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This Article Full Text Full Text (PDF) All Versions of this Article: 297/5/L1002    most recent 90347.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Salazar, K. D. Articles by Brody, A. R. PubMed PubMed Citation Articles by Salazar, K. D. Articles by Brody, A. R.

Mesenchymal stem cells produce Wnt isoforms and TGF-β₁ that mediate proliferation and procollagen expression by lung fibroblasts

Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, North Carolina

Submitted 12 June 2008 ; accepted in final form 1 September 2009

Studies have been carried out previously to determine whether mesenchymal stem cells (MSC) influence the progression of pulmonary fibrosis. Here, we asked whether MSC (derived from mouse bone marrow and human umbilical cord blood) produce factors that mediate lung fibroblast (LF) growth and matrix production. MSC-conditioned media (CM) were found by ELISA to contain significant amounts of PDGF-AA and transforming growth factor-β₁ (TGF-β₁). Proliferation was increased in a concentration-dependent manner in LF cell lines and primary cells cultured in MSC-CM, but neither anti-PDGF antibodies nor PDGF receptor-specific antibodies affected proliferation, nor did a number of other antibodies to well-known mitogenic factors. However, proliferation was significantly inhibited by the Wnt signaling antagonist, secreted frizzled related protein-1 (sFRP-1). In addition, anti-Wnt1 and anti-Wnt2 antibodies attenuated MSC-CM-induced proliferation, and increased expression of Wnt7b was identified. As would be expected in cells activated by Wnt, nuclear β-catenin was increased. The amount of TGF-β₁ in MSC-CM and its biological activity were revealed by activation at acidic pH. The stem cells synthesized and released TGF-β₁ that increased ₁-procollagen gene expression by LF target cells. Addition of anti-TGF-β to the MSC-CM blocked upregulation of collagen gene expression. These data demonstrate that MSC from mice and humans produce Wnt proteins and TGF-β₁ that respectively stimulate LF proliferation and matrix production, two hallmarks of fibroproliferative lung disease. It will be essential to determine whether these factors can play a role in attempts to use MSC for therapeutic approaches.

peptide growth factors; pulmonary fibrosis