TY - JOUR
T1 - Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage
AU - Saito, Shigeki
AU - Nakayama, Takayuki
AU - Hashimoto, Naozumi
AU - Miyata, Yasuhiko
AU - Egashira, Kensuke
AU - Nakao, Norihiko
AU - Nishiwaki, Satoshi
AU - Hasegawa, Minoru
AU - Hasegawa, Yoshinori
AU - Naoe, Tomoki
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2011.05.027
DO - 10.1016/j.ajpath.2011.05.027
M3 - Article
C2 - 21741938
AN - SCOPUS:80052833354
SN - 0002-9440
VL - 179
SP - 1088
EP - 1094
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -