Abstract 1841: Stromal Cell Derived Factor-1 Increases Capillary Density But Does Not Contribute To Cardiomyocyte Replacement After Experimental Myocardial Infarction

Background. The mechanisms by which regenerative therapies improve cardiac function are incompletely defined. Numerous laboratories have demonstrated that the stem cell chemoattractant Stromal cell derived factor-1 (SDF-1) improves cardiac function after myocardial infarction (MI). This study used a genetic fate-mapping approach to ask the question: Is the beneficial effect of SDF-1 delivery due to cardiomyocyte regeneration, increased capillary density, or both? Methods. We used a genetic fate-mapping system that allows “pulse-chase” studies of cardiomyocyte turnover in mice. We crossed an inducible cardiomyocyte-specific Mer-Cre-Mer transgenic mouse with Z/EG reporter mice. Using a high-efficiency 4-OH-tamoxifen protocol, we then induced Cre recombination and expression of GFP in cardiomyocytes only. SDF-1(S4V), a protease-resistant form of SDF-1, was delivered with nanofibers after coronary ligation. Results. The percentage of pulse-labeled GFP+ cardiomyocytes was 81±4% (n=6) in sham-operated mice, as anticipated with this system. GFP+ cardiomyocytes were 60±5% and 69±4% (n=11) respectively at MI border and MI remote areas of the control nanofiber group, consistent with our previous study and suggesting a significant stem/precursor cell contribution to cardiomyocyte replacement after injury (P<0.0001). GFP+ cardiomyocytes were 65±9% and 76±6% (n=10) respectively at MI border and MI remote areas of the SDF-1(S4V)-RAD group (p=ns vs nanofiber control group), indicating no significantly increase in cardiomyocyte refreshment attributable to SDF-1. However, capillary density increased from 204.7 ± 10.1/mm2 in the nanofiber control group to 308.9 ± 21.9/mm2 in SDF-1(S4V)-RAD + nanofiber group (p =0.0003). Conclusion. Using genetic “pulse-chase” fate mapping, these data indicate that the stem cell chemoattractant SDF-1 does not induce measurable adult mammalian cardiomyocyte replacement by stem/precursor cells following injury. However, SDF-1 significantly increases myocardial capillary density, suggesting that increased angiogenesis but not cardiogenesis is responsible for the beneficial effects of SDF-1 on cardiac function.

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Statin Administration Does Not Improve the Mobilization of Very Small Embryonic-Like Stem Cells (VSELs) in Contrast to Resveratrol Treatment in a Murine Model of Acute Myocardial Infarction

Physiological Research ◽

10.33549/physiolres.932390 ◽

2012 ◽

pp. 543-549 ◽

Cited By ~ 6

Author(s):

H. WANG ◽

Y.-J. YANG ◽

H.-Y. QIAN ◽

Q. ZHANG ◽

L.-J. GAO ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Stem Cell ◽

Cardiac Function ◽

Stromal Cell ◽

Statin Treatment ◽

Positive Control ◽

Short Term ◽

Cellular Cardiomyoplasty ◽

Stromal Cell Derived Factor

We have found that short-term statin treatment plus stem cell transplantation in acutely infarcted hearts improves cardiac function because statins promote the efficacy of cellular cardiomyoplasty. Autologous Sca-1+Lin-CD45-(CXCR+) very small embryonic-like stem cell (VSEL) mobilization in acute myocardial infarction (AMI) correlates with the preservation of cardiac function. Whether short-term atorvastatin (Ator) can enhance the mobilization or recruitment of VSELs in AMI is still unclear. We divided mice into 4 groups: 1) sham; 2) AMI; 3) AMI+resveratrol (RSV) as a positive control; and 4) AMI+Ator. There was an increase in the circulating VSEL/full population of leukocytes (FPL) ratio 48 hours after AMI, and AMI+RSV increased it further. Ator administration did not increase the VSEL/FPL ratio. The cardiac stromal cell-derived factor-1 (SDF-1) and SDF-1α levels were in agreement with the results of VSEL mobilization. One week after AMI, more Sca-1+CXCR+ cells were recruited to the myocardium of AMI+RSV mice but not AMI+Ator mice. Short-term Ator administration failed to upregulate cardiac SDF-1 and could not enhance the recruitment of VSELs early after AMI.

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Abstract 3899: SDF-1α Mediates the Therapeutic Effect of Human Adipose-Derived Stem Cells on Acute Myocardial Infarction Recruiting Bone Marrow-Derived Endothelial Progenitor Cells

Circulation ◽

10.1161/circ.118.suppl_18.s_500 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Masaaki Ii ◽

Ayumi Yokoyama ◽

Miki Horii ◽

Hiroshi Akimaru ◽

Takayuki Asahara

Keyword(s):

Myocardial Infarction ◽

Stem Cells ◽

Cardiac Function ◽

Therapeutic Effect ◽

Heart Diseases ◽

Capillary Density ◽

Ischemic Myocardium ◽

Control Group ◽

Adipose Derived Stem Cells ◽

Ischemic Heart Diseases

Background: Recently, human multipotent adipose-derived stem cells (hMADSs) have been isolated featuring extensive expansion capacity ex vivo. However, little is known about the therapeutic efficacy of hMADS in ischemic heart diseases. We tested the hypothesis that hMADS transplantation may contribute to cardiac functional recovery following myocardial infarction (MI). Methods and Results: Nude rats were either transplanted with hMADSs (5x10 5 /rat, n=10) or PBS (control, n=9) in ischemic myocardium immediately following MI induction. The cardiac function, infarct size and capillary density in the peri-infarct area were evaluated by echocardiography and immunostaining 28 days after surgery. The cardiac function was significantly greater with increased capillary density and reduced fibrosis area in the hMADS group than that in the control group. Next, we examined tissue regeneration in the infarct heart by the transplanted hMADSs. However, remarkable differentiation of hMADSs into any cardiac cell lineages was not detected. To explore another mechanism for the favorable effect of hMADSs, we further examined mRNA expression of cytokines in hMADSs under hypoxic conditions. Although hypoxia decreased the expressions, robust VEGF, bFGF, and SDF-1α expressions were detected in hMADSs. Notably, the stem/progenitor chemokine SDF-1α expression in hMADSs was significantly greater than that in human mesenchymal stem cells that are well known to have a therapeutic effect on ischemic heart diseases. We then focused on SDF-1α /CXCR4 axis and examined the contribution of bone marrow (BM)-derived endothelial progenitor cells (EPCs), that have CXCR4 receptor for SDF-1v, to ischemic myocardium using a Tie2/LacZ BM transplantation nude mouse model. β-gal positive EPCs are frequently observed in ischemic myocardium in the hMADS group compared to the control group. Conclusion: hMADSs exhibit a therapeutic effect on cardiac function following MI with the production of VEGF, bFGF, and SDF-1α demonstrating paracrine effects rather than direct contribution to cardiac regeneration. These findings suggest that transplanted hMADSs and recruited EPCs may synergistically promote angiogenesis playing a role in ischemic myocardium.

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