Affiliation:
1. 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.).
Abstract
Objective—
To establish the cellular source of plasma factor (F)XIII-A.
Approach and Results—
A novel mouse floxed for the
F13a1
gene, FXIII-A
flox/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-A
pos
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.
Conclusions—
This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
42 articles.
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