SDF-1/CXCR4-mediated migration of transplanted bone marrow stromal cells toward areas of heart myocardial infarction through activation of PI3K/Akt.
Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are crucial for homing and migration of multiple stem cell types. Their potential role in mediating bone marrow-derived mesenchymal stem cell (BMSC) migration in areas of myocardial infarction (MI) has not been demonstrated. In this study, rat heart MI was created by left coronary artery ligation, and green fluorescent protein-labeled BMSCs were directly infused into the left ventricular cavity. Reverse transcriptase-polymerase chain reaction and Western blot analysis showed that SDF-1 was predominantly localized in the MI lesion, and its levels peaked by 3 to 7 days and were maintained at least 14 days. Additionally, this was matched with increased accumulation of BMSCs and an improvement in cardiac function. Furthermore, this effect was blocked by the phosphoinositide 3-kinase inhibitor, LY294002. In vitro experiments showed that CXCR4 expression by BMSCs was elevated during hypoxia and SDF-1 induced a concentration-dependent migration of BMSCs. This migration was CXCR4-dependent as confirmed by its total inhibition by AMD3100, a CXCR4-specific antagonist. Migration was also almost completely blocked by LY294002. Analysis showed that phosphorylated Akt was highly increased in SDF-1-treated BMSCs. Together these results demonstrated that SDF-1/CXCR4 may mediate the migration of BMSCs toward heart MI through activation of PI3K/Akt.
Yu
Jun
J
Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China.
Li
Mincai
M
Qu
Zhiling
Z
Yan
Dan
D
Li
Dujuan
D
Ruan
Qiurong
Q
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D002633:Chemotaxis; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009203:Myocardial Infarction / Q000378:metabolism* / Q000601:surgery; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation
D054377:Chemokine CXCL12; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; C486264:Cxcr4 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one