A Major Fraction of Fibronectin Present in the Extracellular Matrix of Tissues Is Plasma-derived

Abstract

The origin of the fibronectin (FN) found in the extracellular matrix of tissues has not been defined experimentally. Previous studies suggest that there is contribution from both local tissue production and transfer from plasma, but the extent of this phenomenon has not been addressed. We have shown before that engineered mice constitutively expressing extra domain A-containing FN (EDA ؉ FN) have a significant decrease of FN levels in plasma and most tissues. We showed that hepatocytes modified to produce EDA ؉ FN have normal extracellular matrix-FN levels but secrete less soluble FN. When we performed a liver-specific EDA-exon deletion in these animals, FN levels were restored both in plasma and tissues. Therefore, an important fraction of tissue FN, approximately an equal amount of that produced by the tissue itself, is actually plasma-derived, suggesting that plasma is an important source of tissue FN. The present results have potential significance for understanding the contributions of plasma FN, and perhaps other plasma proteins, in the modulation of cellular activities and in the formation of the extracellular matrix of tissues. Fibronectins (FN)3 are a family of multifunctional glycoproteins known to play key roles in fundamental processes related to adhesive and migratory behavior of cells, such as embryogenesis, malignancy, homeostasis, wound healing, and maintenance of tissue integrity (1). FN generates protein diversity as a consequence of alternative processing of a single primary transcript at three different sites, the extra domain A (EDA), the extra domain B (EDB), and the type III homologies connecting segment (IIICS) (2-4). Two major forms of FN exist, plasma FN (pFN) and cellular FN. pFN is a soluble dimeric form that is secreted into the bloodstream by hepatocytes (5, 6) and found at 300 and 580 g/ml in plasma of humans and mice, respectively (1, 7). pFN lacks both the EDA and EDB domains, whereas cellular FN is locally produced and deposited as insoluble fibrils in the extracellular matrix of tissues and contains these domains at variable proportions (1, 8, 9). Previous studies suggested that circulating pFN contributes to the extracellular matrix of tissues (10, 11) but the extent of the phenomenon has not been addressed.The levels of FN in plasma are critical for hemostasis, tissue repair, and susceptibility to infections. Depletion of pFN (liver-specific knockout of FN) results in increased brain injury after transient focal cerebral ischemia (12), a delay in thrombus formation and decreased thrombus stability (13), decreased angiogenesis (14), and increased susceptibility to bacterial infections (15). Heterozygous null FN mice appear healthy and fertile (7) but show delayed thrombus growth in injured arterioles (16). Regrettably, the levels of FN present in the tissues of heterozygous null FN and in the pFN null mice have not been reported.We have previously shown that knock-in mice having constitutive inclusion of the EDA exon of the FN gene (EDA ϩ/ϩ strain) had up to 70 -80% reduction ...

An Essential Role for Fibronectin Extra Type III Domain A in Pulmonary Fibrosis

“…Coupled with our data, we conclude that EDA cFN, whether cell derived or ECM associated, is critical for influencing wound healing through its effects on fibroblast phenotypes. Recently, our group has shown that a substantial portion of extracellular FN is derived from plasma (37). Because plasma FN is hepatocyte derived and lacks the EDA, it stands to reason that locally produced and deposited EDA cFN is a key regulator of tissue repair.…”

Factor XIII-A transglutaminase acts as a switch between preadipocyte proliferation and differentiation

“…35,36 In the physiological setting, FN exists as 2 pools: as cellular FN (cFN) synthesized by tissue-resident cells and as plasma FN (pFN) produced by the liver. 31 pFN has recently been shown to accumulate from the circulation into several tissues (liver, brain, testis, heart, lungs, and bone), 37,38 and to contribute to the majority of the FN extracellular matrix associated with several cell types. 16,[31][32][33] FXIII-A has been shown to increase FN matrix accumulation in fibroblasts.…”

Conformational remodeling of the fibronectin matrix selectively regulates VEGF signaling

“…Anastellin inhibition of angiogenesis has also been reported to require plasma fibronectin (Yi et al, 2003). A previous study has shown that plasma fibronectin makes up ,50% of the fibronectin in tissues (Moretti et al, 2007). This finding suggests that the requirement for plasma fibronectin in mediating the action of anastellin stems from the ability of plasma fibronectin to bind to anastellin and target it to tissues undergoing active remodeling.…”