Open AccessMesenchymal stem cells inhibit cutaneous radiation‐induced fibrosis by suppressing chronic inflammation
Author(s) -
Horton Jason A.,
Hudak Kathryn E.,
Chung Eun Joo,
White Ayla O.,
Scroggins Bradley T.,
Burkeen Jeffrey F.,
Citrin Deborah E.
Publication year - 2013
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1483
Subject(s) - mesenchymal stem cell , fibrosis , biology , proinflammatory cytokine , inflammation , cancer research , cd163 , tumor necrosis factor alpha , bone marrow , immunology , stromal cell , m2 macrophage , pathology , macrophage , microbiology and biotechnology , medicine , in vitro , biochemistry
Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow‐derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR‐induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis‐targeted assay demonstrated increased expression of interleukin‐10 (IL‐10) and decreased expression of IL‐1β in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80 + macrophages and increased numbers of anti‐inflammatory regulatory CD163 + macrophages in irradiated skin of BMSC‐treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL‐10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor‐receptor 2 (TNF‐R2) mediates IL‐10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation‐induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF‐R2‐dependent fashion. S tem C ells 2013;31:2231–2241