Allogeneic Adipose Tissue-derived Matrix Mitigate Radiation-induced Fibrosis (RIF)
Year: 2022
Type: article
Abstract: PURPOSE: Radiation-induced fibrosis (RIF) is a complex tissue response characterized by massive deposition of extracellular matrix (ECM) and excessive fibroblast proliferation resulting in loss of tissue function and quality of life. (1) In this study, we tested the efficacy of allograft adipose tissue-derived matrix (AATM) to mitigate RIF. METHODS: We used 40 Gy hind limb irradiated C57BL/6 mice as a skin fibrosis model and injected 200 μl AATM on the 14th post-irradiation day to investigate the inhibition of fibrosis on day 40. PBS and adipose stem cell (ASC) injection were negative and positive controls, respectively. The degree of limb excursion, skin epithelium thickness, and collagen deposition was measured as a marker of fibrosis. Molecular changes in treated and control skins were measured at gene and protein levels using real-time PCR and Luminex assay respectively. As a possible contributor to mitigation, the presence of hepatocyte growth factor (HGF) was measured in AATM using HGF- ELISA assay. In vitro, trans-well studies were performed to analyze the effect of direct co-culture of irradiated cells with AATM on pro-fibrotic gene expressions. RESULTS: Our results demonstrate that a single dose of 200 μl of AATM mitigates fibrosis. The mitigation efficiency of AATM was comparable to autologous ASCs. At day 40, epithelial thickness, collagen depositions, and limb excursion were similar to ASC treatment and were significantly better than PBS treated cohort. Real-time PCR analysis reveals the down-regulation in the expression of pro-fibrotic genes TGF-β, CTGF, Col1, Col2, and TNF-alpha in AATM treated mice. Similarly, direct co-culture studies revealed downregulation of pro-fibrotic genes in irradiated fibroblast upon co-culture with AATM. ELISA results showed the presence of HGF. The noncontact trans-well co-culture of HGF knockout ASCs above a monolayer of irradiated mouse bone marrow stromal cells failed to downregulate fibrosis-related gene TGF-β expression. CONCLUSION: Our findings suggest that allogeneic adipose tissue-derived matrix (AATM) is an effective therapeutic option to mitigate fibrosis. Further studies to optimize the time and dose of the therapy will be a significant step forward towards clinical adaptation as a RIF mitigator. REFERENCES: 1. Borrelli MR, Shen AH, Lee GK, Momeni A, Longaker MT, Wan DC. Radiation-induced skin fibrosis. Annals of Plastic Surgery. 2019;83(4S). doi:10.1097/sap.0000000000002098
Authors: Yusuf Surucu, J. Peter Rubin, Asim Ejaz
Institution: University of Pittsburgh
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,195
OpenAlex ID: W4385327024