Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells

Abstract

Mice deficient in complement C3 (C3 À/À ) are hematologically normal under steady-state conditions, and yet displayed a significant delay in hematopoietic recovery from either irradiation or transplantation of wild-type (WT) hematopoietic stem/ progenitor cells (HSPC). Transplantation of histocompatible WT Sca-1 þ cells into C3 À/À mice resulted in a (i) decrease in day 12 CFU-S, (ii) 5-7-day delay in platelet and leukocyte recovery, and (iii) reduced number of BM CFU-GM progenitors at day 16 after transplantation. Nevertheless, HSPC from C3 À/À mice engrafted normally into irradiated WT mice, suggesting that there was a defect in the hematopoietic environment of C3 À/À mice. Since C3 À/À mice cannot activate/cleave C3, the C3 fragments C3a, C3a des-Arg , and iC3b were examined for a role in HSPC engraftment. Liquid-phase C3a and C3a des-Arg increased CXCR4 incorporation into membrane lipid rafts (thus potentiating HSPC responses to SDF-1 gradients), whereas iC3b was deposited onto irradiated BM cells and functioned to tether CR3(CD11b/CD18) þ HSPC to damaged stroma. The activity of C3a des-Arg suggested that C3aR þ HSPC also expressed the C5L2 (receptor for C3a and C3a des-Arg ) and this was confirmed. In conclusion, a novel mechanism for HSC engraftment was identified, which involves complement activation and specific C3 fragments that promote conditioning for transplantation and enhance HSPC engraftment.

Innate immunity as orchestrator of stem cell mobilization

“…[71][72][73][74][75][76] Overall, the activation of CC during HSPC mobilization was confirmed by (i) Enzyme-linked immunosorbent assay to detect C3a and C5a clevage fragments in plasma, 19 (ii) immunofluorescence showing deposition of iC3b on BM stroma and endothelial cells [41][42][43] and (iii) Enzyme-linked immunosorbent assay and histochemical detection of membrane attack complex (MAC) in BM tissue. 21 Work from our laboratory demonstrates that CC activation in BM is triggered by several mobilizing agents, including G-CSF, mobilizing polysaccharides, such as zymosan, 22 as well as AMD3100.…”

“…28,61 Mobilization could also be achieved by the administration of some types of polysaccharides (for example, zymosan or fucoidans) that in animal models have been demonstrated to efficiently mobilize HSPCs within 1 h after a single injection. 66,67 Elements of innate immunity involved in stem cell mobilization Evidence from our, [41][42][43][44]68 and other laboratories 69,70 indicates that innate immunity orchestrates egress of HSPCs from BM into PB. Innate or natural immunity is inborn and thus naturally present in an organism; it does not require previous sensitization to an antigen.…”

Future of cord blood for oncology uses

“…Another interesting area of future investigation involves the utilization of reagents that enhance HSC homing, such as diprotin A 32,33 and C 0 fragment 3a. [34][35][36] Both reagents have been shown in murine models to enhance homing through SDF1-mediated mechanisms.…”

Umbilical cord blood graft enhancement strategies: has the time come to move these into the clinic?

“…20 Priming with C3a complement component Preclinical data showed the ability of complement component C3a to enhance homing and engraftment of HPC. 21 A phase I study demonstrated that co-infusion of a C3a-primed and an unprimed UCB unit to patients with hematological malignancies after a myeloablative conditioning was safe and feasible. Priming with C3a was very simple and performed by incubation of a UCB unit with commercially available human C3a complement component for 30 min.…”