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The Role Of Complement In Mobilization And Engrfatment Of Hematopoietic Stem/progenitor Cells - A Novel Link Between Innate Immunity And Hematopoiesis | 6650
ISSN: 2157-7633

Journal of Stem Cell Research & Therapy
Open Access

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The role of complement in mobilization and engrfatment of hematopoietic stem/progenitor cells - A novel link between innate immunity and hematopoiesis

International Conference on Regenerative & Functional Medicine

Mariusz Z. Ratajczak

ScientificTracks Abstracts: J Stem Cell Res Ther

DOI: 10.4172/2157-7633.S1.005

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 mobilizers. 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 β 2-defensin. 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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