Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization.
Lymphoid differentiation of hematopoietic stem cells requires efficient Cxcr4 desensitization.
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DOI：
10.1084/jem.20160806
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发表时间：
2017-07-03
期刊：
影响因子：
--
通讯作者：
Balabanian K
中科院分区：
文献类型：
--
作者：
Freitas C;Wittner M;Nguyen J;Rondeau V;Biajoux V;Aknin ML;Gaudin F;Beaussant-Cohen S;Bertrand Y;Bellanné-Chantelot C;Donadieu J;Bachelerie F;Espéli M;Dalloul A;Louache F;Balabanian K
Freitas等人使用携带天然存在的WHIM综合征相关功能获得性Cxcr 4突变的小鼠模型，表明Cxcr 4脱敏对于小鼠短期造血干细胞的静止/循环平衡及其分化为多能和下游淋巴偏向祖细胞至关重要。CXCL 12/CXCR 4信号传导在促进造血干细胞和祖细胞（HSPC）在骨髓中的滞留和静止中发挥主导作用。影响受体同源脱敏的功能获得性CXCR 4突变已在WHIM综合征（WS）中报道，这是一种以淋巴细胞减少为特征的罕见免疫缺陷。其背后的机制仍不清楚。使用具有天然存在的WS相关功能获得性Cxcr 4突变的小鼠模型，我们探索了WS中淋巴细胞减少症由HSPC水平缺陷引起的可能性。我们报道了Cxcr 4脱敏是小鼠短期造血干细胞的静止/循环平衡及其分化为多能和下游淋巴偏向祖细胞所必需的。Cxcr 4脱敏的改变导致5例WS患者循环HSPCs减少。这在WS小鼠中也得到了证实，并通过HSPCs在脾脏中的积累反映出来，我们观察到髓外造血增强。因此，有效的Cxcr 4脱敏对于HSPC的淋巴样分化至关重要，并且其损伤是支持在小鼠中以及可能在WS患者中观察到的淋巴细胞减少症的关键机制。
Using a mouse model harboring a naturally occurring WHIM syndrome–linked gain-of-function Cxcr4 mutation, Freitas et al. show that Cxcr4 desensitization is critical for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. The CXCL12/CXCR4 signaling exerts a dominant role in promoting hematopoietic stem and progenitor cell (HSPC) retention and quiescence in bone marrow. Gain-of-function CXCR4 mutations that affect homologous desensitization of the receptor have been reported in the WHIM Syndrome (WS), a rare immunodeficiency characterized by lymphopenia. The mechanisms underpinning this remain obscure. Using a mouse model with a naturally occurring WS-linked gain-of-function Cxcr4 mutation, we explored the possibility that the lymphopenia in WS arises from defects at the HSPC level. We reported that Cxcr4 desensitization is required for quiescence/cycling balance of murine short-term hematopoietic stem cells and their differentiation into multipotent and downstream lymphoid-biased progenitors. Alteration in Cxcr4 desensitization resulted in decrease of circulating HSPCs in five patients with WS. This was also evidenced in WS mice and mirrored by accumulation of HSPCs in the spleen, where we observed enhanced extramedullary hematopoiesis. Therefore, efficient Cxcr4 desensitization is critical for lymphoid differentiation of HSPCs, and its impairment is a key mechanism underpinning the lymphopenia observed in mice and likely in WS patients.
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影响因子：
64.8
作者：
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DOI：
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发表时间：
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影响因子：
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