Cancer-Derived Lysophosphatidic Acid Stimulates Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells

Authors

  • Eun Su Jeon,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Hyun Jung Moon,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Mi Jeong Lee,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Hae Young Song,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Young Mi Kim,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Mong Cho,

    1. Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Republic of Korea
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  • Dong-Soo Suh,

    1. Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Busan, Republic of Korea
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  • Man-Soo Yoon,

    1. Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Busan, Republic of Korea
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  • Chulhun L. Chang,

    1. Department of Laboratory Medicine, College of Medicine, Pusan National University, Busan, Republic of Korea
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  • Jin Sup Jung,

    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
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  • Jae Ho Kim Ph.D.

    Corresponding author
    1. Medical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea
    • Department of Physiology, School of Medicine, Pusan National University, 1-Ga, Ami-Dong, Suh-Gu, Busan, 602-739, Republic of Korea. Telephone: 82-51-240-7732; Fax: 82-51-246-6001
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Abstract

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 α-smooth muscle actin (α-SMA), a marker for myofibroblasts, in human adipose tissue-derived mesenchymal stem cells (hADSCs). The LPA-induced expression of α-SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA1 or LPA2 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 α-SMA and phosphorylation of Smad2/3. LPA-induced secretion of transforming growth factor (TGF)-β1 in hADSCs, and pretreatment of the cells with SB431542, a TGF-β type I receptor kinase inhibitor, or anti-TGF-β1 neutralizing antibody inhibited the LPA-induced expression of α-SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of α-SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of α-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-β1-Smad signaling pathway.

Disclosure of potential conflicts of interest is found at the end of this article.

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