Dissecting and targeting hematopoiesis and HSC-niche interactions in diseases associated with erythropoietic stress

A novel picture of hematopoietic hierarchy has been disclosed by single-cell analysis, revealing a dynamic cell flux model, based on transitional states, rather than a static differentiation landscape. Thus, the organization of hematopoietic subpopulations has been re-defined in healthy bone marrow (BM) but remains still underexplored in diseases affecting hematopoietic stem cell (HSC) progeny. As a paradigm of a naturally occurring stress condition, we will focus on ß-thalassemia (Bthal) where we demonstrated HSC impairment due to a defective BM niche. HSC lentiviral (LV)-mediated gene therapy (GT) of Bthal resulted in transfusion independence in patients with a positive correlation between proportion of in vivo engrafting corrected HSCs and degree of anemia correction. However, the rescue of ineffective erythropoiesis, which is associated with clinical complications, was not achieved. Variability in terms of HSC transduction and in vivo reconstitution poses limitations for clinical outcome and the status of BM microenvironment influences the quality of HSC, harvested for genetic engineering, and supports its engraftment and reconstitution capacity once transplanted. Thus, the comprehension of the hematopoietic hierarchy and the mutual interactions between the niche component and HSC in non-malignant diseases offers new avenues to improve GT and develop combined transplantation approaches. In this project we will aim: 1) to dissect molecular and cellular factors regulating the shape of hematopoiesis in erythropoietic diseases providing valuable clues to design therapeutic approaches combining genetic correction with restoration of erythroid maturation allowing a full rescue of disease hallmarks; 2) to define key elements (cellular and molecular) of altered HSC-niche regulation in Bthal and in other anemias for the development of strategies to rescue normal BM homeostasis; 3) to improve GT outcome by exploiting combined strategies based on novel insight of HSC-niche biology.