Mobilization studies in complement-deficient mice reveal that optimal AMD3100 mobilization of hematopoietic stem cells depends on complement cascade activation by AMD3100-stimulated granulocytes

Stem Cell Institute at 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: 10.43). 03/2010; 24(3):573-82. DOI: 10.1038/leu.2009.271
Source: PubMed


We reported that complement cascade (CC) becomes activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF) and C5 cleavage has an important function in optimal egress of HSPCs. In this work, we explored whether CC is involved in mobilization of HSPCs induced by the CXCR4 antagonist, AMD3100. To address this question, we performed mobilization studies in mice that display a defect in the activation of the proximal steps of CC (Rag(-/-), severe combined immune deficient (SCID), C2.Cfb(-/-)) as well as in mice that do not activate the distal steps of CC (C5(-/-)). We noticed that proximal CC activation-deficient mice (above C5 level), in contrast to distal step CC activation-deficient C5(-/-) ones, mobilize normally in response to AMD3100 administration. We hypothesized that this discrepancy in mobilization could be explained by AMD3100-activating C5 in Rag(-/-), SCID, and C2.Cfb(-/-) animals in a non-canonical mechanism involving activated granulocytes. To support this, granulocytes (i) first egress from BM and (ii) secrete several proteases that cleave/activate C5 in response to AMD3100. We conclude that AMD3100-directed mobilization of HSPCs, similarly to G-CSF-induced mobilization, depends on activation of CC; however, in contrast to G-CSF, AMD3100 activates the distal steps of CC directly at the C5 level. Overall, these data support that C5 cleavage fragments and distal steps of CC activation are required for optimal mobilization of HSPCs.

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Available from: Marcin Wysoczynski, Aug 06, 2014
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    • "Hematopoietic stem/progenitor cells (HSPCs) escape their BM niche in response to chemotactic gradients and can be detected in the PB under steady state conditions [7]. Numerous factors have been shown to be responsible for HSPC mobilization including strenuous exercise [8], tissue, or organ injury (including ischemic cardiac events) [9, 10] and may significantly increase in circulation after administration of pharmacological agents [11, 12]. BMSPCs have multifaceted roles in an adult organism most importantly being involved in lymphohematopoiesis [7] and immune surveillance [13]. "
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    • "Since then, several factors have been reported to sensitize the responsiveness of HSPCs to a SDF-1 gradient. These factors include elements of innate immunity, such as cleavage fragments of the complement cascade molecule C3 (Reca et al., 2003), cationic antimicrobial peptides, such as cathelicidin (LL-37) and ␤-defensins (Lee et al., 2010–Lehrer, 2004), and PGE2, a member of the eicosanoid family (Goichberg et al., 2006–Hoggatt et al., 2009). Several arms of the innate immunity system are shown to be involved in regulation of HSPC egress and mobilization, including the complement system and neutrophil activation, as described herein. "
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    • "In addition, leukapheresis products which are enriched in activated granulocytes are known to release several cationic peptides and activate complement cascades [13]. We recently noted that activated granulocyte-derived cationic peptide positively primes responsiveness of murine HSPCs to a CXCL12 gradient [25]. "
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