HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0742v1 26/3/789    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Jeon, E. S. Articles by Kim, J. H. Search for Related Content PubMed PubMed Citation Articles by Jeon, E. S. Articles by Kim, J. H.

THE STEM CELL NICHE

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

^aMedical Research Center for Ischemic Tissue Regeneration of Pusan National University and the Medical Research Institute, Busan, Republic of Korea;
^bDepartment of Internal Medicine,
^cDepartment of Obstetrics and Gynecology, and
^dDepartment of Laboratory Medicine, College of Medicine, Pusan National University, Busan, Republic of Korea

Key Words. Lysophosphatidic acid • Mesenchymal stem cells • Myofibroblasts • Stromal cell-derived factor-1; -smooth muscle actin

Correspondence: Jae Ho Kim, Ph.D., 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. e-mail: jhkimst{at}pusan.ac.kr

Received September 4, 2007; accepted for publication November 26, 2007.
First published online in STEM CELLS EXPRESS   December 6, 2007.



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 -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 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 -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 -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-β1-Smad signaling pathway.

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