Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage

Shigeki Saito, Takayuki Nakayama, Naozumi Hashimoto, Yasuhiko Miyata, Kensuke Egashira, Norihiko Nakao, Satoshi Nishiwaki, Minoru Hasegawa, Yoshinori Hasegawa, Tomoki Naoe

    Research output: Contribution to journalArticlepeer-review

    34 Citations (Scopus)

    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-MSCinduced 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.

    Original languageEnglish
    Pages (from-to)1088-1094
    Number of pages7
    JournalAmerican Journal of Pathology
    Volume179
    Issue number3
    DOIs
    Publication statusPublished - Sep 2011

    All Science Journal Classification (ASJC) codes

    • Pathology and Forensic Medicine

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