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Dissecting the molecular regulation of hematopoietic stem cell emergence using pluripotent stem cells to improve ex vivo therapies

Project description

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.


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.

Host institution

Net EU contribution
€ 2 000 000,00
20132 Milano

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Nord-Ovest Lombardia Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Total cost
€ 2 000 000,00

Beneficiaries (1)