Description du projet
Comprendre la régulation de l’émergence des cellules souches hématopoïétiques avec les cellules souches pluripotentes induites
Les approches de thérapie génique utilisant des cellules souches hématopoïétiques (CSH) constituent des traitements innovants pour de nombreuses maladies, mais l’absence de protocoles d’expansion fiables pour les CSH limite les possibilités d’application de cette thérapie cellulaire. Les procédures ex vivo critiques requises pour l’ingénierie des CSH entraînent souvent une perte du potentiel de souche. Les cellules souches pluripotentes induites (CPI) spécifiques au patient pourraient constituer une source potentiellement illimitée de CSH. Le projet HSC-reNEW, financé par le CER, entend déterminer comment, au cours du développement embryonnaire, le programme d’expression génique des CSH est établi pour la première fois et découvrir les régulateurs moléculaires de l’auto-renouvellement des CSH, permettant ainsi une génération solide de CSH à partir de CPI. L’objectif est de développer des stratégies permettant de relancer le vaste programme d’autorenouvellement embryonnaire dans les CSH postnatales en vue d’une expansion in vitro.
Objectif
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.
Champ scientifique
- 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
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
20132 Milano
Italie