Beckers Cora M L, Simpson Kingsley R, Griffin Kathryn J, Brown Jane M, Cheah Lih T, Smith Kerrie A, Vacher Jean, Cordell Paul A, Kearney Mark T, Grant Peter J, Pease Richard J
From the Leeds Institute for Cardiovascular and Metabolic Medicine, LIGHT Laboratories, University of Leeds, United Kingdom (C.M.L.B., K.R.S., K.J.G., J.M.B., L.T.C., K.A.S., P.A.C., M.T.K., P.J.G., R.J.P.); and Clinical Research Institute of Montreal, McGill University, Canada (J.V.).
Arterioscler Thromb Vasc Biol. 2017 Aug;37(8):1494-1502. doi: 10.1161/ATVBAHA.117.309271. Epub 2017 Jun 8.
To establish the cellular source of plasma factor (F)XIII-A.
A novel mouse floxed for the gene, FXIII-A (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% (<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-A 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% (=0.003) and 30±7% (<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.
确定血浆因子（F）XIII - A的细胞来源。
将一种新型的F XIII - A基因条件性敲除小鼠（Flox）与表达髓系和血小板特异性cre的小鼠进行杂交，并检测细胞F XIII - A mRNA表达以及血浆和血小板中F XIII - A水平。血小板因子4 - cre.Flox杂交导致血小板F XIII - A缺失，血浆F XIII - A水平降至23±3%（<0.001）。然而，血小板因子4 - cre对血浆F XIII - A的影响并非通过巨核细胞系发挥，因为尽管Mpl小鼠存在明显血小板减少，但血浆F XIII - A水平并未降低。支持这一观点的是，血小板因子4 - cre使Flox小鼠脑、主动脉和心脏中的F XIII - A mRNA减少，其中F XIII - A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杂交小鼠中，血浆F XIII - A分别降至75±5%（P = 0.003）和30±7%（<0.001），每个血小板中F XIII - A含量无变化，这进一步支持血浆F XIII - A来源于巨噬细胞。不同小鼠基因型间血浆F XIII - A水平的变化与主动脉中F XIII - A mRNA表达的变化一致。将F XIII - A骨髓移植到F XIII - A小鼠体内可使血浆F XIII - A恢复到正常水平，并替代主动脉和心脏中的F XIII - A mRNA，而将其移植到F XIII - A小鼠体内则不会增加血浆F XIII - A水平，这表明存在有限数量的微环境支持释放F XIII - A的细胞。
这项研究表明，组织驻留巨噬细胞维持血浆F XIII - A水平，血小板系并非主要贡献者。
