Abstract
C-kit positive cardiac stem cells (CSCs) have been shown to contribute to myocardial regeneration after infarction. Previously, we have shown that the c-kit ligand stem cell factor (SCF) can induce CSC migration into the infarcted area during myocardial infarction (MI). However, the precise mechanism involved is not fully understood. In this study, we found that CSCs also express C-X-C chemokine receptor type 4 (CXCR4), which is a typical member of the seven transmembrane-spanning G protein-coupled receptor (GPCR). In vitro, activation of c-kit signalling by SCF promotes migration of CSCs with increased phosphorylation of CXCR4-serine 339, p38 mitogen-activated protein kinase (p38 MAPK) and extracellular regulated protein kinases 1/2 (ERK1/2). Knockdown of CXCR4 expression by siRNA reduces SCF/c-kit-induced migration and downstream signalling. As previously reported, CXCR4-serine 339 phosphorylation is mainly regulated by GPCR kinase 6 (GRK6); thus, silencing of GRK6 expression by siRNA impairs CXCR4-serine 339 phosphorylation and migration of CSCs caused by SCF. In vivo, knockdown of GRK6 impairs the ability of CSCs to migrate into peri-infarcted areas. These results demonstrate that SCF-induced CSC migration is regulated by the transactivation of CXCR4-serine 339 phosphorylation, which is mediated by GRK6.
Highlights
C-X-C chemokine receptor type 4 (CXCR4) is a typical member of the seven transmembrane-spanning G protein-coupled receptor (GPCR) and is expressed in CSCs8, which can be activated by agonist stimulation, i.e., the stromal cell-derived factor 1 (SDF-1)
In rat aortic vascular smooth muscle cells, both platelet-derived growth factor receptors (PDGFR) and EGFR are phosphorylated in response to sphingosine 1-phosphate (S1P), which is a ligand for the S1PR family of GPCRs20, and stimulation of β1 -adrenergic receptors induces EGFR transactivation and contributes to cardioprotection[21]
When the hearts were administered both types of cardiac stem cells (CSCs) (Fig. 7C, mock cells in green and siGRK6 cells in red), we found a significant reduction in the accumulation of siGRK6 CSCs in the peri-infarcted regions, especially the region near the apex, where almost only mock cells could be found
Summary
C-X-C chemokine receptor type 4 (CXCR4) is a typical member of the seven transmembrane-spanning G protein-coupled receptor (GPCR) and is expressed in CSCs8, which can be activated by agonist stimulation, i.e., the stromal cell-derived factor 1 (SDF-1). Activation of CXCR4 by SDF-1 has been implicated in the homeostasis and activation of the immune system and influences a range of biological systems under both normal and pathological conditions[9,10,11,12] These include angiogenesis, cell survival, cell mobilization and migration, tumour growth and metastasis, and so forth[9,10,11]. In rat aortic vascular smooth muscle cells, both platelet-derived growth factor receptors (PDGFR) and EGFR are phosphorylated in response to sphingosine 1-phosphate (S1P), which is a ligand for the S1PR family of GPCRs20, and stimulation of β1 -adrenergic receptors induces EGFR transactivation and contributes to cardioprotection[21]. We have examined the potential cross-talk in the signal transduction pathways between CXCR4 and c-kit and identified a new mechanism that CXCR4-serine 339 transactivation by SCF/c-kit signalling is necessary for CSC migration
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