Evidence that a lipolytic enzyme--hematopoietic-specific phospholipase C-β2--promotes mobilization of hematopoietic stem cells by decreasing their lipid raft-mediated bone marrow retention and increasing the promobilizing effects of granulocytes.
Evidence that a lipolytic enzyme--hematopoietic-specific phospholipase C-β2--promotes mobilization of hematopoietic stem cells by decreasing their lipid raft-mediated bone marrow retention and increasing the promobilizing effects of granulocytes.
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脂解酶 - 毛 - 毛 - 毛 - 霍普生特异性磷脂酶C-β2-促进造血干细胞的动员，通过减少其脂质筏介导的骨髓保留率并增加颗粒细胞的宣传作用。
DOI：
10.1038/leu.2015.315
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发表时间：
2016-04
期刊：
影响因子：
11.4
通讯作者：
Ratajczak MZ
中科院分区：
文献类型：
--
作者：
Adamiak M;Poniewierska-Baran A;Borkowska S;Schneider G;Abdelbaset-Ismail A;Suszynska M;Abdel-Latif A;Kucia M;Ratajczak J;Ratajczak MZ
造血干/祖细胞（HSPCs）存在于骨髓（BM）微环境中，并通过膜脂筏相关受体（如α-趋化因子受体CXCR 4和α4β1-整合素）的相互作用保留在那里（VLA-4，极晚期抗原4受体）受体，与它们各自的特异性配体基质衍生因子1和血管细胞粘附分子1，在BM干细胞龛中表达。含有这些受体的脂筏的完整性由糖脂糖基磷脂酰肌醇锚（GPI-A）维持。据报道，激活的补体级联的第五组分C5 a的切割片段在动员HSPC进入外周血（PB）中具有重要作用，其通过（i）诱导BM驻留的粒细胞的脱粒和（ii）促进它们从BM进入PB，使得它们透化内皮屏障用于HSPC的后续排出。我们在这里报告，造血细胞特异性磷脂酶C-β2（PLC-β2）在HSPCs的药理动员中起着至关重要的作用。一方面，当在粒细胞脱粒过程中释放时，它会破坏GPI-A，从而破坏膜脂筏并损害HSPC在BM小生境中的保留。另一方面，它是粒细胞脱粒及其从BM排出所需的细胞内酶。为了支持这种双重作用，我们证明PLC-β2基因敲除小鼠是较差的动员者，并首次提供了这种脂解酶参与HSPC动员的证据。
Hematopoietic stem/progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment and are retained there by the interaction of membrane lipid raft-associated receptors, such as the α-chemokine receptor CXCR4 and the α4β1-integrin (VLA-4, very late antigen 4 receptor) receptor, with their respective specific ligands, stromal-derived factor 1 and vascular cell adhesion molecule 1, expressed in BM stem cell niches. The integrity of the lipid rafts containing these receptors is maintained by the glycolipid glycosylphosphatidylinositol anchor (GPI-A). It has been reported that a cleavage fragment of the fifth component of the activated complement cascade, C5a, has an important role in mobilizing HSPCs into the peripheral blood (PB) by (i) inducing degranulation of BM-residing granulocytes and (ii) promoting their egress from the BM into the PB so that they permeabilize the endothelial barrier for subsequent egress of HSPCs. We report here that hematopoietic cell-specific phospholipase C-β2 (PLC-β2) has a crucial role in pharmacological mobilization of HSPCs. On the one hand, when released during degranulation of granulocytes, it digests GPI-A, thereby disrupting membrane lipid rafts and impairing retention of HSPCs in BM niches. On the other hand, it is an intracellular enzyme required for degranulation of granulocytes and their egress from BM. In support of this dual role, we demonstrate that PLC-β2-knockout mice are poor mobilizers and provide, for the first time, evidence for the involvement of this lipolytic enzyme in the mobilization of HSPCs.