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Int. J. Mol. Sci. 2017, 18(6), 1320; doi:10.3390/ijms18061320

Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis

1
Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA
2
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 336-745, Korea
3
Departments of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 330-930, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Gehua Zhen
Received: 1 March 2017 / Revised: 10 June 2017 / Accepted: 17 June 2017 / Published: 21 June 2017
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
View Full-Text   |   Download PDF [3249 KB, uploaded 21 June 2017]   |  

Abstract

Mesenchymal stem cells (MSC) are ideal materials for stem cell-based therapy. As MSCs reside in hypoxic microenvironments (low oxygen tension of 1% to 7%), several studies have focused on the beneficial effects of hypoxic preconditioning on MSC survival; however, the mechanisms underlying such effects remain unclear. This study aimed to uncover the potential mechanism involving 78-kDa glucose-regulated protein (GRP78) to explain the enhanced MSC bioactivity and survival in hindlimb ischemia. Under hypoxia (2% O2), the expression of GRP78 was significantly increased via hypoxia-inducible factor (HIF)-1α. Hypoxia-induced GRP78 promoted the proliferation and migration potential of MSCs through the HIF-1α-GRP78-Akt signal axis. In a murine hind-limb ischemia model, hypoxic preconditioning enhanced the survival and proliferation of transplanted MSCs through suppression of the cell death signal pathway and augmentation of angiogenic cytokine secretion. These effects were regulated by GRP78. Our findings indicate that hypoxic preconditioning promotes survival, proliferation, and angiogenic cytokine secretion of MSCs via the HIF-1α-GRP78-Akt signal pathway, suggesting that hypoxia-preconditioned MSCs might provide a therapeutic strategy for MSC-based therapies and that GRP78 represents a potential target for the development of functional MSCs. View Full-Text
Keywords: mesenchymal stem cell; hypoxia; 78-kDa glucose-regulated protein; cell survival; proliferation; ischemic injury mesenchymal stem cell; hypoxia; 78-kDa glucose-regulated protein; cell survival; proliferation; ischemic injury
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lee, J.H.; Yoon, Y.M.; Lee, S.H. Hypoxic Preconditioning Promotes the Bioactivities of Mesenchymal Stem Cells via the HIF-1α-GRP78-Akt Axis. Int. J. Mol. Sci. 2017, 18, 1320.

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