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TRANSLATIONAL AND CLINICAL RESEARCH: MESENCHYMAL STEM CELLS SERIES
Angiogenic Effects of Human Multipotent Stromal Cell Conditioned Medium Activate the PI3K-Akt Pathway in Hypoxic Endothelial Cells to Inhibit Apoptosis, Increase Survival, and Stimulate Angiogenesis
Shih-Chieh Hunga,b,c, Radhika R. Pochampallya, Sy-Chi Chenb, Shu-Ching Hsua, Darwin J. Prockopa
aCenter for Gene Therapy, Tulane University Health Science Center, New Orleans, Louisiana, USA;
bStem Cell Laboratory, Veterans General Hospital-Taipei, Taipei, Taiwan;
cInstitute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
Key Words. Bone marrow stromal cells • Hypoxia • Endothelial cell • Angiogenesis • Apoptosis • Human aortic endothelial cells Interleukin-6 • Therapeutic potential
Correspondence: Darwin J. Prockop, Ph.D., M.D., Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-99, New Orleans, Louisiana 70112, USA. Telephone: (504) 988-7711; Fax: (504) 988-7710; e-mail: ; or Shih-Chieh Hung, Ph.D., M.D., Department of Medical Research and Education, Veteran General Hospital-Taipei, 201, Sec2, Shih-Pai Road, Taipei, Taiwan. Telephone: 886-2-28757396; Fax: 886-2-28757396; e-mail: Received October 26, 2006; accepted for publication May 18, 2007.
First published online in STEM CELLS EXPRESS May 31, 2007.
Recent reports indicated that vascular remodeling and angiogenesis are promoted by conditioned medium from the cells referred to as multipotent stromal cells (MSCs). However, the molecular events triggered by MSC-conditioned medium (CdM) were not defined. We examined the effects of CdM from human MSCs on cultures of primary human aortic endothelial cells (HAECs). The CdM inhibited hypoxia-induced apoptosis and cell death of HAECs. It also promoted tube formation by HAECs in an assay in vitro. Conditioned medium from multipotent stromal cells incubated under hypoxic conditions in serum-free endothelial basal medium for 2 days (CdMHyp) from hypoxic culture of MSCs was more effective than conditioned medium from MSCs incubated under normoxic conditions in serum-free endothelial basal medium for 2 days from normoxic cultures of MSCs, an observation in part explained by its higher content of antiapoptotic and angiogenic factors, such as interleukin (IL)-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein (MCP)-1. The effects of CdMHyp on hypoxic HAECs were partially duplicated by the addition of IL-6 in a dose-dependent manner; however, anti-IL-6, anti-MCP-1, and anti-VEGF blocking antibodies added independently did not attenuate the effects. Also, addition of CdMHyp activated the PI3K-Akt pathway; the levels of p-Akt and several of its downstream targets were increased by CdMHyp, and both the increase in p-Akt and the increase in angiogenesis were blocked by an inhibitor of PI3K-Akt or by expression of a dominant negative gene for PI3K. CdMHyp also increased the levels of p-extracellular signal-regulated kinase (ERK), but there was a minimal effect on p-signal transducer and activator of transcription-3, and an inhibitor of the ERK1/2 pathway had no effect on hypoxia-induced apoptosis of the HAECs. The results are consistent with suggestions that administration of MSCs or factors secreted by MSCs may provide a therapeutic method of decreasing apoptosis and enhancing angiogenesis.
Disclosure of potential conflicts of interest is found at the end of this article.
