Abstract 18178: Role of Mesenchymal Stem Cell SDF-1 Release and Myocardial CXCR4 Expression in Post -MI Cardiac Repair
Introduction: Adult stem cell based repair of the heart is due to paracrine factor release. SDF-1 has been shown to affect multiple pathways involved in tissue repair and is secreted by mesenchymal stem cells (MSC). In this study we directly tested the importance of MSC SDF-1 release on myocardial response to MSC engraftment after myocardial infarction (MI).
Methods: Cardiac myocyte (CM)-CXCR4 null mice were generated using tamoxifen inducible cardiac specific cre by crossing the CXCR4 floxed with the MCM-cre mouse. Studies were performed in littermates who did (CM-CXCR4 null) or did not (control) receive tamoxifen at least 3 weeks before MI. Mice were randomly selected to receive either 100,000 GFP positive MSC or saline 1 d after MI. Cardiac stem cells (CSC) population in the heart 7 days post MI were investigated by flow cytometry. Serial echocardiography was used to assess cardiac function. The number of TUNEL positive cardiac myocytes in the infarct border zone was quantified 4 days after AMI. Vascular density and infarct size were measured 21 d after AMI.
Results: The αMHC-MerCreMer promoter is activated in both endogenous CSC and cardiac myocytes. There was a similar level of MSC engraftment in wild-type (WT) and CM-CXCR4 null mice 7 days following MSC infusion. MSC engraftment led to a significant increase of CSC recruitment (100.9%, p<0.01) in the heart of WT mice 7 days after MI that was decreased to 55.4% in CM-CXCR4 null mice. MSC treatment decreased CM apoptosis by 44% in WT mice but only 23% in CM-CXCR4 null mice (p<0.01). Consistent with improved CM survival, MSC infusion led to an 80% (p<0.05) increase in ejection fraction in WT mice compared to a 40% (p=NS) increase in CM-CXCR4 null mice despite similar levels of an increase (16%) in vascular density in the presence or absence of CM-CXCR4.
Conclusion: Our results demonstrate a specific paracrine mechanism of MSC engraftment and support an important role for SDF-1/CXCR4 in CSC recruitment and cardiac myocyte survival after AMI. Furthermore, our data demonstrate that in the absence of SDF-1 mediated increases in cardiac myocyte survival and CSC recruitment, the increase in vascular density induced by MSC engraftment is unchanged but insufficient to induce significant improvements in cardiac function after AMI.
- © 2011 by American Heart Association, Inc.