Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells
Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells
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DOI：
10.1634/stemcells.2007-0742
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Kim, Jae Ho
中科院分区：
文献类型：
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作者：
Jeon, Eun Su;Moon, Hyun Jung;Kim, Jae Ho
溶血磷脂酸（LPA）在卵巢癌患者腹水中富集，并参与卵巢癌细胞的生长和侵袭。越来越多的证据表明，癌症相关肌成纤维细胞通过分泌基质细胞衍生因子-1（SDF-1）在肿瘤发生中发挥关键作用。在本研究中，我们证明，LPA诱导表达α-平滑肌肌动蛋白（α-SMA），肌成纤维细胞的标志物，在人脂肪组织来源的间充质干细胞（hADSC）。通过用Ki 16425（LPA受体的拮抗剂）预处理细胞或通过用小干扰RNA（siRNA）沉默LPA 1或LPA 2亚型表达，LPA诱导的α-SMA表达被完全废除。LPA引起Smad 2/3的磷酸化，并且siRNA介导的内源性Smad 2/3的耗竭或Smad 7（抑制性Smad）的腺病毒表达废除了LPA诱导的α-SMA表达和Smad 2/3的磷酸化。LPA诱导的hADSC中转化生长因子（TGF）-β 1的分泌，以及用SB 431542（TGF-β I型受体激酶抑制剂）或抗TGF-β 1中和抗体预处理细胞，可抑制LPA诱导的α-SMA表达和Smad 2磷酸化。此外，卵巢癌患者的腹水或卵巢癌细胞的条件培养基诱导α-SMA的表达和Smad 2的磷酸化，并且用Ki 16425或SB 431542预处理细胞废除α-SMA的表达和Smad 2的磷酸化。此外，LPA增加了hADSCs中SDF-1的表达，并且用Ki 16425或SB 431562预处理细胞减弱了LPA刺激的SDF-1的表达。这些结果表明，癌源性LPA通过激活自分泌TGF-β 1-Smad信号通路刺激hADSC向肌纤维母细胞样细胞分化并增加SDF-1表达。
Lysophosphatidic acid (LPA) is enriched in ascites of ovarian cancer patients and is involved in growth and invasion of ovarian cancer cells. Accumulating evidence suggests cancer-associated myofibroblasts play a pivotal role in tumorigenesis through secreting stromal cell-derived factor-1 (SDF-1). In the present study, we demonstrate that LPA induces expression of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, in human adipose tissue-derived mesenchymal stem cells (hADSCs). The LPA-induced expression of alpha-SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA 1 or LPA 2 isoform expression with small interference RNA (siRNA). LPA elicited phosphorylation of Smad2/3, and siRNA-mediated depletion of endogenous Smad2/3 or adenoviral expression of Smad7, an inhibitory Smad, abrogated the LPA induced expression of alpha-SMA and phosphorylation of Smad2/3. LPA-induced secretion of transforming growth factor (TGF)-beta 1 in hADSCs, and pretreatment of the cells with SB431542, a TGF-beta type I receptor kinase inhibitor, or anti-TGF-beta 1 neutralizing antibody inhibited the LPA-induced expression of alpha-SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of alpha-SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of alpha-SMA and phosphorylation of Smad2. In addition, LPA increased the expression of SDF-1 in hADSCs, and pretreatment of the cells with Ki16425 or SB431562 attenuated the LPA-stimulated expression of SDF-1. These results suggest that cancer-derived LPA stimulates differentiation of hADSCs to myofibroblast-like cells and increases SDF-1 expression through activating autocrine TGF-beta 1-Smad signaling pathway.