title: Mesenchymal stem cells inhibit cutaneous radiation-induced fibrosis by suppressing chronic inflammation.
abstract: 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.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Horton
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Hudak
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Chung
authors.forename: Ayla O
authors.initials: AO
authors.lastname: White
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Scroggins
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Burkeen
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Citrin
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D015870:Gene Expression; D018836:Inflammation Mediators / Q000502:physiology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D012867:Skin / Q000276:immunology / Q000473:pathology / Q000528:radiation effects; D012871:Skin Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy*
chemical_list: D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D047889:Receptors, Tumor Necrosis Factor, Type II; D016753:Interleukin-10
keywords: Chronic inflammation; Dermal fibrosis; Ionizing radiation; Mesenchymal stem cell
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