The retention of hematopoietic stem/progenitor cells (HSPCs) in bone marrow (BM) is mainly regulated by interaction
between stroma cell-secreted stromal derived factor-1 (SDF-1) ? and CXCR4 receptor expressed on HSPCs. Mounting
evidence accumulates that this process is modulated by elements of innate immunity (e.g, complement cascade, and granulocytes).
Accordingly, complement cascade (CC) becomes activated in bone marrow (BM) during both granulocyte colony stimulating
factor (G-CSF)-induced mobilization of HSPCs as well as after conditioning for hematopoietic transplantation by lethal
irradiation. Research from my laboratory indicates also that CC and granulocytes are major regulators of both processes.
In mobilization process of HSPCs the activation of CC leads first to release from BM-residing granulocytes/monocytes of
several proteolytic enzymes (MMP-2, MMP-9, catepsin G, neutrophil elastase) that impair SDF-1-CXCR4 mediated retention
of HSPCs in BM niches. We also noticed that activation/cleavage of CC releases C3a and C5a anaphylatoxins that differently
regulate mobilization. Accordingly, C3a, by enhancing responsiveness of HSPCs to decreasing concentrations of SDF-1 in BM,
prevents mobilization and promotes their BM-retention. On other hand C5a-mediated pro-mobilization effects are mediated by
granulocytes. Accordingly, C5aR
granulocytes are chemoattracted by plasma C5 cleavage fragments, being the first wave of cells
leaving BM. This facilitates subsequent egress of HSPCs. It explains why granulocytopenic mice or C5 deficient mice are poor
In an opposite process of HSPCs homing to the BM activation of CC leads to release several factors in BM microenvironment
that increase responsiveness of HSPCs to SDF-1 gradient and facilitate engraftment of HSPCs such as C3 complement cascade
cleavage fragments and antimicrobial cationic peptides, such as cathelicidin/LL-37 or
Based on this it is proposed a novel paradigm that activation of CC play an important and underappreciated role in trafficking
of HSPCs. Our data also indicate that modulation of CC as a novel strategy to optimize and accelerate both mobilization and
homing of HSPCs.
Mariusz Z. Ratajczak is a Director of Stem Cell Institute at James Graham Brown Cancer Center, Professor of Medicine for the of Department of
Medicine, Professor of Immunology for the Department of Microbiology, University of Louisville, Louisville, Ky. Henry and Stella Hoenig Endowed
Chair in Cancer Biology. Foreign member of Polish Academy of Art and Science. He has received his MD from Pomeranian Medical University,
Poland (1975-1981) and PhD in Experimental Hematology from Polish Academy of Sciences, Warsaw (1886). He received the 2008 President?s
Award for Outstanding Scholarship, Research and Creativity from the University of Louisville, the 2007 Mosaic Award from Jewish Family and
Vocational Service, the 2006 Award.
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