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Mobilization studies in C3-deficient mice unravel the involvement of a novel crosstalk between the coagulation and complement cascades in mobilization of hematopoietic stem/progenitor cells

Leukemia volume 27, pages 1928–1930 (2013)Cite this article

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Hematopoietic stem/progenitor cells (HSPCs) express chemokine receptor CXCR4 and very late antigen-4 (VLA-4, also known as α4β1 integrin) receptor on their cell surface, and are retained in bone marrow (BM) niches by the interaction of these receptors with their respective ligands, α-chemokine stromal-derived growth factor-1 (SDF-1) and vascular adhesion molecule-1 (VCAM-1, also known as CD106), which are expressed by cells in the BM microenvironment (for example, osteoblasts and fibroblasts). HSPCs residing in BM are released from their niches and circulate under steady-state conditions at detectable levels in the peripheral blood (PB), and their number increases in response to (i) systemic or local inflammation, (ii) strenuous exercise, (iii) stress, (iv) tissue/organ injury and (v) pharmacological agents.1, 2, 3, 4, 5 The mobilization process has been postulated to be directed by (i) a decrease in SDF-1–CXCR4 and VLA-4–VCAM-1 interactions in BM microenvironment (for example, due to the release of proteolytic enzymes or after molecular blockade by administration of small molecular CXCR4 or VLA-4 antagonists), (ii) release of neurotransmitters from the synapses of the nerves that innervate the BM microenvironment (for example, involving the dopamine and β2-adrenergic receptors), (iii) reversal of the trans-endothelial chemotactic gradient between the BM microenvironment and plasma, (iv) activation of the plasminogen system, as recently proposed, and (v) activation of the complement cascade (ComC), as we have demonstrated.1, 2, 3, 4, 5 Lending additional support to this latter effect, it is known that the ComC becomes activated in all the mechanisms leading to mobilization of HSPCs (for example, systemic inflammation, organ injury, strenuous exercise, as well as administration of mobilizing drugs).2

We previously reported that mice defective in the third complement protein (C3), which is a proximal component of the ComC, are easy mobilizers.6 This has been explained by a lack of C3a formation, which normally increases retention signals for HSPCs in response to a BM SDF-1 gradient, and thus prevents uncontrolled release of these cells into PB. By contrast, mice defective in the fifth complement protein (C5), which is a distal component of the ComC, display a profound defect in mobilization of HSPCs.7 To explain this phenomenon, we demonstrated that C5 cleavage fragments (C5a and C5b) are essential for egress of HSPCs into PB. Accordingly, C5a generated in the BM microenvironment above the BM–PB barrier is responsible during the mobilization process for augmenting the release of proteolytic enzymes from myeloid cells, which attenuates SDF-1–CXCR4 and VLA-4–VCAM-1 retention signals in BM niches. In addition, C5a generated down from the BM–PB barrier in BM sinusoids is a potent chemoattractant for granulocytes and monocytes that, as the first cells egressing from the BM, has an important role in permeabilization of the BM–PB barrier, and thus facilitate the subsequent egress of HSPCs.7 Moreover, another C5 cleavage fragment, C5b, is involved in the formation of C5b–C9, also known as the membrane attack complex (MAC), which increases the PB level of a potent chemoattractant for HSPCs, sphingosine-1-phosphate.8 Thus, the failure of C5-deficient mice to generate both C5a and MAC explains why they are poor mobilizers.7, 8

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Acknowledgements

This work was supported by NIH 2R01 DK074720 and Maestro grant 2011/02/A/NZ4/00035 to MZR and AHA 13SDG14560005 to MW.

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  1. Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    S Borkowska, M Suszynska & M Z Ratajczak

  2. Department of Physiology, Pomeranian University of Medicine, Szczecin, Poland

    S Borkowska, M Suszynska & M Z Ratajczak

  3. Institute of Molecular Cardiology, University of Louisville, Louisville, KY, USA

    M Wysoczynski

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Correspondence to M Z Ratajczak.

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Borkowska, S., Suszynska, M., Wysoczynski, M. et al. Mobilization studies in C3-deficient mice unravel the involvement of a novel crosstalk between the coagulation and complement cascades in mobilization of hematopoietic stem/progenitor cells. Leukemia 27, 1928–1930 (2013). https://doi.org/10.1038/leu.2013.84

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