Normal HematopoiesisBLOS2 maintains hematopoietic stem cells in the fetal liver via repressing Notch signaling

- Bloc1s2 expression is enriched in lineage negative, Sca 1 positive, c-kit negative cells of E13.5 FL.
- Bloc1s2 is essential for hematopoietic stem cell maintenance in E13.5 FL.
- Elevated notch signaling accounts for hematopoietic defects in Bloc1s2−/− FL.

During development, hematopoietic stem cells (HSCs) undergo a rapid expansion in the fetal liver (FL) after their emergence in the aorta-gonad-mesonephros (AGM) region. We recently reported that the endolysosomal trafficking factor BLOS2, encoded by the Bloc1s2 gene, regulates HSC/hematopoietic progenitor cell emergence in the AGM region; however, whether it plays a role in the FL remains unknown. Here, we show that BLOS2 plays an essential role in the regulation of HSC proliferation and differentiation in the FL. Bloc1s2 depletion leads to elevated Notch signaling, with an increased frequency but weakened self-renewal ability of FL HSCs. Functional assays show that Bloc1s2−/− FL HSCs harbor impaired lymphoid and myeloid differentiation abilities. These findings reveal that balanced control of Notch signaling by BLOS2 is required for HSC homeostasis during FL hematopoiesis.