title: Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage.
abstract: Acute respiratory distress syndrome (ARDS) is a crippling disease with no effective therapy characterized by progressive dyspnea. Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for ARDS because MSCs can attenuate inflammation and repair the damaged tissue by differentiating into several cell types. Macrophages participate in the development of ARDS; however, MSCs only weakly modulate macrophage function. The chemokine CCL2 is a potent inducer of macrophage recruitment and activation, and its expression is elevated in patients with ARDS. We established MSCs that are stably transduced by a lentiviral vector expressing 7ND, a dominant-negative inhibitor of CCL2, to enhance the therapeutic function of MSCs. 7ND-MSCs retained the innate properties of MSCs and produced a large amount of 7ND. Many 7ND-MSCs were detected in bleomycin-treated lungs (immunostaining 24 hours after injection), suggesting that MSCs could work as a drug delivery tool. Mice treated with 7ND-MSCs showed significantly milder weight loss, lung injury, collagen content, accumulation of inflammatory cells and inflammatory mediators that were induced by bleomycin, and subsequent survival benefit. No evidence of 7ND-MSC-induced toxicity was observed during or after treatment. Thus, inhibiting the effects of macrophages may greatly enhance the ability of MSCs to effect lung repair in ARDS.
authors: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Shigeki
authors: S
authors: Saito
authors: Takayuki
authors: T
authors: Nakayama
authors: Naozumi
authors: N
authors: Hashimoto
authors: Yasuhiko
authors: Y
authors: Miyata
authors: Kensuke
authors: K
authors: Egashira
authors: Norihiko
authors: N
authors: Nakao
authors: Satoshi
authors: S
authors: Nishiwaki
authors: Minoru
authors: M
authors: Hasegawa
authors: Yoshinori
authors: Y
authors: Hasegawa
authors: Tomoki
authors: T
authors: Naoe
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus; D055370:Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012128:Respiratory Distress Syndrome / Q000628:therapy; D014161:Transduction, Genetic / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; D018932:Chemokine CCL2; D001761:Bleomycin