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: Shigeki Saito, Takayuki Nakayama, Naozumi Hashimoto, Yasuhiko Miyata, Kensuke Egashira, Norihiko Nakao, Satoshi Nishiwaki, Minoru Hasegawa, Yoshinori Hasegawa, Tomoki Naoe
• Journal: The American journal of pathology (Am J Pathol) Vol. 179 Issue 3 Pg. 1088-94 (Sep 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21741938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antibiotics, Antineoplastic
• Chemokine CCL2
• Bleomycin

Topics

• Animals
• Antibiotics, Antineoplastic (toxicity)
• Bleomycin (toxicity)
• Chemokine CCL2 (antagonists & inhibitors, genetics)
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Lentivirus
• Lung Injury (chemically induced, prevention & control)
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells (physiology)
• Mice
• Mice, Inbred C57BL
• Respiratory Distress Syndrome (therapy)
• Transduction, Genetic (methods)