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THE STEM CELL NICHE

Lysophosphatidic Acid Protects Mesenchymal Stem Cells Against Hypoxia and Serum Deprivation-Induced Apoptosis

^aResearch Center for Cardiovascular Regenerative Medicine, The Ministry of Health of China, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China;
^bUniversity of Hertfordshire, Faculty of Health and Human Sciences, School of Life Sciences, College Lane, Hatfield, United Kingdom

Key Words. Lysophosphatidic acid • Mesenchymal stem cells • Hypoxia/serum deprivation • Apoptosis • Survival

Correspondence: Correspondence: Xi Chen, Ph.D. and Shengshou Hu, M.D., Research Center for Cardiovascular Regenerative Medicine, the Ministry of Health of China, 167 Beilishilu, Beijing 100037, People's Republic of China. Telephone: 86-10-88398584; Fax: 86-10-88398584; e-mail: chenxifw{at}yahoo.com.cn and e-mail: huss{at}vip.sohu.com

Received on February 25, 2007; accepted for publication on September 25, 2007.

First published online in STEM CELLS EXPRESS  October 11, 2007.


Bone marrow-derived mesenchymal stem cells (MSCs) have shown great promise for cardiac repair. However, poor viability of transplanted MSCs within the ischemic heart has limited their therapeutic potential. Our previous studies have documented that hypoxia and serum deprivation (hypoxia/SD), induced MSCs apoptosis through the mitochondrial apoptotic pathway. Since serum lysophosphatidic acid (LPA) levels are known to be significantly elevated after acute myocardial infarction and that LPA enhanced survival of other cell systems, we embarked on determining whether LPA protects MSCs against hypoxia/SD-induced apoptosis. We have also investigated the potential mechanism(s) that may mediate such actions of LPA. All experiments were carried out on rat bone marrow MSCs. Apoptosis was induced by exposure of cells to hypoxia/SD in a sealed GENbox hypoxic chamber. Effects of LPA were investigated in the absence and presence of inhibitors that target either G_iproteins, the mitogen activated protein kinases ERK1/2, or phosphoinositide 3-kinase (PI3K). The data obtained showed that hypoxia/SD-induced apoptosis was significantly attenuated by LPA through Gi-coupled LPA₁ receptors linked to the downstream ERK1/2 and PI3K/Akt signaling pathways that function in parallel. Additional studies have demonstrated that hypoxia/SD-induced activation of mitochondrial dysfunction was virtually abolished by LPA treatment and that inhibition of the LPA₁ receptor, Gi proteins, the PI3K/Akt pathway, or ERKs effectively reversed this protective action of LPA. Taken together, our findings indicate that LPA is a novel, potent survival factor for MSCs and this may prove to be of considerable therapeutic significance in terms of exploiting MSC-based therapy in the infracted myocardium.

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

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