Abstract
Stromal cell-derived factor 1 (SDF-1) is a chemokine that can be expressed in injured cardiomyocytes after myocardial infarction (MI). By combining with its receptor CXCR4, SDF-1 induced stem and progenitor cells migration. CXCR7, a novel receptor for SDF-1, has been identified recently. We aimed to explore the roles of SDF-1/CXCR4 and SDF-1/CXCR7 pathway and their crosstalk in CSCs migration. In the present study, CXCR4 and CXCR7 expression were identified in CSCs. Transwell assay showed that SDF-1 caused CSCs migration in a dose- and time-dependent manner, which could be significantly suppressed by CXCR4 or CXCR7 siRNA. Phospho-ERK, phospho-Akt and Raf-1 significantly elevated in CSCs with SDF-1 stimulation. Knockdown of CXCR4 or CXCR7 significantly decreased phospho-ERK or phospho-Akt, respectively, and eventually resulted in the inhibition of CSCs migration. Moreover, western blot showed that MK2206 (Akt inhibitor) increased the expression of phospho-ERK and Raf-1, whereas PD98059 (ERK inhibitor) had no effect on phospho-Akt and Raf-1. GW5074 (Raf-1 inhibitor) upregulated the expression of phospho-ERK, but had no effect on phospho-Akt. The present study indicated that SDF-1/CXCR7/Akt and SDF-1/CXCR4/ERK pathway played important roles in CSCs migration. Akt phosphorylation inhibited Raf-1 activity, which in turn dephosphorylated ERK and negatively regulated CSCs migration.
Highlights
In 2005, SDF-1 was revealed to bind a second chemokine receptor CXCR7 with an even 10-fold higher affinity compared with CXCR414
The expressions of CXCR4 and CXCR7 in cardiac stem cells (CSCs) were determined by reverse transcription (RT)-PCR and western blot in which 4T1 cells were treated as a positive control (Fig. 1B,C)
All these results indicated that CXCR4 and CXCR7 could be detected in CSCs
Summary
In 2005, SDF-1 was revealed to bind a second chemokine receptor CXCR7 with an even 10-fold higher affinity compared with CXCR414. Recent reports indicated that CXCR7 can activate Akt, MAPK, and JAK/STAT3 cascades, either by direct modulation, through a β -arrest independent pathway[26,27,28,29], or after heterodimerization with CXCR418,20,28,30. Based on these findings, the aim of the present study was to elucidate the role of SDF-1/CXCR4 and SDF-1/CXCR7 pathway in regulating CSCs migration and explore the crosstalk of the signal cascades involving in it
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