Human B-lymphopoiesis: Clinical challenges in B cell reconstitution and advances in in vitro modeling

• We revise the clinical occurrence of persistent B cell aplasia and hypogammaglobulinemia upon B cell deple on. • We summarize the impact of the bone marrow niche on B lymphopoiesis. • We describe the state of the art in in vitro modeling of human B cell development from feeder-based, feeder-free and iPSC cultures to bone marrow organoid models. The B cell compartment is maintained by continuous replenishment from hematopoietic stem cells (HSCs) and multipotent progenitors, as well as from B cell precursors. B cell depletion is a common therapeutic approach, not only in the context of B cell malignancies, but also in autoimmunity. The targeted elimination of B cells can be achieved through the use of chimeric antigen receptor (CAR)-T cells or monoclonal antibodies or bispecific antibodies that target both B and NK cells or B and T cells. When B cells are depleted, repopulation from bone marrow precursors occurs within three months to one year, following ontogeny. Nevertheless, prolonged B cell aplasia is observed in some patients and is associated with a progressive reduction of serum immunoglobulins and an increased susceptibility to infections. The mechanisms underlying such defects in B cell replenishment remain to be fully elucidated and studies on human B lymphopoiesis are needed in this context. Mouse models can be helpful in studying mechanisms of B cell development and the role of multiple (B cell-specific) genes in this process; however, they do not always mirror the human developmental dynamics and signals. Hence further tools are needed to study human B lymphopoiesis defects. In this review, we summarize the reported studies and cases of prolonged B cell aplasia following B cell depletion and discuss potential underlying causes. We then provide a comprehensive overview of the various in vitro models that can be used to study the dynamic of B lymphopoiesis to dissect B cell developmental defects in humans.