title: Novel evidence that crosstalk between the complement, coagulation and fibrinolysis proteolytic cascades is involved in mobilization of hematopoietic stem/progenitor cells (HSPCs).
abstract: The role of blood proteinases in the mobilization of hematopoietic stem/progenitor cells (HSPCs) is still not well understood. As previously reported, activation of the complement cascade (ComC) and cleavage of C5 by C5 convertase are enabling events in the release of C5a that plays a crucial role in the egress of HSPCs from bone marrow (BM) into peripheral blood (PB) and explains why C5-deficient mice are poor mobilizers. Here we provide evidence that during granulocyte colony-stimulating factor- and AMD3100-induced mobilization, not only the ComC but also two other evolutionarily ancient proteolytic enzyme cascades, the coagulation cascade (CoaC) and the fibrynolytic cascade (FibC), become activated. Activation of all three cascades was measured by generation of C5a, decrease in prothrombin time and activated partial thromboplastin time as well as an increase in the concentrations of plasmin/antiplasmin and thrombin/antithrombin. More importantly, the CoaC and FibC, by generating thrombin and plasmin, respectively, provide C5 convertase activity, explaining why mobilization of HSPCs in C3-deficient mice, which do not generate ComC-generated C5a convertase, is not impaired. Our observations shed more light on how the CoaC and FibC modulate stem cell mobilization and may lead to the development of more efficient mobilization strategies in poor mobilizers. Furthermore, as it is known that all these cascades are activated in all the situations in which HSPCs are mobilized from BM into PB (for example, infections, tissue/organ damage or strenuous exercise) and show a circadian rhythm of activation, they must be involved in both stress-induced and circadian changes in HSPC trafficking in PB.
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Borkowska
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Suszynska
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: K
authors.initials: K
authors.lastname: Mierzejewska
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Ismail
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Budkowska
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: D
authors.initials: D
authors.lastname: Salata
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Dolegowska
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Kucia
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Ratajczak
authors.affiliation: 1] Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA [2] Department of Physiology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: M Z
authors.initials: MZ
authors.lastname: Ratajczak
mesh_terms: D000818:Animals; D001596:Benzylamines; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism*; D000080027:Cyclams; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D014148:Tranexamic Acid / Q000494:pharmacology
chemical_list: D001596:Benzylamines; D003176:Complement C3; D000080027:Cyclams; D005343:Fibrinolytic Agents; D006571:Heterocyclic Compounds; D006629:Hirudins; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D014148:Tranexamic Acid; D015936:Complement C5a; C088327:plerixafor; C083544:lepirudin