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Conditioning for hematopoietic transplantation activates the complement cascade and induces a proteolytic environment in bone marrow: a novel role for bioactive lipids and soluble C5b-C9 as homing factors

Department of Medicine, Stem Cell Institute at the James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 9.38). 07/2011; 26(1):106-16. DOI: 10.1038/leu.2011.185
Source: PubMed

ABSTRACT We have observed that conditioning for hematopoietic transplantation by lethal irradiation induces a proteolytic microenvironment in the bone marrow (BM) that activates the complement cascade (CC). As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC). At the same time, proteolytic enzymes induced in irradiated BM impair the chemotactic activity of α-chemokine stromal-derived factor-1 (SDF-1). As SDF-1 is considered a crucial BM chemoattractant for transplanted hematopoietic stem/progenitor cells (HSPCs), we sought to determine whether other factors that are resistant to proteolytic enzymes have a role in this process, focusing on proteolysis-resistant bioactive lipids. We found that the concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) increase in the BM after conditioning for transplantation and that both S1P and, as we show here for the first time, C1P are potent chemoattractants for HSPCs. Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs. In support of a role for MAC in homing and engraftment, we found that soluble MAC enhances in a CR3 (CD11b/CD18)-dependent manner the adhesion of HSPCs to BM stromal cells and increases the secretion of SDF-1 by BM stroma. We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

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Available from: Chihwa Kim, Jul 16, 2014
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    • "The promotion of cell migration by extracellular C1P has been recently confirmed in other cell types. For instance, Kim and co-workers found that extracellular C1P potently stimulated migration of hematopoietic stem progenitor cells [33], multipotent stromal cells, and endothelial progenitor cells [14]. In addition, Karapetyan and co-workers reported that extracellular C1P stimulated migration of bone marrow derived stem cells in patients suffering from acute myocardial infarction [34]. "
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    ABSTRACT: Ceramide 1-phosphate (C1P) was recently demonstrated to potently induce cell migration. This action could only be observed when C1P was applied exogenously to cells in culture, and was inhibited by pertussis toxin. However, the mechanisms involved in this process are poorly understood. In this work, we found that phosphatidic acid (PA), which is structurally related to C1P, displaced radiolabeled C1P from its membrane-binding site and inhibited C1P-stimulated macrophage migration. This effect was independent of the saturated fatty acid chain length or the presence of a double bond in each of the fatty acyl chains of PA. Treatment of RAW264.7 macrophages with exogenous phospholipase D (PLD), an enzyme that produces PA from membrane phospholipids, also inhibited C1P-stimulated cell migration. Likewise, PA or exogenous PLD inhibited C1P-stimulated extracellularly regulated kinases (ERK) 1 and 2 phosphorylation, leading to inhibition of cell migration. However, PA did not inhibit C1P-stimulated Akt phosphorylation. It is concluded that PA is a physiological regulator of C1P-stimulated macrophage migration. These actions of PA may have important implications in the control of pathophysiological functions that are regulated by C1P, including inflammation and various cellular processes associated with cell migration such as organogenesis or tumor metastasis.
    Biochemical Pharmacology 10/2014; DOI:10.1016/j.bcp.2014.10.005 · 4.65 Impact Factor
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    • "Ceramide-1 phosphate (C1P) is another bioactive lipid derivative that was previously identified as a chemoattractant for mouse monocytes (Granado et al., 2009). Activation of CC correlated with an increase in the BM levels of both S1P and C1P (Kim et al., 2012). Interestingly, while S1P levels increase in PB mostly during mobilization, the C1P concentration in the BM fluids increases upon myeloablative conditioning for transplantation. "
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    ABSTRACT: Hematopoietic stem and progenitor cells (HSPCs) continuously egress out of the bone marrow (BM) to the circulation under homeostatic conditions. Their enhanced recruitment to the periphery in response to exogenous stimulation is a process, termed mobilization. HSPC mobilization is induced clinically or experimentally in animal models by a wide variety of agents, such as cytokines (e.g. G-CSF), chemotherapeutic agents (e.g. cyclophosphamide) and small molecules (e.g. the CXCR4 antagonist AMD3100). The major source for clinical transplantation protocols is via peripheral blood (PB) mobilization of BM derived HSPCs. Thus, deciphering mechanisms that regulate HSPC motility can be utilized for the development of improved mobilization regimens. The chemokine stromal derived factor-1 (SDF-1, also termed CXCL12) and its major receptor CXCR4 are crucial in mediating both retention and mobilization of HSPCs, and this chapter will emphasize its recently revealed roles in directing steady state egress and rapid mobilization. Loss of retention is mediated by disruption of adhesion interactions, such as those mediated by integrins and CD44, and intrinsic signaling pathways such as Rho GTPases dependent signaling. Pivotal roles for the hemostatic fibrinolytic and stress-induced proteolytic enzymatic machineries in regulating HSPC recruitment are also discussed. Nevertheless, breakdown of adhesion interactions and activity of proteases are only part of the story, as accumulating evidences present the BM microenvironment, not only as maintaining HSPC quiescence and proliferation, but also as controlling HSPC retention and motility. Differentiating myeloid cells, bone remodeling by osteoblasts and osteoclasts, stimuli of the innate immunity as well as of the nervous system, including signals emanating the circadian clock, highly regulate various aspects of HSPC function, including egress, recruitment and mobilization. This review aims at presenting up to-date results concerning the dynamic interplay between the BM microenvironment and the HSPCs, focusing on molecular mechanisms that lead eventually to mobilization of HSPCs from the BM into the circulation.
    StemBook, 12/2012; Harvard Stem Cell Institute.
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    • "For example, our recent mass spectrometry (MS) analysis revealed that the major isoforms of C1P and S1P were detected at higher concentrations in supernatants harvested from irradiated BM. Taken together with their potent chemotactic effects, these changes in concentration of bioactive lipids in BM after myeloablative conditioning for transplantation suggest that these factors play an important role in the homing process for HSPCs [9]. However, both bioactive lipids have a limited half-life, with S1P degraded by several enzymes, such as S1P lyase (SPL), lipid phosphate phosphatases (LPP1–3), and S1P- specific phosphatases (SPP1 and SPP2), while C1P is degraded by LPP1–3 [93] [94] [95] [96] [97] [98] [99] [100] [101]. "
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    ABSTRACT: The α-chemokine stromal derived factor 1 (SDF-1), which binds to the CXCR4 and CXCR7 receptors, directs migration and homing of CXCR4+ hematopoietic stem/progenitor cells (HSPCs) to bone marrow (BM) and plays a crucial role in retention of these cells in stem cell niches. However, this unique role of SDF-1 has been recently challenged by several observations supporting SDF-1-CXCR4-independent BM homing. Specifically, it has been demonstrated that HSPCs respond robustly to some bioactive lipids, such as sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P), and migrate in response to gradients of certain extracellular nucleotides, including uridine triphosphate (UTP) and adenosine triphosphate (ATP). Moreover, the responsiveness of HSPCs to an SDF-1 gradient is enhanced by some elements of innate immunity (e.g., C3 complement cascade cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 or β2-defensin) as well as prostaglandin E2 (PGE2). Since all these factors are upregulated in BM after myeloblative conditioning for transplantation, a more complex picture of homing emerges that involves several factors supporting, and in some situations even replacing, the SDF-1-CXCR4 axis.
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