Deciphering the fibrotic process: mechanism of chronic radiation skin injury fibrosis

Wang, Yiren; Chen, Shouying; Bao, Shuilan; Yao, Li; Wen, Zhongjian; Xu, Lixia; Chen, Xiaoman; Guo, Shengmin; Pang, Haowen; Zhou, Yun; Zhou, Ping

doi:10.3389/fimmu.2024.1338922

Cited by 7 publications

(1 citation statement)

References 141 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Skin fibrosis is a consequence of an exaggerated and prolonged wound healing response clinically manifesting as thickened, tightened, and hardened cutaneous areas that become firmly adherent to the underlying soft tissues and, ultimately, may cause considerable morbidity with loss of flexibility, joint contractures, and disfigurement [ 1 , 2 ]. The wide and heterogeneous spectrum of fibrotic skin conditions includes disorders as various as hypertrophic and keloid scars, morphea (localized scleroderma), systemic sclerosis (scleroderma), chronic graft-versus-host disease, nephrogenic fibrosing dermopathy, Dupuytren’s contracture, eosinophilic fasciitis, and chemical- and radiation-induced and post-burn trauma skin fibrosis [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. These diseases are characterized by exceptionally high medical needs and, very frequently, poor treatment effects [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Blockade of Sialylation with Decrease in Polysialic Acid Levels Counteracts Transforming Growth Factor β1-Induced Skin Fibroblast-to-Myofibroblast Transition

Fioretto,

Rosa,

Tani

et al. 2024

Cells

View full text Add to dashboard Cite

Aberrant sialylation with overexpression of the homopolymeric glycan polysialic acid (polySia) was recently reported in fibroblasts from fibrotic skin lesions. Yet, whether such a rise in polySia levels or sialylation in general may be functionally implicated in profibrotic activation of fibroblasts and their transition to myofibroblasts remains unknown. Therefore, we herein explored whether inhibition of sialylation could interfere with the process of skin fibroblast-to-myofibroblast transition induced by the master profibrotic mediator transforming growth factor β1 (TGFβ1). Adult human skin fibroblasts were pretreated with the competitive pan-sialyltransferase inhibitor 3-Fax-peracetyl-Neu5Ac (3-Fax) before stimulation with recombinant human TGFβ1, and then analyzed for polySia expression, cell viability, proliferation, migratory ability, and acquisition of myofibroblast-like morphofunctional features. Skin fibroblast stimulation with TGFβ1 resulted in overexpression of polySia, which was effectively blunted by 3-Fax pre-administration. Pretreatment with 3-Fax efficiently lessened TGFβ1-induced skin fibroblast proliferation, migration, changes in cell morphology, and phenotypic and functional differentiation into myofibroblasts, as testified by a significant reduction in FAP, ACTA2, COL1A1, COL1A2, and FN1 gene expression, and α-smooth muscle actin, N-cadherin, COL1A1, and FN-EDA protein levels, as well as a reduced contractile capability. Moreover, skin fibroblasts pre-administered with 3-Fax displayed a significant decrease in Smad3-dependent canonical TGFβ1 signaling. Collectively, our in vitro findings demonstrate for the first time that aberrant sialylation with increased polySia levels has a functional role in skin fibroblast-to-myofibroblast transition and suggest that competitive sialyltransferase inhibition might offer new therapeutic opportunities against skin fibrosis.

show abstract