotenzialità.
Le cellule staminàli embrionali, invece, possono essere
mantenute in coltura per moltissimi cicli di divisione, addirittura
per più di dieci anni, senza perdere di pluripótenzialità.
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Adult Stem Cells
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Pro e Contro Embryonic SC
“Pluripotent”
Stable. Can undergo many cell divisions.
Easy to obtain but blastocyst is destroyed (Ethics)
Possibility of immune rejection
High potential for tumours
Adult SC
“Multipotent” Less Stable. Capacity for self-
renewal is limited. Difficult to isolate in adult tissue. No ethical concerns Host rejection minimized or absent Less tumorigenic potential
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Reprogramming
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In 1997, Sir Ian Wilmut and his team surprised the world by presenting the
first cloned mammal, Dolly the sheep, engineered via SCNT.
The generation of live animals by NT demonstrated that the epigenetic state of somatic cells, including that of terminally differentiated cells, while stable, is not irreversibly fixed but can be reprogrammed to an embryonic state that is capable of directing development of a new organism. After Dolly was cloned, it was believed that SCNT would become the method of choice for generating patient-specific pluripotent cells. However, the process is very inefficient and the reprogramming incomplete leading to Dolly’s premature death and early onset of a number of degenerative diseases.
Rudolf J, Young R. 2008
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• La clonazione di Dolly aveva dimostrato la capacità dell’oocita di riprogrammare i nuclei di cellule terminalmente differenziate.
• La riprogrammazione avviene grazie a
fattori presenti nel citoplasma dell’oocita fecondato.
Reprogramming
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Dr. Shinya Yamanaka, PhD
Human iPSCs
Dr. Kazutoshi Takahashi, PhD
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iPSCs
24 candidate genes for pluripotency factors
Ecat1, Dpp5(Esg1), Fbx015, Nanog, ERas,
Dnmt3l, Ecat8, Gdf3, Sox15, Dppa4, Dppa2,
Fthl17, Sall4, Oct4, Sox2, Rex1, Utf1, Tcl1,
Dppa3, Klf4, b-cat, cMyc, Stat3, Grb2
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(Geoghegan and Byrnes, 2008)
iPSCs
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iPSCs
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iPSCs
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Putative role of reprogramming factors during iPSC formation.
Stadtfeld M , Hochedlinger K Genes Dev. 2010;24:2239-2263
©2010 by Cold Spring Harbor Laboratory Press
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Integration
Integration free
iPSCs
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iPSCs
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iPSCs
http://circres.ahajournals.org/content/110/7/1014.long
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miRNAs and Stemness
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Fatica A, Bozzoni I Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014
Non-coding RNAs in development
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iPSCs
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Potential applications of iPSCs.
Stadtfeld M , Hochedlinger K Genes Dev. 2010;24:2239-2263
©2010 by Cold Spring Harbor Laboratory Press
Spinal muscular atrophy refers to a
group of autosomal recessive
neuromuscular disorders characterized
by degeneration of the anterior horn
cells of the spinal cord, leading to
symmetrical muscle weakness and
atrophy. SMA is the second most
common lethal, autosomal recessive
disease in Caucasians after cystic
fibrosis(Wirth, 2000).
spinal muscular atrophy type I (SMA I)
is caused by mutation or deletion in the
copy of the SMN gene, known as SMN1
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iPSCs
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Limiti
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Limiti
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Limiti
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Applicazioni
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SCNTs
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SCNTs
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SCNTs
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Cancer stem cell theory
• These CSCs cells persist in tumors as a
distinct population that likely causes
relapses and metastasis.
• This theory explains why are many cancers so difficult to treat.
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WRONG TARGET. Traditional cancer therapies (top) kill rapidly dividing tumor cells
(blue) but may spare stem cells (yellow) that can give rise to a new tumor. In theory, killing
cancer stem cells (bottom) should halt a tumor's growth lead to its disappearance.
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“Abbiamo finalmente un nuovo eccezionale obiettivo per la ricerca: le
staminali del cancro”, ha dichiarato oggi il Professor Umberto Veronesi, Direttore
Scientifico dell’Istituto Europeo di Oncologia di Milano, nell’ambito dell’annuale
presentazione dei risultati e dei programmi di ricerca dello IEO. “Le cellule staminali
tumorali non sono altro che cellule, più indifferenziate delle altre, che sono in grado di
alimentare la proliferazione del tumore. Sono in pratica il serbatoio dal quale il cancro si
approvvigiona. Essere capaci di intervenire su questo serbatoio potrebbe quindi
rappresentare la svolta finale per la soluzione globale del problema cancro.
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Applicazioni Cliniche
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Applicazioni Cliniche
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Applicazioni Cliniche
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Applicazioni Cliniche
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TERAPIA CELLULARE
Definizione di protocolli sperimentali e clinici mirati alla applicazione clinica di:
• -cellule staminali dell'epitelio corneale per la ricostruzione della superficie oculare in diverse patologie, quali ustioni chimiche e termiche associate a deficit di cellule staminali limbari;
• -cellule staminali dell'epidermide in diverse patologie cutanee, quali ustioni di terzo grado, ulcere croniche degli arti inferiori, malattie della pigmentazione;
• - cellule staminali dell'epitelio congiuntivale, uretrale e buccale per la cura di patologie quali distruzioni traumatiche dell’epitelio congiuntivale, sindrome dell’occhio secco, ipospadia posteriore, stenosi uretrali recidivanti, chirurgia ricostruttiva nella cecità dovuta a danni bilaterali della superficie oculare.
TERAPIA GENICA
• Definizione di protocolli sperimentali e clinici per la terapia genica di:
• - malattie genetiche della pelle (quali le diverse forme di epidermolisi bollosa e ittiosi lamellare)
• -malattie genetiche degli epiteli oculari (quali le diverse forme di distrofia corneale)
• mediante correzione ex-vivo di cellule staminali epiteliali.
Applicazioni Cliniche
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Applicazioni Cliniche
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Applicazioni Cliniche
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Applicazioni Cliniche
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Holoclar® è un prodotto di ingegneria dei tessuti per terapie avanzate consistente in
un epitelio corneale umano autologo ricostruito ex-vivo contenente cellule
staminali, indicato per la ricostruzione della superficie corneale in pazienti con
mancanza di cellule staminali limbari dovuta ad ustioni oculari.
Il principio attivo di Holoclar® è rappresentato dalle cellule staminali epiteliali in esso
contenute che, una volta attecchite, rigenerano in modo permanente l’epitelio
corneale ripristinandone la piena funzionalità e consentendo così il recupero della
capacità visiva.
Applicazioni Cliniche
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Applicazioni Cliniche
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Epidermolisi Bullosa
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Epidermolisi Bullosa
Type Number of subtypes
Inheritance of subtypes
Key genes affected
EBS ~ 12 subtypes dominant or recessive
Keratins 5, 14, Plectin
JEB ~ 6 subtypes recessive Collagen XVII, Integrin, Laminin
DEB ~ 13 subtypes dominant or recessive
Collagen VII
Types of epidermolysis bullosa (EB)
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Epidermolisi Bullosa
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• Applicazioni correnti: Adult Stem Cells
• Tantissime Potenzialità con la riprogrammazione nucleare
• Implementare la ricerca di base
To Take Home
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To Take Home