Complement activation in the context of stem cells and tissue repair

Figure 1 Schematic presentation of the complement pathways with emphasis on outcomes relevant to tissue repair and regeneration. The complement system can be activated by three pathways, two of which are part of innate immunity, the alternative and lectin pathways, whereas the classical pathway is normally initiated by immunoglobulins. All routes converge on the cleavage by complex enzymes referred to as C3 convertases of component C3 (Mr: about 195000) to C3a (Mr: about 8500) and C3b (Mr: about 185000). As a consequence of C3b deposition on C3 convertase, C5 convertase is created that acts similarly producing from component C5 (Mr: about 196000) the activation peptide C5a (Mr: about 11000) and C5b (Mr: about 185000). The anaphylatoxins, C3a and C5a, are important for elaboration of mechanisms of wound healing and regeneration. These small mediators are recognized by their cognate receptors: C3aR and C5aR/C5L2 that are GPCRs found on a diversity of cells inclusive of immune cells, endothelial cells, differentiated repair cells, and stem cells. In addition C3b and its split product iC3b, C3d are recognized by receptors inclusive of CR1-4 that assist clearance of microorganisms, cellular debris, immune complexes, and apoptotic cells. The ultimate outcome of complement activation is the formation of the MAC that is a transmembrane pore (100 Ǻ) assembly that embeds in target cell membranes. In the absence of proximal phospholipid membranes, the terminal components of complement associate into complexes referred to as SC5b-9. These are probable heterogeneous and contain multiple copies of vitronectin and clusterin (apolipoprotein J). Because vitronectin in an oligomeric state can present the canonical tripeptide, Arg-Gly-Asp, to integrins on a variety of restorative cells, such as fibroblasts and keratinocytes, SC5b-9 may have a wound healing function. MAC: Membrane attack complex; MSC: Mesenchymal stem cells; HDL: High density lipo-protein; HSC: Hematopoietic stem cells; PMNs: Polymorphonuclear cells.