Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada.
Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Laval, QC, Canada; Centre d'Excellence de Recherche sur les Maladies Orphelines - Fondation Courtois (CERMO-FC), Montreal, QC, Canada.
Stem Cell Reports. 2022 Oct 11;17(10):2303-2317. doi: 10.1016/j.stemcr.2022.08.004. Epub 2022 Sep 8.
Emergency hematopoiesis involves the activation of bone marrow hematopoietic stem/progenitor cells (HSPCs) in response to systemic inflammation by a combination of cell-autonomous and stroma-dependent signals and leads to their release from bone marrow and migration to periphery. We have previously shown that FZD6 plays a pivotal role in regulating HSPC expansion and long-term maintenance. Now we sought to better understand the underlying mechanisms. Using lipopolysaccharide (LPS)-induced emergency granulopoiesis as a model, we show that failed expansion was intrinsic to FZD6-deficient HSPCs but also required a FZD6-deficient environment. FZD6-deficient HSPCs became more strongly activated, but their mobilization to peripheral blood was impaired and they were more susceptible to inflammatory cell death, leading to enhanced release of pro-inflammatory cytokines in the marrow. These studies indicate that FZD6 has a protective effect in the bone marrow to prevent an overactive inflammatory response and further suggest that mobilization improves HSPC survival during bone marrow inflammation.
应急造血涉及骨髓造血干细胞/祖细胞（HSPCs）在全身性炎症反应下通过细胞自主和基质依赖信号的组合被激活，并导致它们从骨髓中释放出来并迁移到外周。我们之前已经表明，FZD6 在调节 HSPC 扩增和长期维持中起着关键作用。现在我们试图更好地理解潜在的机制。我们使用脂多糖（LPS）诱导的应急粒系生成作为模型，表明 FZD6 缺陷的 HSPC 中扩增失败是内在的，但也需要 FZD6 缺陷的环境。FZD6 缺陷的 HSPCs 被更强烈地激活，但它们向外周血的动员受损，并且更容易受到炎症细胞死亡的影响，导致骨髓中促炎细胞因子的释放增加。这些研究表明，FZD6 在骨髓中具有保护作用，以防止过度活跃的炎症反应，并进一步表明动员改善了骨髓炎症期间 HSPC 的存活。
