Deletion of Vhl in Dmp1-Expressing Cells Causes Microenvironmental Impairment of B Cell Lymphopoiesis.
Deletion of Vhl in Dmp1-Expressing Cells Causes Microenvironmental Impairment of B Cell Lymphopoiesis.
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DOI：
10.3389/fimmu.2022.780945
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发表时间：
2022
影响因子：
7.3
通讯作者：
Manilay JO
中科院分区：
文献类型：
--
作者：
Chicana B;Abbasizadeh N;Burns C;Taglinao H;Spencer JA;Manilay JO
骨骼细胞对骨髓（BM）中B细胞发育过程的贡献尚未完全描述。von-Hippel Lindau蛋白（VHL）在细胞对缺氧的反应中发挥关键作用。先前的工作表明，Dmp 1-Cre; Vhl条件性敲除小鼠（VhIcKO），其在间充质干细胞、晚期成骨细胞和骨细胞的亚群中缺失Vhl，显示出骨生长失调和B细胞减少。在这里，我们研究了B细胞缺陷的机制，使用流式细胞术和高分辨率成像。在VhIcKO BM中，B细胞祖细胞的频率和数量增加，而哈代级分B-F减少。VhIcKO级分B-C细胞显示增加的凋亡和静止。相互BM嵌合体证实了VhIcKO B细胞缺陷的B细胞外源性来源。为了支持这一点，VhIcKO BM上清液含有降低的CXCL 12和升高的EPO水平。活体和离体成像显示VhIcKO BM血管具有增加的直径、体积和减少的血液-BM屏障。用细胞内缺氧标记物对VhlcKO B细胞进行染色表明局部氧张力不同的不同B细胞微环境的天然存在，并且VhlcKO BM中的B细胞发育缺陷不是由缺氧引发的。我们的研究确定了新的机制，改变骨稳态与剧烈的BM微环境变化，失调B细胞的发展。
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 deletes Vhl in subsets of mesenchymal stem cells, 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 supernatant contained reduced CXCL12 and elevated EPO levels. Intravital and ex vivo imaging revealed VhlcKO BM blood vessels with increased diameter, volume, and a diminished blood-BM barrier. 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 and that the B cell developmental defects in VhlcKO BM are not initiated by hypoxia. Our studies identify novel mechanisms linking altered bone homeostasis with drastic BM microenvironmental changes that dysregulate B cell development.
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DOI：
10.1084/jem.20042393
发表时间：
2005-03-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dias S;Silva H Jr;Cumano A;Vieira P
通讯作者：
Vieira P
影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
64.8
作者：
Cho, Sung Hoon;Raybuck, Ariel L.;Stengel, Kristy;Wei, Mei;Beck, Thomas C.;Volanakis, Emmanuel;Thomas, James W.;Hiebert, Scott;Haase, Volker H.;Boothby, Mark R.
通讯作者：
Boothby, Mark R.
影响因子：
5.4
作者：
Balciunaite, G;Ceredig, R;Rolink, AG
通讯作者：
Rolink, AG
小鼠CRE模型用于研究骨骼疾病。
影响因子：
4.3
作者：
Dallas SL;Xie Y;Shiflett LA;Ueki Y
通讯作者：
Ueki Y