Abstract
Fibrosis, the thickening and scarring of injured connective tissue, leads to a loss of organ function. Multiple cell types, including T-cells, macrophages, fibrocytes, and fibroblasts/myofibroblasts contribute to scar formation via secretion of inflammatory factors. This event results in an increase in oxidative stress and deposition of excessive extracellular matrix (ECM), characteristic of fibrosis. Further, aging is known to predispose connective tissue to fibrosis due to reduced tissue regeneration. In this study, we investigated the anti-fibrotic activity of a flowable placental formulation (FPF) using a bleomycin-induced dermal fibrosis model in aged mice. FPF consisted of placental amnion/chorion- and umbilical tissue-derived ECM and cells. The mice were injected with either FPF or PBS, followed by multiple doses of bleomycin. Histological assessment of FPF-treated skin samples revealed reduced dermal fibrosis, inflammation, and TGF-β signaling compared to the control group. Quantitative RT-PCR and Next Generation Sequencing analysis of miRNAs further confirmed anti-fibrotic changes in the FPF-treated group at both the gene and transcriptional levels. The observed modulation in miRNAs was associated with inflammation, TGF-β signaling, fibroblast proliferation, epithelial-mesenchymal transition and ECM deposition. These results demonstrate the potential of FPF in preventing fibrosis and may be of therapeutic benefit for those at higher risk of fibrosis due to wounds, aging, exposure to radiation and genetic predisposition.
Highlights
Fibrosis is pathologically characterized by excessive buildup of extracellular matrix (ECM) resulting in the thickening of injured tissue
Hoechst 33342 and SYTOX Orange stains confirmed the presence of viable cells in flowable placental formulation (FPF) post-thaw with no significant differences observed compared to freshly-prepared FPF (Figure 1A)
To determine whether FPF diminishes the degree of fibrosis in vivo, we studied bleomycin-induced dermal injury in an aged C57BL/6 mouse model
Summary
Fibrosis is pathologically characterized by excessive buildup of extracellular matrix (ECM) resulting in the thickening of injured tissue. Fibrotic or scar tissue can be found in most tissue types and, in severe cases, can lead to tissue or organ dysfunction. Fibrosis in diseases such as end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis, and heart failure results in fatal outcomes. The resulting increase in secretion of inflammatory factors would lead to heightened levels of oxidative stress and an abnormal accumulation of ECM. These atypical changes are initiated by multiple cell types, including platelets, neutrophils, mast cells and macrophages, fibrocytes, fibroblasts and myofibroblasts. A major goal in the development of successful anti-fibrotic therapies is either restoration of a reparative phenotype in injured tissue or a reduction in fibrosis progression
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