Descrizione del progetto
Cellule staminali pluripotenti indotte per comprendere la regolazione della comparsa delle cellule staminali ematopoietiche
Sebbene gli approcci di terapia genica che si avvalgono delle cellule staminali ematopoietiche (HSC, Haematopoietic Stem Cell) costituiscano trattamenti innovativi per numerose malattie, l’assenza di protocolli di espansione affidabili per tali cellule limita le possibilità applicative per questo tipo di terapia cellulare. Le procedure critiche ex vivo richieste per l’ingegneria delle HSC comportano spesso la perdita di potenziale in termini di staminalità. Le cellule staminali pluripotenti indotte specifiche per paziente potrebbero fornire una fonte potenzialmente illimitata di HSC. Il progetto HSC-reNEW, finanziato dal CER, si propone di determinare le modalità con cui il programma di espressione genica delle HSC viene stabilito nella fase iniziale di sviluppo dell’embrione e di svelare i regolatori molecolari dell’auto-rinnovamento delle HSC, consentendo di realizzare una solida generazione di queste cellule a partire da cellule staminali pluripotenti indotte. L’obiettivo è quello di sviluppare strategie volte a riavviare l’ampio programma di auto-rinnovamento dell’embrione delle HSC postnatali per l’espansione in vitro.
Obiettivo
Although hematopoietic stem cell (HSCs) transplantation is routinely used to treat blood disorders, immune incompatibility and donor shortage remain critical clinical barriers. Likewise, since high number of HSCs are needed for successful transplants, the absence of reliable expansion protocols prevents the wider application of this cell therapy. In fact, while HSC-based gene therapy represents a revolutionary treatment also for novel and unexpected indications, the ex vivo manipulation required for HSCs engineering results in loss of their stemness potential. Patient-specific induced pluripotent stem cells (PSCs) could serve as a solution to these problems, as they would provide a potentially unlimited, easy to engineer, source of immunologically matched HSCs. However, despite recent advances, the robust de novo generation of HSCs remains unrealized due to an incomplete understanding of how HSCs are generated during embryonic development, a process that, as such, cannot be accurately recapitulated in vitro. To tackle these issues, in this proposal we will leverage on our proven expertise in PSC differentiation and hematopoietic development. In particular, we will use innovative in vitro assays and systematic measurements to determine at the molecular level how HSC precursors control their gene expression to generate blood cells (Aim 1). Combining the study of the highly proliferative emerging embryonic HSCs with a CRISPR-based gain-of-function screen, we will uncover the molecular regulators of the extensive embryonic self-renewal, thus enabling robust specification of HSCs from PSCs (Aim 2). We will design strategies to resurrect this embryonic self-renewal program in postnatal HSCs for their in vitro expansion (Aim 3). The successful completion of these studies will accomplish the long-standing goals of generating and expanding HSCs in vitro, allowing the fully exploitation of the transformative therapeutic potential of HSC-based cell and gene therapies.
Campo scientifico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesdevelopmental biology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicinehematology
- medical and health sciencesclinical medicinetransplantation
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
ERC - Support for frontier research (ERC)Istituzione ospitante
20132 Milano
Italia