Role of Tagln-Expressing Cells in Hypoxia-Mediated Disruption of B Cell Development 4523

Abstract Description Bone marrow (BM) microenvironments support B lymphocyte development, but the impact of hypoxia pathway dysregulation in specific niche components remains unclear. Previous studies using a constitutive Vhl knockout in osteocytes (Dmp1-Cre; Vhlfl/fl) showed BM occlusion, leaky vasculature, and reduced B cell development due to microenvironmental changes. However, current models cannot study Vhl deficiency’s impact on immune cell development in postnatal BM. Pre-osteoblasts (Tagln-expressing osteocyte precursors) support B cell maturation, but their specific roles remain unclear. We developed inducible Tagln-driven Vhl conditional knockout (iVhlcKO) mouse models to investigate early-stage osteoblasts and arterioles in B cell development. Tagln-ERT2-Cre;Vhlfl/fl mice allowed temporal Vhl deletion in pre-osteoblasts, while Tagln-ERT2-Cre;Ai213;Vhlfl/fl mice (iVhlcKOr) enabled in vivo visualization of these cells via GFP labeling. In iVhlcKOr mice, Vhl deletion reduced BM B cell frequencies at 30 weeks post-induction. Live imaging and flow cytometry revealed altered interactions between B cell progenitors and hypoxia-affected Tagln+ niches. As Tagln also marks arterial smooth muscle cells, iVhlcKO models may uncover arterioles’ novel roles in B cell development. These findings highlight the critical role of Tagln-expressing cells in maintaining BM homeostasis and how hypoxic stress disrupts immune cell development, providing insights into the skeletal-immune system interplay. Funding Sources NIH R21AI156469-01 Topic Categories Hematopoiesis and Immune System Development (HEM)