Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A.
Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A.
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DOI：
10.1161/atvbaha.117.309271
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Pease RJ
中科院分区：
文献类型：
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作者：
Beckers CML;Simpson KR;Griffin KJ;Brown JM;Cheah LT;Smith KA;Vacher J;Cordell PA;Kearney MT;Grant PJ;Pease RJ
文本中提供了补充数字内容。建立血浆因子 (F)XIII-A 的细胞来源。将 F13a1 基因的新型 flox 小鼠 FXIII-Aflox/flox (Flox) 与表达骨髓和血小板 cre 的小鼠杂交，并测量细胞 FXIII-A mRNA 表达以及血浆和血小板 FXIII-A 水平。血小板因子4-cre.Flox交叉消除血小板FXIII-A并将血浆FXIII-A降低至23±3%（P<0.001）。然而，血小板因子 4-cre 对血浆 FXIII-A 的影响是在巨核细胞谱系之外发挥的，因为尽管有明显的血小板减少，但 Mpl−/− 小鼠中血浆 FXIII-A 并未减少。为了支持这一点，血小板因子 4-cre 耗尽了 floxed 小鼠的大脑、主动脉和心脏中的 FXIII-A mRNA，其中 FXIII-Apos 细胞被鉴定为巨噬细胞，因为它们与 CD163 共染色。在整合素αM-cre.Flox和双拷贝溶菌酶2-cre.cre.Flox杂交中，血浆FXIII-A分别降低至75±5%（P=0.003）和30±7%（P<0.001），每个血小板的FXIII-A含量没有变化，进一步与血浆FXIII-A的巨噬细胞来源一致。不同基因型小鼠血浆 FXIII-A 水平的变化反映了主动脉中 FXIII-A mRNA 表达的变化。将 FXIII-A+/+ 骨髓移植到 FXIII-A−/− 小鼠中，均可将血浆 FXIII-A 恢复至正常水平，并取代主动脉和心脏 FXIII-A mRNA，而将其移植到 FXIII-A+/+ 小鼠中并不会增加血浆 FXIII-A 水平，这表明存在有限的生态位群体，支持 FXIII-A 释放细胞。这项工作表明，常驻巨噬细胞维持血浆 FXIII-A 并排除血小板谱系作为主要贡献者。
Supplemental Digital Content is available in the text. To establish the cellular source of plasma factor (F)XIII-A. A novel mouse floxed for the F13a1 gene, FXIII-Aflox/flox (Flox), was crossed with myeloid- and platelet-cre–expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.Flox cross abolished platelet FXIII-A and reduced plasma FXIII-A to 23±3% (P<0.001). However, the effect of platelet factor 4-cre on plasma FXIII-A was exerted outside of the megakaryocyte lineage because plasma FXIII-A was not reduced in the Mpl−/− mouse, despite marked thrombocytopenia. In support of this, platelet factor 4-cre depleted FXIII-A mRNA in brain, aorta, and heart of floxed mice, where FXIII-Apos cells were identified as macrophages as they costained with CD163. In the integrin αM-cre.Flox and the double copy lysozyme 2-cre.cre.Flox crosses, plasma FXIII-A was reduced to, respectively, 75±5% (P=0.003) and 30±7% (P<0.001), with no change in FXIII-A content per platelet, further consistent with a macrophage origin of plasma FXIII-A. The change in plasma FXIII-A levels across the various mouse genotypes mirrored the change in FXIII-A mRNA expression in aorta. Bone marrow transplantation of FXIII-A+/+ bone marrow into FXIII-A−/− mice both restored plasma FXIII-A to normal levels and replaced aortic and cardiac FXIII-A mRNA, while its transplantation into FXIII-A+/+ mice did not increase plasma FXIII-A levels, suggesting that a limited population of niches exists that support FXIII-A-releasing cells. This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor.