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Purpose
We investigated the roles of stem cell factor(SCF)–c-kit and stromal derived factor-1(SDF-1)–chemokine receptor type 4(CXCR4) stem cell signaling axes in transmyocardial revascularization (TMR)-enhanced engraftment of transplanted mesenchymal stem cells (MSC) in infarcted hearts.
Methods and Materials
3 weeks after LAD ligation, female Lewis rats underwent 10-channel needle TMR, followed by daily IV injections of 1 million male donor MSC for 5 days, either wild type (WT) or with knockdown (K/D) of c-kit or CXCR4, accomplished via a shRNA+plasmid in a lentiviral vector. Experimental groups included: WT MSC with or without TMR, c-kit K/D MSC with or without TMR, and CXCR4 K/D MSC with or without TMR (N=6/group).
Results
In vitro cell surface expression of c-kit (N=3) was reduced from 14±0.7% of WT MSC to 1.6±0.4% c-kit K/D MSC, and CXCR4 (N=3) was reduced from 39±10% WT MSCs to 3.7±0.7% CXCR4 K/D MSC after 1 week (p<0.05). The number of MSCs that had homed into infarct was affected by both TMR and donor cell type at 3 days(TMR, cell type, & interaction, p<0.05) and 1 week (TMR & cell type, p<0.05) after the last MSC injection, with greater MSC engraftment with TMR and with WT MSC. At 3 days, TMR significantly upregulated in vivo transcription of c-kit (TMR, p<0.05), SCF (TMR & cell type, p<0.05), CXCR4 (TMR & cell type, p<0.05), and SDF-1 (TMR & cell type, p<0.05). At 1 week, we saw similar declines in expression of c-kit (cell type, p<0.05), SCF (TMR, p<0.05), CXCR4 (TMR & cell type, p<0.05), and SDF-1 (TMR, p<0.05). At 1 week, TMR improved LVEF (N=5) when WT MSCs were infused, but K/D of either c-kit or CXCR4 completely abrogated this TMR-mediated augmentation of MSC reparative effect (TMR & cell type, p<0.05).
Conclusions
Downregulation of either c-kit or CXCR4 in MSC decreased engraftment of circulating MSC and inhibited the reparative effects of TMR. Hence, both SCF–c-kit and SDF-1–CXCR4 signaling axes are required for TMR-augmented repair of the infarcted heart.
Article info
Identification
Copyright
© 2013 Published by Elsevier Inc.
