B-1 lymphocytes are a small but unique component of the innate immune-like cells. However, their ontogenic origin is still a matter of debate. While it is widely accepted that B-1 cells originate early in fetal life, whether or not they arise from hematopoietic stem cells (HSCs) is still unclear.

In order to shed light on the B-1 cell origin, we set out to determine whether their lineage specification is dependent on Notch signaling, which is essential for the HSC generation and therefore, all derivatives lineages. Using mouse embryonic stem cells (mESCs) to recapitulate murine embryonic development, we have studied the requirement for Notch signaling during the earliest B-lymphopoiesis and found that Rbpj-deficient mESCs are able to generate B-1 cells. Their Notch-independence was confirmed in ex vivo experiments using Rbpj-deficient embryos. In addition, we found that upregulation of Notch signaling induced the emergence of B-2 lymphoid cells. Taken together, these findings indicate that control of Notch signaling dosage is critical for different B-cell lineages specification from endothelial cells and provides pivotal information for their in vitro generation from PSCs for therapeutic applications.

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