Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
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Communicated by Darwin J. Prockop, Tulane University, New Orleans, LA, May 16, 2007 (received for review April 3, 2007)
Abstract
Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1α-dependent T cell line and inhibit production of TNF-α by activated macrophages in vitro. Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-α, IL-1α, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-α and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: dphinne{at}tulane.edu
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Author contributions: L.A.O. and D.G.P. designed research; L.A.O., M.D., C.F., A.C.P., G.T., K.G., and D.G.P. performed research; L.A.O., M.D., C.F., and D.G.P. analyzed data; and L.A.O. and D.G.P. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0704421104/DC1.
- Abbreviations:
- BAL,
- bronchoalveolar lavage;
- BLM,
- bleomycin;
- IL1RN,
- interluekin 1 receptor antagonist;
- ILD,
- interstitial lung disease;
- MSC,
- mesenchymal stem cell;
- SAGE,
- serial analysis of gene expression.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury
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