Hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor-1α-CXCR4 axis

• Published in: PloS one Vol. 7; no. 7; p. e37948
• Main Authors: Yan, Fengdi, Yao, Yuyu, Chen, Lijuan, Li, Yefei, Sheng, Zulong, Ma, Genshan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.07.2012; Public Library of Science (PLoS)
• Subjects: AKT protein; Animals; Apoptosis; Bcl-2 protein; Beads; Biology; Bone marrow; c-Kit protein; Cardiology; Cardiomyocytes; Cardiomyopathy; Cell Hypoxia; Cell Movement; Cell Survival; Cell- and Tissue-Based Therapy; Cells (biology); Chemokine CXCL12 - metabolism; Chemokines; Cloning; CXCR4 protein; Cytometry; Fibroblasts; Flow cytometry; Gene expression; Genes; Heart; Heart diseases; Hypoxia; Hypoxia-inducible factors; Ischemia; Ischemic Preconditioning, Myocardial - methods; Leukemia; Male; Medical imaging; Medical schools; Medicine; Metastasis; Mice; Mice, Inbred C57BL; Myocardial infarction; Myocardial Infarction - pathology; Myocardial Infarction - therapy; Myocardium; Myocardium - pathology; Oxidative stress; Phenotype; Preconditioning; Receptors, CXCR4 - metabolism; Retention; Stem cells; Stem Cells - metabolism; Stem Cells - pathology; Studies; Survival; Therapy; Tissue engineering; Tomography; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0037948

Cardiac progenitor cells (CPCs) have been shown to be suitable in stem cell therapy for resurrecting damaged myocardium, but poor retention of transplanted cells in the ischemic myocardium causes ineffective cell therapy. Hypoxic preconditioning of cells can increase the expression of CXCR4 and pro-survival genes to promote better cell survival; however, it is unknown whether hypoxia preconditioning will influence the survival and retention of CPCs via the SDF-1α/CXCR4 axis. CPCs were isolated from adult mouse hearts and purified by magnetic activated cell sorting using c-kit magnetic beads. These cells were cultured at various times in either normoxic or hypoxic conditions, and cell survival was analyzed using flow cytometry and the expression of hypoxia-inducible factor-1α (HIF-1α), CXCR4, phosphorylated Akt and Bcl-2 were measured by Western blot. Results showed that the expression of pro-survival genes significantly increased after hypoxia treatment, especially in cells cultured in hypoxic conditions for six hours. Upon completion of hypoxia preconditioning from c-kit+ CPCs for six hours, the anti-apoptosis, migration and cardiac repair potential were evaluated. Results showed a significant enhancement in anti-apoptosis and migration in vitro, and better survival and cardiac function after being transplanted into acute myocardial infarction (MI) mice in vivo. The beneficial effects induced by hypoxia preconditioning of c-kit+ CPCs could largely be blocked by the addition of CXCR4 selective antagonist AMD3100. Hypoxic preconditioning may improve the survival and retention of c-kit+ CPCs in the ischemic heart tissue through activating the SDF-1α/CXCR4 axis and the downstream anti-apoptosis pathway. Strategies targeting this aspect may enhance the effectiveness of cell-based cardiac regenerative therapy.