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

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.

[1]  J. H. Lee,et al.  Hypoxia-induced expression of cellular prion protein improves the therapeutic potential of mesenchymal stem cells , 2016, Cell Death and Disease.

[2]  L. Deng,et al.  Should hypoxia preconditioning become the standardized procedure for bone marrow MSCs preparation for clinical use? , 2016, Stem cells.

[3]  E. Giannoni,et al.  Reactive Oxygen Species in Stem Cells , 2015, Oxidative medicine and cellular longevity.

[4]  J. H. Lee,et al.  The Sulfated Polysaccharide Fucoidan Rescues Senescence of Endothelial Colony‐Forming Cells for Ischemic Repair , 2015, Stem cells.

[5]  J. Nolta,et al.  Hypoxic Preconditioning of Mesenchymal Stromal Cells Induces Metabolic Changes, Enhances Survival, and Promotes Cell Retention In Vivo , 2015, Stem cells.

[6]  Changhua Wang,et al.  Cell Surface GRP78 Accelerated Breast Cancer Cell Proliferation and Migration by Activating STAT3 , 2015, PloS one.

[7]  Dan-dan Song,et al.  Endoplasmic reticulum chaperone GRP78 is involved in autophagy activation induced by ischemic preconditioning in neural cells , 2015, Molecular Brain.

[8]  A. Levchenko,et al.  Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer , 2014, Cell Death and Disease.

[9]  E. Andreeva,et al.  Mesenchymal stem cells and hypoxia: where are we? , 2014, Mitochondrion.

[10]  Sergei A. Vinogradov,et al.  Direct measurement of local oxygen concentration in the bone marrow of live animals , 2014, Nature.

[11]  Mohammad Tariqur Rahman,et al.  Hypoxic Culture Conditions as a Solution for Mesenchymal Stem Cell Based Regenerative Therapy , 2013, TheScientificWorldJournal.

[12]  W. Xue,et al.  The Role of SDF-1-CXCR4/CXCR7 Axis in the Therapeutic Effects of Hypoxia-Preconditioned Mesenchymal Stem Cells for Renal Ischemia/Reperfusion Injury , 2012, PloS one.

[13]  S. Hung,et al.  Benefits of hypoxic culture on bone marrow multipotent stromal cells. , 2012, American journal of blood research.

[14]  Abraham Weizman,et al.  Peptide-binding GRP78 protects neurons from hypoxia-induced apoptosis , 2011, Apoptosis.

[15]  S. Karlsson,et al.  Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. , 2011, Cell stem cell.

[16]  Lunxu Liu,et al.  Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells. , 2011, Lung cancer.

[17]  A. Caplan,et al.  Mesenchymal stem cells: mechanisms of inflammation. , 2011, Annual review of pathology.

[18]  B. Hardy,et al.  Peptide-binding heat shock protein GRP78 protects cardiomyocytes from hypoxia-induced apoptosis , 2010, Journal of Molecular Medicine.

[19]  D. Link,et al.  Hypoxic Preconditioning Results in Increased Motility and Improved Therapeutic Potential of Human Mesenchymal Stem Cells , 2008, Stem cells.

[20]  Guanghui Liu,et al.  Upregulation of GRP78 and caspase-12 in diastolic failing heart. , 2008, Acta biochimica Polonica.

[21]  Giselle Chamberlain,et al.  Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing , 2007, Stem cells.

[22]  Lewis C. Cantley,et al.  AKT/PKB Signaling: Navigating Downstream , 2007, Cell.

[23]  N. Hay,et al.  Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. , 2006, Cancer cell.

[24]  Makoto Nakajima,et al.  Ischemic preconditioning protects cardiomyocytes against ischemic injury by inducing GRP78. , 2006, Biochemical and biophysical research communications.

[25]  Mark A Sussman,et al.  Endoplasmic Reticulum Stress Gene Induction and Protection From Ischemia/Reperfusion Injury in the Hearts of Transgenic Mice With a Tamoxifen-Regulated Form of ATF6 , 2006, Circulation research.

[26]  Feng Zhao,et al.  Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs , 2006, Journal of cellular physiology.

[27]  K. Tanabe,et al.  Role of the unfolded protein response in cell death , 2006, Apoptosis.

[28]  R. Kaufman,et al.  The mammalian unfolded protein response. , 2003, Annual review of biochemistry.

[29]  Li Lin,et al.  HSP70 and GRP78 Induced by Endothelin-1 Pretreatment Enhance Tolerance to Hypoxia in Cultured Neonatal Rat Cardiomyocytes , 2004, Journal of cardiovascular pharmacology.

[30]  G. Semenza.  Targeting HIF-1 for cancer therapy , 2003, Nature Reviews Cancer.

[31]  Amy S. Lee,et al.  The glucose-regulated proteins: stress induction and clinical applications. , 2001, Trends in biochemical sciences.