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Transmyocardial Revascularization Enhances Bone Marrow Stem Cell Engraftment in Infarcted Hearts Through SCF—C-kit and SDF-1—CXCR4 Signaling Axes

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Abstract

Background

We investigated the roles of stem cell factor (SCF)–c-kit and stromal derived factor-1 (SDF-1)–CXCR4 signaling axes in transmyocardial revascularization (TMR)-enhanced engraftment of transplanted bone marrow stem cells (BMSCs) in infarcted hearts.

Methods

3 weeks after LAD ligation, female Lewis rats underwent 10-channel needle-TMR, followed by daily IV injections of 1 million male donor BMSC 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 (N = 6/group).

Results

In our rat infarct model, 3 days after last BMSC injection, the number of BMSCs that homed into infarct was affected by both TMR and donor cell type, with greater BMSC engraftment with TMR and with WT BMSC (TMR, cell type, and interaction, P < 0.05). At 1 week, these differences persisted (TMR and cell type, P < 0.05). At 3 days, TMR significantly upregulated transcription of c-kit (TMR, p < 0.05), SCF (TMR and cell type, P < 0.05), CXCR4 (TMR and cell type, p < 0.05), and SDF-1 (TMR and 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 and cell type, P < 0.05), and SDF-1 (TMR, P < 0.05). At 1 week, TMR improved LV ejection fraction (LVEF) (N = 5) when WT BMSCs were infused, but knockdown of either c-kit or CXCR4 completely abrogated this TMR-mediated augmentation of BMSC reparative effect (TMR and cell type, P < 0.05).

Conclusions

Downregulation of either c-kit or CXCR4 in BMSC decreased engraftment of circulating BMSC and inhibited reparative effects of TMR.

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Acknowledgments

TMY holds the Angelo & Lorenza DeGasperis Chair in Cardiovascular Surgery Research.

Conflict of Interest

The authors declare no potential conflicts of interest.

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Authors and Affiliations

  1. Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada

    Uswa Shahzad, Guangming Li, Yaoguang Zhang, Ren-Ke Li, Vivek Rao & Terrence M. Yau

  2. McEwen Center for Regenerative Medicine, Toronto General Hospital, Toronto, ON, Canada

    Uswa Shahzad, Guangming Li, Yaoguang Zhang, Ren-Ke Li, Vivek Rao & Terrence M. Yau

  3. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Uswa Shahzad

  4. Collaborative Program in Cardiovascular Science, University of Toronto, Toronto, ON, Canada

    Uswa Shahzad

  5. Department of Surgery, University of Toronto, Toronto, ON, Canada

    Ren-Ke Li, Vivek Rao & Terrence M. Yau

  6. Angelo & Lorenza DeGasperis Chair in Cardiovascular Surgery Research, 4N-470, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON, Canada, M5G2C4

    Terrence M. Yau

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  1. Uswa Shahzad
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Correspondence to Terrence M. Yau.

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Shahzad, U., Li, G., Zhang, Y. et al. Transmyocardial Revascularization Enhances Bone Marrow Stem Cell Engraftment in Infarcted Hearts Through SCF—C-kit and SDF-1—CXCR4 Signaling Axes. Stem Cell Rev and Rep 11, 332–346 (2015). https://doi.org/10.1007/s12015-014-9571-7

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