Defective engraftment of C3aR-/- hematopoietic stem progenitor cells shows a novel role of the C3a-C3aR axis in bone marrow homing.
Defective engraftment of C3aR-/- hematopoietic stem progenitor cells shows a novel role of the C3a-C3aR axis in bone marrow homing.
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我们报道了补体(C)在造血移植预处理期间在骨髓（BM）中被激活和切割，第三个C组分（C3）切割片段C3a和desArgC3a增加造血干细胞/祖细胞（HSPCs）对基质衍生因子-1 （SDF-1）的反应性。我们还证明了这种促进归巢的作用不依赖于C3a受体（C3aR）。在此，我们报告了我们的新观察，将C3aR-/- HSPCs移植到致命照射的受体中会导致：1)血小板和白细胞恢复延迟~ 5-7天；2)第12天集落形成单位-脾脏（CFU-S）形成减少；3)移植后第16天BM腔内供体源性cfu -粒细胞-巨噬细胞（GM）祖细胞数量减少。与小鼠数据一致，C3aR拮抗剂SB290157阻断C3aR对人脐带血CD34+细胞的作用，会损害其在非肥胖糖尿病/严重联合免疫缺陷（NOD/SCID）小鼠中的植入。然而，C3a刺激C3aR-/-小鼠的HSPCs对SDF-1梯度的反应更好，暴露于C3a后，它们分泌的基质金属蛋白酶-9 （matrix metalloprotease-9, MMP-9）减少，对基质细胞的粘附能力受损。我们得出结论，C3a除了以C3aR独立的方式增强HSPC对SDF-1梯度的反应性外，还可能通过增加C3aR介导的MMP-9分泌和细胞粘附直接调节HSPC归巢。
We reported that complement (C) becomes activated and cleaved in bone marrow (BM) during preconditioning for hematopoietic transplantation and the third C component (C3) cleavage fragments C3a and desArgC3a increase responsiveness of hematopoietic stem/progenitor cells (HSPCs) to stromal derived factor-1 (SDF-1). We also demonstrated that this homing promoting effect is not C3a receptor (C3aR) dependent. Herein, we report our new observation that transplantation of C3aR-/- HSPCs into lethally irradiated recipients results in: 1) ∼5-7 day delay in recovery of platelets and leukocytes; 2) decrease in formation of day 12 colony-forming units-spleen (CFU-S); and 3) decrease in the number of donor-derived CFU-granulocyte-macrophage (GM) progenitors detectable in the BM cavities at day 16 after transplantation. In agreement with the murine data, blockage of C3aR on human umbilical cord blood CD34+ cells by C3aR antagonist SB290157 impairs their engraftment in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice. However, HSPCs from C3aR-/- mice stimulated by C3a still better responded to SDF-1 gradient, after exposure to C3a, they secrete less matrix metalloprotease-9 (MMP-9) and show impaired adhesion to stroma cells. We conclude that C3a, in addition to enhancing responsiveness of HSPCs to SDF-1 gradient in a C3aR independent manner, may also directly modulate HSPC homing by augmenting C3aR-mediated secretion of MMP-9 and cell adhesion.
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DOI：
10.1007/978-0-387-78952-1_4
发表时间：
2008-01-01
期刊：
CURRENT TOPICS IN COMPLEMENT II
影响因子：
--
作者：
Ratajczak, Mariusz Z.;Wysoczynski, Marcin;Ratajczak, Janina
通讯作者：
Ratajczak, Janina
影响因子：
20.3
作者：
Peled, A;Kollet, O;Lapidot, T
通讯作者：
Lapidot, T
DOI：
10.1073/pnas.92.21.9647
发表时间：
1995-10-10
影响因子：
11.1
作者：
PAPAYANNOPOULOU, T;CRADDOCK, C;WOLF, NS
通讯作者：
WOLF, NS
影响因子：
11.4
作者：
Ratajczak, MZ;Reca, R;Ross, GD
通讯作者：
Ross, GD
影响因子：
64.8
作者：
Hirsch, E;Iglesias, A;Fassler, R
通讯作者：
Fassler, R