I dati esposti all’interno di questa tesi definiscono il ruolo dei progenitori mesangiogenici nell’ambito della nicchia staminale mielomatosa.
Le MPCs, oggetto di studio da alcuni anni a questa parte, presentano una maggiore capacità angiogenica nei pazienti rispetto ai soggetti sani. Questa maggiore attività potrebbe dipendere dai pathways molecolari che la malattia attiva all’interno del midollo e che modulano anche le vie di Wnt cui fa capo il differenziamento delle MPCs.
La capacità differenziativa angiogenica, sorprendentemente riscontrata nelle supposte “early MSCs” avvalora l’ipotesi che, seppur sotto stimolo mesengenico, le MPCs patologiche attivino comunque un differenziamento angiogenico, come suggerito dall’indipendenza dal calmidazolo e dalla spiccata sensibilità al bortezomib in queste condizioni. Questo suggerisce che la malattia mielomatosa possa modificare il destino differenziativo delle cellule della linea mesangioblastica, forzandole maggiormente verso il “fate” angiogenico.
Le indagini sul ruolo delle cellule progenitrici mesangiogeniche non si possono ritenere concluse.
È necessario confermare la capacità della malattia mielomatosa di favorire ed implementare il potenziale angiogenico delle MPCs e stabilire una correlazione più forte tra l’attività di malattia e lo sprouting angiogenico. Sarebbe importante valutare la presenza di un’eventuale correlazione anche con patologie prive di impegno osseo, ma dotate di altri connotati clinici come ad esempio il danno renale.
Infine, risulta fondamentale capire quanto le modifiche operate dalla patologia sul microambiente possano condizionare il destino differenziativo cellulare. Sarebbe auspicabile programmare degli esperimenti volti a valutare la capacità di sprouting delle “late MSCs” (P2); se anche queste cellule presentassero capacità differenziante angiogenica si potrebbe sostenere la capacità del Mieloma Multiplo di modificare il destino cellulare al fine di garantire la proliferazione della neoplasia stessa.
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70
RINGRAZIAMENTI
Desidero esprimere la mia profonda gratitudine al Professor Mario Petrini per avermi fatto appassionare all’Ematologia ed avermi affidato questo progetto di tesi, che mi ha permesso di cimentarmi nell’attività di ricerca.
Un ringraziamento di cuore al mio correlatore Dott. Gabriele Buda per il grande supporto, la pazienza e l’impegno profusi nell’accompagnare parte del mio, ancora lungo, percorso di crescita professionale e personale.
Allo stesso modo voglio ringraziare la Dott.ssa Marina Montali, il Dott. Simone Pacini, la Dott.ssa Serena Barachini e la Dott.ssa Francesca Margherita Panvini per avermi accolto nel Laboratorio di Manipolazione Cellulare e per la loro infinita disponibilità nel supportarmi e dirimere i miei dubbi.
Un importante ringraziamento va a tutta la U.O. di Ematologia Universitaria per la grande disponibilità dimostrata. Ringrazio sentitamente il Professor Federico Papineschi, il Dott. Enrico Orciuolo, il Dott. Francesco Caracciolo, il Dott. Giovanni Consani, il Dott. Edoardo Benedetti, il Dott. Carulli, la Dott.ssa Claudia Baratè, la Dott.ssa Sara Galimberti e tutti gli specializzandi: la Dott.ssa Francesca Martini, la Dott.ssa Rita Tavarozzi, il Dott. Francesco Mazziotta per i loro insegnamenti e preziosissimi consigli.
Un ringraziamento profondo va a mia madre ed a mio padre per tutto quello che hanno fatto per me in questi anni, per avermi dato senza chiedere mai e perché solo un albero con delle radici solide può crescere rigoglioso ed io posso contare su delle radici straordinarie. La mia riconoscenza non sarà mai abbastanza.
Ringrazio tutta la mia famiglia perché ciascuno di loro è parte di me ed i miei nonni che mi hanno tramandato tanti fondamentali insegnamenti di vita.
Grazie a tutti i miei amici: a Chiara e Fabiola, sorelle scelte con cui ho condiviso tutto in 13 anni di amicizia. Il loro sostegno in questi anni è stato imprescindibile e prezioso, sono riuscite a starmi accanto in ogni momento nonostante la distanza, le mie assenze e le mie pecche. Un semplice grazie non basta, ma credo conoscano la reale essenza di queste poche righe.
Ringrazio Matteo e Carlo per la loro gentilezza, la loro comprensione, l’aiuto e le belle parole che spesso hanno speso per me. Un doveroso ringraziamento va ad Annalisa, Alessia, Niko e Antonio che hanno aspettato questo grande giorno con me (e forse più di me), sostenendomi nonostante i continui impegni. In generale devo dire grazie a tutti i miei amici che hanno sempre fatto il tifo “per la loro amica dottoressa” e hanno saputo rendere più leggero questo lungo percorso.
71
Ringrazio tutte le meravigliose persone che ho conosciuto qui a Pisa e che hanno reso questa città la mia seconda casa. Grazie a Marta e e Ludovica compagne di studio e di vita con cui ho condiviso interamente questi sei anni e grazie alle quali sono maturata, anche in questo caso la mia gratitudine va ben oltre le parole.
Grazie a Virginia che è stata una grande fonte di stimoli positivi ed energia soprattutto negli ultimi due anni.
Un ringraziamento speciale va ad Adele, con la quale condivido tanti, forse anche troppi, pensieri. Grazie anche a Francesca, con la quale condivido la passione per l’Ematologia, a Ilaria, a Letizia ed a Giorgio: diventati pian piano parti fondamentali della mia vita. A tutti loro mi lega un profondo affetto ed una stima incondinzionata.
Ringrazio i miei coinquilini: Gabriele, Domitilla e Domenico per il meraviglioso clima d’affetto ed unità che hanno saputo creare nella nostra casa. Un ringraziamento particolare a Domenico per tutti i momenti in cui ha trovato il tempo di ascoltarmi e di spronarmi, a Gabriele per avermi spinto a riflettere su me stessa ed a Domitilla per avermi sempre manifestato il suo affetto. Per ultimo voglio ringraziare Giordano, instancabilmente al mio fianco da sei anni, con costanza, pazienza ed amore. È una delle colonne portanti della mia vita, fonte inesauribile di sostegno, consigli, aiuti e stimoli a migliorare. Purtroppo queste poche righe non bastano per esprimere totalmente la mia riconoscenza, pertanto mi affido alla sua conoscenza del reale significato di questo ringraziamento.