Improving cell-based therapy in Sickle Cell Disease: study of hematopoietic stem cells and progenitors

Abstract

The bone marrow microenvironment and its cellular and molecular complexity in sickle cell anemia (SCA) are still poorly understood. SCA is a genetic disease characterized by the synthesis of an altered hemoglobin, HbS. Under hypoxia, HbS polymerizes and results in hemolysis and episodes of vaso-occlusion, leading to important clinical complications, with evident inflammation. The consequences of the constant inflammatory process of SCA, and the conventional treatment (hydroxyurea and transfusion) for the hematopoietic microenvironment, specifically for hematopoietic stem and progenitor cells (HSPCs) are not yet clear. This proposal aims to evaluate the molecular heterogeneity of HSPCs (CD34 +) in the bone marrow of patients with SCA. For that, an integrative approach of gene and protein expression, at the level of individual cells (single-cell RNA sequencing), will be used to understand the effects of systemic inflammation and the action of HU on hematopoiesis. This approach has a translational potential, mainly by assessing the quality of HSPCs for gene therapies, in the context of diseases such as SCA. The results expected in this project may provide the basis for new strategies and therapeutic targets for improving the quality of life of patients, as well as curing SCA. (AU)