During hematopoiesis, the bone marrow microenvironment triggers specific signalling in hematopoietic stem cells (HSCs), inducing their differentiation into multiple immune lineages. A main constraint in the field is the lack of human in vitro models to recapitulate this process and provide mechanistic insights into the early steps of immune cell differentiation. I propose an innovative, multidisciplinary approach to decode the role of the bone marrow microenvironment in shaping cell identity and function. I will define the essential cellular niche driving HSC to B-cell differentiation in the developing human bone marrow by analysing single-cell genomics datasets. This reference will guide the engineering of feeder cells (human bone marrow-like-stromal cells, hBMLSCs) from human induced pluripotent stem cells (hiPSCs) using synthetic biology tools. Finally, I will design novel 3D-cultures to co-culture my engineered feeder cells and HSCs, and induce their differentiation towards the B-cell lineage. My proposal combines single-cell and computational technologies with cell and tissue engineering to provide the first artificial bone marrow model in humans. This model promises to transform the study of hematological disease and pave the way to a new era in immunotherapies. In addition, the experimental and computational framework will guide the future improvement of in vitro models using single-cell genomics data.