Extra-Domain-A Fibronectin: A New Marker of Fibrosis in Cutaneous Graft-Versus-Host Disease

Abstract

One of the major complications that limit the success of allogeneic stem cell transplantation is graft-versus-host disease (GVHD). The major target organ in GVHD is the skin. Cutaneous GVHD can eventually lead to fibrosis of the skin. Fibronectin mediates a variety of cellular interactions with the extracellular matrix. The molecular and functional diversity of fibronectin (FN) arises from alternative splicing of pre-mRNA. In normal circumstances endothelial cells and fibroblasts synthesize FN without the ED-A domain. In tissue repair and pathologic circumstances such as fibrosis, the ED-A domain is expressed. We hypothesize that expression of ED-A FN is upregulated in patients with cutaneous GVHD. In frozen skin biopsies the expression of ED-A FN was measured at the protein level by immunohistochemistry and at the mRNA level by quantitative real-time PCR (qPCR). In normal control skin, immunohistochemistry showed slight deposits of ED-A FN just under the basal layer. The expression of ED-A FN significantly increased in acute cutaneous GVHD (p<0.05) and ED-A FN was strongly deposited in chronic cutaneous GVHD (p<0.001). Quantitative PCR also showed increased expression of ED-A FN mRNA in acute and chronic cutaneous GVHD compared with normal control skin (p=0.07 and 0.039, respectively). The expression of ED-A FN is increased in the skin of patients with cutaneous GVHD measured both with immunohistochemistry and qPCR. ED-A FN is a new marker of fibrosis in the skin of patients with cutaneous GVHD.

Enhanced fibrillin-2 expression is a general feature of wound healing and sclerosis: potential alteration of cell attachment and storage of TGF-β

“…Especially, the composition of the extracellular matrix in wound healing and sclerosis shares many features of an embryo-fetal matrix. This 'embryonic reprogramming' was shown for collagen and its modification, 12,14,15,17,32,33 for adhesive glycoproteins, [34][35][36][37] and for matricellular proteins. 38 The data presented here show that the microfibrillar protein fibrillin-2, which is a typical component of embryonic skin but only scarcely expressed at the dermoepidermal junction in adult skin, is strongly re-expressed throughout the The isodesmosine (Ide) and desmosine (Des) content of collagenase-digested and hydrolyzed skin specimens was measured by amino acid analysis.…”

Interleukin-10 spot-forming cells as a novel biomarker of chronic graft-versus-host disease

“…Fibronectin was described to be strongly deposited under the basal layer of the skin in cutaneous chronic GVHD. 42 Fibronectin is an adhesive extracellular matrix glycoprotein that plays crucial roles in various cellular functions, including cell adhesion, migration, proliferation, and differentiation. 43 The CD29 expression of monocytes increases following fibronectin fragmentation.…”

“…The plates were incubated for approximately 40 h at 37 °C with 5% CO 2 in a humid atmosphere. The m. Hirayama et al 42 haematologica | 2013; 98(1) …”

Levels of extra domain A containing fibronectin in human atherosclerotic plaques are associated with a stable plaque phenotype

“…However, in diabetic patients EDA is released from the vessel wall into the circulation and EDA levels are associated with diabetes [8]. EDA is involved in many other processes and disorders related to pathophysiological circumstances in the vessel wall [4][5][6][7][8][9][10][11][12][13]. EDA levels in plasma may also represent other pathological or physiological changes and might mask the changes due to atherosclerosis.…”

“…Expression of fibronectin containing EDA is increased in pathophysiological conditions, for example, in graft versus host disease leading to fibrosis of the skin, fibrosis in lung, liver and kidney, diabetes, rheumatoid arthritis, cardiac transplantation, vascular intimal proliferation and vascular hypertension [4][5][6][7][8][9][10][11][12][13].…”