title: Gene-modified mesenchymal stem cells protect against radiation-induced lung injury.
abstract: Radiation-induced lung injury (RILI) presents a common and major obstacle in the radiotherapy of thoracic cancers. The aim of this study was to examine whether RILI could be alleviated by mesenchymal stem cells (MSCs) expressing soluble transforming growth factor-β (TGF-β) type II receptor via an adenovirus (Ad-sTβR). Here, we systemically administered male MSCs into female mice challenged with thoracic irradiation. The data showed that either MSCs or Ad-sTβR transduced MSCs (Ad-sTβR-MSCs) specifically migrated into radiation-injured lung. Ad-sTβR-MSCs obviously alleviated lung injury, as reflected by survival and histopathology data, as well as the assays of malondialdehyde (MDA), hydroxyproline, plasma cytokines, and the expression of connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). Furthermore, MSCs and Ad-sTβR-MSCs could adopt the characteristics of alveolar type II (ATII) cells. However, the MSCs levels in the lungs were relatively low to account for the noted therapeutic effects, suggesting the presence of other mechanisms. In vivo, MSCs-conditioned medium (MSCs CM) significantly attenuated RILI. In vitro, MSCs CM protected ATII cells against radiation-induced apoptosis and DNA damage, and modulated the inflammatory response, indicating the beneficial effects of MSCs are largely due to its paracrine activity. Our results provide a novel insight for RILI therapy that currently lack efficient treatments.
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, PR China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xue
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: You
authors.initials: Y
authors.lastname: Lu
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Lan
authors.forename: Shurui
authors.initials: S
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Sun
authors.forename: Li
authors.initials: L
authors.lastname: Jia
authors.forename: Xianming
authors.initials: X
authors.lastname: Mo
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004249:DNA Damage; D005260:Female; D005822:Genetic Vectors; D006909:Hydroxyproline / Q000097:blood; D008168:Lung / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D019899:Paracrine Communication; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017564:Radiation Pneumonitis / Q000473:pathology* / Q000628:therapy*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C526318:CCN2 protein, mouse; D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D055513:Connective Tissue Growth Factor; D008315:Malondialdehyde; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D006909:Hydroxyproline