Cre/lox studies identify resident macrophages as the major source of circulating coagulation factor XIII-A

Cora M. L. Beckers, Kingsley R. Simpson, Kathryn J. Griffin, Jane M. Brown, Lih T. Cheah, Kerrie A. Smith, Jean Vacher, Paul A. Cordell, Mark T. Kearney, Peter J. Grant, Richard J. Pease

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)

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 μM-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.

Original languageEnglish
Pages (from-to)1494-1502
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number8
Early online date8 Jun 2017
DOIs
Publication statusPublished - 1 Aug 2017
Externally publishedYes

Keywords

  • animal models of human disease
  • bone marrow
  • macrophages
  • platelets
  • transplantation

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