Submitted on September 4, 2007
Accepted on November 26, 2007
Cancer-Derived Lysophosphatidic Acid Stimulates Differentiation of Human Mesenchymal Stem Cells to Myofibroblast-Like Cells
Eun Su Jeon 1,
Hyun Jung Moon 1,
Mi Jeong Lee 1,
Hae Young Song 1,
Young Mi Kim 1,
Mong Cho 2,
Dong-Soo Suh 3,
Man-Soo Yoon 3,
Chulhun L. Chang 4,
Jin Sup Jung 1,
Jae Ho Kim 1*
1 Medical Research Center for Ischemic Tissue Regeneration of Pusan National University the Medical Research Institute, Busan 602-739, Republic of Korea.
2 Department of Internal Medicine, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea
3 Department of Obstetrics and Gynecology, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea
4 Department of Laboratory Medicine, College of Medicine, Pusan National University, Busan 602-739, Republic of Korea
* To whom correspondence should be addressed. E-mail: jhkimst{at}pusan.ac.kr.
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Abstract |
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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 a pivotal role of cancer-associated myofibroblasts played in tumorigenesis through secreting stromal cell-derived factor-1 (SDF-1). In the present study, we demonstrate that LPA induces expression of 
-smooth muscle actin (-SMA), a marker for myofibroblasts, in human adipose tissue-derived mesenchymal stem cells (hADSCs). The LPA-induced expression of -SMA was completely abrogated by pretreatment of the cells with Ki16425, an antagonist of LPA receptors, or by silencing LPA1 or LPA2 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 -SMA and phosphorylation of Smad2/3. LPA induced secretion of TGF-
1 in hADSCs, and pretreatment of the cells with SB-431542, a TGF- type I receptor kinase inhibitor, or anti-TGF-1 neutralizing antibody inhibited the LPA-induced expression of -SMA and phosphorylation of Smad2. Furthermore, ascites from ovarian cancer patients or conditioned medium from ovarian cancer cells induced expression of -SMA and phosphorylation of Smad2, and pretreatment of the cells with Ki16425 or SB431542 abrogated the expression of -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-1-Smad signaling pathway.
Key Words.
Lysophosphatidic acid, Mesenchymal stem cells, Myofibroblasts, Stromal cell-derived factor-1, -smooth muscle actin
