Modeling human B cell development with pluripotent stem cells

Summary The ability to generate functional B cells from human pluripotent stem cells (hPSCs) would open new opportunities to develop novel B cell-based therapies to treat a range of human diseases and disorders. Towards this goal, we established a protocol that promotes the efficient development of B lineage cells from definitive hematopoietic progenitors generated from different hPSC lines. Flow cytometric and multi-omic scRNA-seq analyses revealed that B cell development from hPSCs transitions through the well-established pro-B, pre-B and naïve B cell stages, accurately recapitulating B lymphopoiesis in the human adult bone marrow. Importantly, the naïve B cells generated with this approach could be induced to mature into plasma cells that secrete antibodies and undergo class switching. Analyses of signaling pathways that regulate B lymphopoiesis in these cultures uncovered a potent inhibitory effect of IL-7 on functional IgH rearrangement, resulting in the development of abnormal cells that failed to undergo pre-B cell maturation. Finally, analysis of the different hPSC-derived hematopoietic programs revealed that both definitive and yolk sac progenitors display B cell potential, indicating that there are distinct developmental sources of human B lineage cells. Taken together, these findings demonstrate the efficient generation of B cells from hPSCs and, in doing so, provide a system for further investigating the earliest stages of human B lymphopoiesis and a source of appropriately staged plasma cells for future therapeutic applications. Competing Interest Statement Sana Biotechnology has licensed intellectual property of D.B. and Washington University in St. Louis. Jasper Therapeutics and Inograft Therapeutics have licensed intellectual property of D.B. and Stanford University. D.B. served on an advisory panel for GlaxoSmithKline on COVID-19 therapeutic antibodies. D.B. serves as a consultant for Hogan Lovells. D.B. serves on the scientific advisory board for Hillevax. D.B. is a scientific cofounder of Aleutian Therapeutics.