Human adipose ECM alleviates radiation-induced skin fibrosis via endothelial cell-mediated M2 macrophage polarization

Somaiah Chinnapaka; Katherine S Yang; Yusuf Surucu; Fuat B Bengur; José A Arellano; Zayaan Tirmizi; Hamid Malekzadeh; Michael W Epperly; Wen Hou; Joel S Greenberger; J Peter Rubin; Asim Ejaz

doi:10.1016/j.isci.2023.107660

Human adipose ECM alleviates radiation-induced skin fibrosis via endothelial cell-mediated M2 macrophage polarization

iScience. 2023 Aug 17;26(9):107660. doi: 10.1016/j.isci.2023.107660. eCollection 2023 Sep 15.

Affiliations

¹ Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.

Abstract

Radiation therapy can lead to late radiation-induced skin fibrosis (RISF), causing movement restriction, pain, and organ dysfunction. This study evaluated adipose-derived extracellular matrix (Ad-ECM) as a mitigator of RISF. Female C57BL/6J mice that were irradiated developed fibrosis, which was mitigated by a single local Ad-ECM injection, improving limb movement and reducing epithelium thickness and collagen deposition. Ad-ECM treatment resulted in decreased expression of pro-inflammatory and fibrotic genes, and upregulation of anti-inflammatory cytokines, promoting M2 macrophage polarization. Co-culture of irradiated human fibroblasts with Ad-ECM down-modulated fibrotic gene expression and enhanced bone marrow cell migration. Ad-ECM treatment also increased interleukin (IL)-4, IL-5, and IL-15 expression in endothelial cells, stimulating M2 macrophage polarization and alleviating RISF. Prophylactic use of Ad-ECM showed effectiveness in mitigation. This study suggests Ad-ECM's potential in treating chronic-stage fibrosis.

Keywords: Cell biology; Dermatology; Fibrosis; Immunology; Stem cells research.