Mesenchymal stem cells produce Wnt isoforms and TGF-β1 that mediate proliferation and procollagen expression by lung fibroblasts
Mesenchymal stem cells produce Wnt isoforms and TGF-β1 that mediate proliferation and procollagen expression by lung fibroblasts
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DOI：
10.1152/ajplung.90347.2008
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发表时间：
2009-11-01
影响因子：
4.9
通讯作者：
Brody, Arnold R.
中科院分区：
文献类型：
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作者：
Salazar, Keith D.;Lankford, Susan M.;Brody, Arnold R.
Salazar KD，Lankford SM，Brody AR.间充质干细胞产生Wnt亚型和TGF-β 1，介导肺成纤维细胞的增殖和前胶原表达。美国生理学杂志肺细胞分子生理学297：L1002-L1011，2009年。首次发表于2009年9月4日; doi：10.1152/ajplung.90347.2008。以前已经进行了研究，以确定间充质干细胞（MSC）是否影响肺纤维化的进展。在这里，我们询问MSC（来自小鼠骨髓和人脐带血）是否产生介导肺成纤维细胞（LF）生长和基质产生的因子。通过ELISA发现MSC条件培养基（CM）含有大量的PDGF-AA和转化生长因子-β（1）（TGF-β（1））。在MSC-CM中培养的LF细胞系和原代细胞中，增殖以浓度依赖性方式增加，但抗PDGF抗体和PDGF受体特异性抗体均不影响增殖，许多其他已知促有丝分裂因子的抗体也不影响增殖。然而，Wnt信号传导拮抗剂分泌卷曲相关蛋白-1（sFRP-1）显著抑制增殖。此外，抗Wnt 1和抗Wnt 2抗体减弱了MSC-CM诱导的增殖，并确定了Wnt 7 b的表达增加。正如在Wnt激活的细胞中预期的那样，核β-连环蛋白增加。MSC-CM中TGF-β（1）的量及其生物活性通过在酸性pH下活化来揭示。干细胞合成并释放TGF-β（1），其增加LF靶细胞的α（1）-前胶原基因表达。在MSC-CM中加入抗TGF-β抗体可阻断胶原基因表达的上调。这些数据表明，来自小鼠和人类的MSC产生Wnt蛋白和TGF-β（1），分别刺激LF增殖和基质产生，这是纤维增生性肺病的两个标志。这将是至关重要的，以确定这些因素是否可以发挥作用，试图使用MSC的治疗方法。
Salazar KD, Lankford SM, Brody AR. Mesenchymal stem cells produce Wnt isoforms and TGF-beta(1) that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 297: L1002-L1011, 2009. First published September 4, 2009; doi: 10.1152/ajplung.90347.2008.-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-beta(1) (TGF-beta(1)). 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 beta-catenin was increased. The amount of TGF-beta(1) in MSC-CM and its biological activity were revealed by activation at acidic pH. The stem cells synthesized and released TGF-beta(1) that increased alpha(1)-procollagen gene expression by LF target cells. Addition of anti-TGF-beta to the MSC-CM blocked upregulation of collagen gene expression. These data demonstrate that MSC from mice and humans produce Wnt proteins and TGF-beta(1) 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.