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
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.
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This work was supported by NIH Grants 2R01 DK074720 and R01HL112788, the Stella and Henry Endowment and Maestro Grant 2011/0/A/NZ4/00035 (to MZR) and the UK COBRE Early Career Program (P20 GM103527), and NIH Grant R56 HL124266 to ABL.
Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu).
Adamiak, M.; Poniewierska-Baran, A.; Borkowska, S.; Schneider, G.; Abdelbaset-Ismail, A.; Suszynska, M.; Abdel-Latif, Ahmed; Kucia, M.; Ratajczak, J.; and Ratajczak, M. Z., "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" (2016). Internal Medicine Faculty Publications. 154.