Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells
Transplantation studies in C3-deficient animals reveal a novel role of the third complement component (C3) in engraftment of bone marrow cells
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DOI：
10.1038/sj.leu.2403446
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发表时间：
2004-09-01
期刊：
影响因子：
11.4
通讯作者：
Ross, GD
中科院分区：
文献类型：
--
作者：
Ratajczak, MZ;Reca, R;Ross, GD
补体C3（C3(-/-)）缺乏的小鼠在稳态条件下血液学正常，但在野生型（WT）造血干细胞/祖细胞（HSPC）照射或移植后，其造血功能恢复明显延迟。将组织相容性WT Sca-1（+）细胞移植到C3（-/-）小鼠体内，可导致(i)第12天CFU-S减少，（ii）血小板和白细胞恢复延迟5-7天，（iii）移植后第16天BM CFU-GM祖细胞数量减少。然而，来自C3（-/-）小鼠的HSPC正常移植到辐照后的WT小鼠体内，提示C3（-/-）小鼠的造血环境存在缺陷。由于C3（-/-）小鼠不能激活/切割C3，我们检测了C3片段C3a、C3a（des-Arg）和iC3b在HSPC植入中的作用。液相C3a和C3（ads - arg）增加了CXCR4与膜脂筏的结合（从而增强了HSPC对SDF-1梯度的反应），而iC3b沉积在辐照的BM细胞上，并起着将CR3(CD11b/CD18)+HSPC连接到受损基质的作用。C3a（des-Arg）的活性表明C3aR(+)HSPC也表达C5L2 （C3a和C3a（des-Arg）的受体），这一点得到了证实。综上所述，我们发现了一种新的HSC移植机制，该机制涉及补体激活和特异性C3片段，它们促进了移植的调节，并增强了HSC的植入。
Mice deficient in complement C3 (C3(-/-)) 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(+) cells into C3(-/-) 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(-/-) mice engrafted normally into irradiated WT mice, suggesting that there was a defect in the hematopoietic environment of C3(-/-) mice. Since C3(-/-) 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 C3(ades-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)+HSPC to damaged stroma. The activity of C3a(des-Arg) suggested that C3aR(+)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.