Cancer-derived lysophosphatidic acid stimulates differentiation of human mesenchymal stem cells to myofibroblast-like cells

被引：142

作者：

Jeon, Eun Su ^{[1
]}

Moon, Hyun Jung ^{[1
]}

Lee, Mi Jeong ^{[1
]}

Song, Hae Young ^{[1
]}

Kim, Young Mi ^{[1
]}

Cho, Mong ^{[4
]}

Suh, Dong-Soo ^{[3
]}

Yoon, Man-Soo ^{[3
]}

Chang, Chulhun L. ^{[2
]}

Jung, Jin Sup ^{[1
]}

Kim, Jae Ho ^{[1
]}

机构：

[1] Pusan Natl Univ, Sch Med, Dept Physiol, Med Res Ctr Ischem Tissue Regenerat, Pusan 602739, South Korea

[2] Pusan Natl Univ, Coll Med, Dept Lab Med, Pusan 602739, South Korea

[3] Pusan Natl Univ, Coll Med, Dept Obstet & Gynecol, Pusan 602739, South Korea

[4] Pusan Natl Univ, Coll Med, Dept Internal Med, Pusan 602739, South Korea

来源：

STEM CELLS | 2008年 / 26卷 / 03期

关键词：

lysophosphatidic acid; mesenchymal stem cells; myofibroblasts; stromal cell-derived factor-1; alpha-smooth muscle actin;

D O I：

10.1634/stemcells.2007-0742

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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.

引用

页码：789 / 797

页数：9

共 55 条

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