Project description DEENESFRITPL Understanding the regulation of haematopoietic stem cell emergence with induced pluripotent stem cells Gene therapy approaches using haematopoietic stem cells (HSCs) represent innovative treatments for many diseases, but the absence of reliable expansion protocols for HSCs limits the application possibilities of this cell therapy. The critical ex vivo procedures required for HSC engineering often result in loss of stemness potential. Patient-specific induced pluripotent stem cells (PSCs) could provide a potentially unlimited source of HSCs. The ERC-funded HSC-reNEW project aims to determine how during embryonic development the HSC gene expression programme is first established and uncover the molecular regulators of HSC self-renewal, enabling robust generation of HSCs from PSCs. The objective is to develop strategies to restart the extensive embryonic self-renewal programme in postnatal HSCs for in vitro expansion. Show the project objective Hide the project objective Objective 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. Fields of science medical and health sciencesmedical biotechnologygenetic engineeringgene therapynatural sciencesbiological sciencesdevelopmental biologymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicinehematologymedical and health sciencesclinical medicinetransplantation Programme(s) HORIZON.1.1 - European Research Council (ERC) Main Programme Topic(s) ERC-2021-COG - ERC CONSOLIDATOR GRANTS Call for proposal ERC-2021-COG See other projects for this call Funding Scheme ERC - Support for frontier research (ERC) Host institution OSPEDALE SAN RAFFAELE SRL Net EU contribution € 2 000 000,00 Address VIA OLGETTINA 60 20132 Milano Italy See on map Region Nord-Ovest Lombardia Milano Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 000 000,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all OSPEDALE SAN RAFFAELE SRL Italy Net EU contribution € 2 000 000,00 Address VIA OLGETTINA 60 20132 Milano See on map Region Nord-Ovest Lombardia Milano Activity type Private for-profit entities (excluding Higher or Secondary Education Establishments) Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 2 000 000,00