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bioRxiv · 10.1101/2021.09.10.459794

Deletion of Vhl in Dmp1-expressing cells causes microenvironmental impairment of B cell lymphopoiesis

Chicana, B.·Abbasizadeh, N.·Burns, C.·Taglinao, H.·Spencer, J. A.·Manilay, J. O.
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Abstract

The contributions of skeletal cells to the processes of B cell development in the bone marrow (BM) have not been completely described. The von-Hippel Lindau protein (VHL) plays a key role in cellular responses to hypoxia. Previous work showed that Dmp1-Cre;Vhl conditional knockout mice (VhlcKO), which delete Vhl in late osteoblasts and osteocytes, display dysregulated bone growth and reduction in B cells. Here, we investigated the mechanisms underlying the B cell defects using flow cytometry and high-resolution imaging. In the VhlcKO BM, B cell progenitors were increased in frequency and number, whereas Hardy Fractions B-F were decreased. VhlcKO Fractions B-C cells showed increased apoptosis and quiescence. Reciprocal BM chimeras confirmed a B cell-extrinsic source of the VhlcKO B cell defects. In support of this, VhlcKO BM serum contained reduced CXCL12 and elevated EPO levels. Staining of VhlcKO B cells with an intracellular hypoxic marker indicated the natural existence of distinct B cell microenvironments that differ in local oxygen tensions. Additionally, intravital and ex vivo imaging revealed VhlcKO BM blood vessels with increased diameter, frequency, volume, and a diminished blood-BM barrier. Our studies identify novel mechanisms linking altered bone homeostasis with drastic BM microenvironmental changes that dysregulate B cell development.

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Chicana, B., Abbasizadeh, N., Burns, C., Taglinao, H., Spencer, J. A., Manilay, J. O.. 2021-09-11. Deletion of Vhl in Dmp1-expressing cells causes microenvironmental impairment of B cell lymphopoiesis. https://doi.org/10.1101/2021.09.10.459794

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