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 marrowderived 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-1b 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 1 macrophages and increased numbers of anti-inflammatory regulatory CD1631 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.

Adipose mesenchymal stromal cells minimize and repair radiation-induced oral mucositis

“…MSCs are multipotent progenitor cells that have multi-lineage differentiation potential and recently identified anti-inflammatory and immunomodulatory properties that have been applied in numerous current preclinical and clinical studies [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70].…”

“…MSCs have been used in the repair of radiation-induced skin injuries where they were administered systemically and lead to decreased radiation-induced skin fibrosis through enhancing the secretion of IL-10 and increasing the infiltration of antiinflammatory regulatory CD163(+) macrophages, decreasing the secretion of IL-1 beta and the numbers of infiltrated pro-inflammatory CD80(+) macrophages [69]. It was suggested that the autologous grafting of MSCs is more efficient than the allogenic grafting in cutaneous radiation syndrome [83].…”

Therapeutic Potential of Gingival Fibroblasts for Cutaneous Radiation Syndrome: Comparison to Bone Marrow-Mesenchymal Stem Cell Grafts

“…More recent studies of wound healing have focused on mesenchymal stem cells (MSCs)-nonhematopoietic, adherent fibroblast-like cells with intrinsic capacity for self-renewal and differentiation-as a possible cell population within the bone marrow that might contribute to cutaneous repair, particularly in radiation burns [4][5][6][7][8][9][10][11].…”

Editorial: 2013—A Year of Clinical Success and Great Scientific Innovation in the Stem Cell Field

“…Manuscripts covered many advances in understanding the fundamental mechanisms that control stem and progenitor cell fate, and advances in working toward treating all tissues, from the lower extremities to the brain. Exciting basic and translational research was reported in using stem cells to treat osteoporosis [11], spinal cord injuries [12,13], radiation-induced fibrosis [14], glaucoma [15], globoid cell leukodystrophy [16], stroke [17], and Huntington's disease [18], to name just a few. It has truly been an exciting year, as we watch the stem cell field explode.…”