PRELEUKMEC · Deciphering the intrinsic and extrinsic mechanisms shaping aging and leukemic evolution of hematopoietic stem cells at the single cell level

Deciphering the intrinsic and extrinsic mechanisms shaping aging and leukemic evolution of hematopoietic stem cells at the single cell level

Hematopoiesis is the production of all blood cellular components, which are derived from hematopoietic stem and progenitor cells (HSPCs) in a stepwise process. Proper regulation of HSPCs behavior is essential for lifelong blood production, immune function and tissue oxygenation. As individuals age, somatic mutations accumulate in HSPCs. Some mutations will confer a proliferative advantage to certain clones in the hematopoietic hierarchy, allowing them to expand disproportionately. This phenomena known as, Clonal Hematopoiesis (CH) is defined as the expansion of HSPCs, harboring specific, disruptive, and recurrent genetic variants, among individuals without clear diagnosis of hematological malignancies. CH is a significant risk factor for hematological malignancies such as Acute Myeloid Leukemia (AML) and Myelodysplastic syndrome (MDS), but also for cardiovascular diseases and all-causes mortality. The objective of this project was to investigate the impact of aging and of disease-associated mutations on human HSPCs, focusing on how they affect lineage commitment and transcriptional programs under varying microenvironmental conditions. As, the project faced challenges related to geopolitical instability, we mainly focused on developing a robust experimental and computational system to deeply characterize normal human HSPC differentiation at single-cell and clonal resolution.Using an innovative lineage-tracing assay combined with single-cell RNA sequencing, we generated the most comprehensive reference map of healthy HSPCs differentiation to date. Establishing this robust baseline is a necessary prerequisite for confidently detecting and interpreting how disease-associated mutations alter hematopoiesis in patient-derived samples. This map captures dynamic clonal trajectories, reveals novel progenitor populations, and uncovers key features of HSPCs biology. Specifically, we showed that HSPCs clones are stochastically driven as they frequently bifurcate into multiple myeloid lineages amid homogeneous signals. At the molecular level, we uncovered evidence of clonal memory extending beyond the differentiation state, including a striking inter-clonal variability in the absolute rate of differentiation. Altogether, we provide an essential baseline for better understanding the dynamics of human HSPCs, with broad application to both healthy individual and patients with hematological disorders. This foundational work not only advances scientific understanding of human blood development but also establishes a critical resource for future studies of hematological diseases. By equipping researchers with high-resolution tools to dissect HSPC fate decisions, the project paves the way for improved modeling of clonal hematopoiesis and blood cancers. The results contribute to European strategies aiming to promote health research innovation and strengthen personalized medicine approaches. Ultimately, this work supports long-term goals of enhancing diagnosis, treatment, and patient outcomes for blood disorders, addressing a significant societal and healthcare challenge.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз