Altered ECM deposition by diabetic foot ulcer‐derived fibroblasts implicates fibronectin in chronic wound repair

Abstract

Current chronic wound treatments often fail to promote healing of diabetic foot ulcers (DFU), leading to amputation and increased patient morbidity. A critical mediator of proper wound healing is the production, assembly, and remodeling of the extracellular matrix (ECM) by fibroblasts. However, little is known about how these processes are altered in fibroblasts within the DFU microenvironment. Thus, we investigated the capacity of multiple, primary DFU-derived fibroblast strains to express, produce, and assemble ECM proteins compared to diabetic patient-derived fibroblasts and healthy donor-derived fibroblasts. Gene expression microarray analysis demonstrated differential expression of ECM and ECM-regulatory genes by DFU-derived fibroblasts which translated to functional differences in a 3D in vitro ECM tissue model. DFU-derived fibroblasts produced thin, fibronectin-rich matrices and responded abnormally when challenged with transforming growth factor-beta (TGF-β), a key regulator of matrix production during healing. These results provide novel evidence that DFU-derived fibroblasts contribute to the defective matrices of DFUs and chronic wound pathogenesis.

Fibronectin 1 promotes migration and invasion of papillary thyroid cancer and predicts papillary thyroid cancer lymph node metastasis

“…As an EMT marker, fibronectin is involved in cell adhesion and migration, including embryogenesis,17 wound healing,18 blood coagulation,19 osteogenesis,20 and metastasis 21,22. EMT is a process involved in embryonic development, during which cells lose their epithelial features and adopt characteristics of mesenchymal cells.…”

Acellular dermal matrix scaffolds coated with connective tissue growth factor accelerate diabetic wound healing by increasing fibronectin through PKC signalling pathway

“…Thus, CTGF loaded on ADM scaffolds is a powerful and cost‐effective strategy for improving diabetic wound healing by increasing the lifetime of CTGF and by providing a platform for regional delivery of CTGF. Previous literature reported that chronic wounds in diabetes mainly occur due to the lack of different macromolecular proteins of the ECM (Maione et al, ; Pankov & Yamada, ). FN, as one composition of ECM, has been proved to be induced by CTGF through PKC signalling pathway in human dermal fibroblasts (Twigg et al, ).Therefore, we determined whether CTGF loaded on ADM scaffolds increases the expression of FN for accelerated diabetic wound healing through the PKC signalling pathway in this experiment.…”

Descriptive vs mechanistic scientific approach to study wound healing and its inhibition: Is there a value of translational research involving human subjects?

“…Most importantly, we can utilize this knowledge to further optimize preclinical models that will better account for clinical hallmarks, confirm the findings from human tissue samples and test for potential effects of novel therapeutic modalities in a complex but more “improved” setting. Recent advances in organotypic skin models utilizing patient's cells and micro‐engineered models of functional human skin, known as organs‐on‐chip, could provide the basis for preclinical assays with greater translational power. A chronic wound organotypic model assembled with primary DFU‐derived fibroblasts and healthy keratinocytes was established, and it maintained the main pathological phenotype of DFUs .…”

“…Recent advances in organotypic skin models utilizing patient's cells and micro‐engineered models of functional human skin, known as organs‐on‐chip, could provide the basis for preclinical assays with greater translational power. A chronic wound organotypic model assembled with primary DFU‐derived fibroblasts and healthy keratinocytes was established, and it maintained the main pathological phenotype of DFUs . More advanced organ‐on‐a‐chip technologies mimicking multilevel organ functions are also being developed and may circumvent the need for animal wound models altogether .…”

“…In vitro studies have shown that primary cells isolated from chronic wounds maintain tissue characteristics and show altered proliferative and migratory capacity accompanied with an inability to respond to wound‐healing stimuli such as growth factors and cytokines . While the actions of multiple cell types are tightly regulated by growth factors, cytokines and signalling molecules during the acute wound‐healing process, this regulation, and interplay between different signalling factors, is dysregulated in chronic wounds .…”