Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A

Abstract

Supplemental Digital Content is available in the text.

Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

“…F13a1 knockout mice on a C57BL/6J background [15] were bred from F13a1 +/− dams mated either with F13a1 +/− or F13a1 −/− sires, since, in agreement with previous findings [18], each of four pregnant C57BL/6J F13a1 knockout mice suffered prenatal or perinatal mortality. C57BL/6J F13a1 −/− pups from these crosses were born below Mendelian expectation (226 observed, 325 expected, p < 0.001).…”

“…F13a1 flox/flox mice maintained on a normal chow diet, to determine whether, as in Apoe expressing F13a1 knockout mice, fibrosis was evident. In previous studies, we established that expression of Pf4-cre abolishes FXIII-A expression within cardiac resident macrophages of Pf4-cre.F13a1 flox/flox mice, whereas conventional myeloid -cre alleles do not [15]. Cardiac fibrosis was undetectable in Pf4-cre.F13a1 flox/flox mice (Fig.…”

“…C57BL/6J Tgm2 −/− /F13a1 −/− pups were also born below Mendelian expectation (246 observed, 331 expected p < 0.01), while Tgm2 −/− mice were born in accordance with Mendelian expectation (80 obtained, 88 expected). Oligonucleotides for genotyping are shown in Supplementary Table 1. C57BL/6J F13a1 flox/flox mice (floxed in coding exon 7 of the F13a1 gene) and progeny from crosses with C57BL/6J Pf4-cre and Cd11b-cre recombinase-expressing mice, were as described previously [15].…”

“…FXIII-A is present both as a soluble plasma protein and within cells, including cardiac macrophages [15]. To determine whether cardiac Fig.…”

“…Blood clotting factor FXIII-A is present as a dimer within the cytosol of megakaryocytes, platelets and resident macrophages of the heart, arteries, lung and placenta [14]. Resident macrophages mediate the release of FXIII-A into the plasma [15], where it circulates as a heterotetrameric zymogen complex with the non-catalytic B-subunit. Following activation by thrombin, FXIII-A cross-links proteins including fibrin and α-2 antiplasmin within blood clots [16] and fibronectin within the extracellular matrix of injured tissues.…”