Abstract 16504: Multipotent Compact Bone-Derived Stem Cells Support the Injured Heart through Transdifferentiation into Five Distinct Phenotypes
Introduction: Clinical trials have demonstrated moderate functional benefits of bone marrow-derived stem cells given after myocardial infarction (MI). Some animal studies have suggested that the mechanism of this improvement is mediated by direct transdifferentiation of stem cells into adult cardiac myocytes. Hypothesis: Compact bone contains multipotent stem cells that repair the injured heart by transdifferentiating into adult cardiomyocytes and vascular cells.
Methods: Rapidly proliferating c-kit+/Sca-1+ compact bone stem cells (CBSCs) were isolated from compact bone of EGFP-transgenic mice. CBSCs were injected into the MI border zone following coronary artery ligation in EGFP-negative mice (n=13). Cardiac function was analyzed at 1, 2, 4 and 6 weeks post-MI using echocardiography and compared to animals that underwent MI surgery with saline injection (n=17) or sham surgery (n=11). Histological changes of stem cell injection sites were analyzed over time.
Results: CBSC-treated animals exhibited improved 6-week survival rate versus saline-injected controls (76.5% v. 50.4%, p=0.016). Improved cardiac function and attenuation of remodeling was observed as early as 1 week (ejection fraction [EF] = 38.8 vs. 23.8%, p=0.0002, end-diastolic volume [EDV] = 62.7 v. 109.8 μ L, p<0.0001, anterior wall thickness [AWT] = 0.86 v. 0.75 mm, p=0.07) and was sustained through 6 weeks post-MI (EF = 40.4 v. 24.7, p=0.0001, EDV = 87.1 v. 133.7μ L, p=0.01, AWT = 0.86 v. 0.68 mm, p=0.007). Engrafted cells began expressing α-sarcomeric actin, α-actinin, and connexin-43 as early as 1 week post-MI. After 6 weeks, five distinct types of EGFP-labeled CBSC-derived cells were observed: 1) cardiomyocytes expressing organized sarcomeres and GAP junctions, 2) cardiomyocyte precursor cells expressing unorganized cardiac actin, (3) small cells lacking any actin expression, (4) smooth muscle actin-positive vascular smooth muscle cells, and (5) von Willebrand factor-positive endothelial cells.
Conclusion: CBSC therapy improves post-MI survival by increasing cardiac function and attenuating remodeling, and these changes are associated with transdifferentiation of CBSCs into five distinct types of mature cardiovascular cells.
- Stem cell therapy
- Myocardial infarction
- Regenerative medicine stem cells
- Cardiac regeneration
- © 2012 by American Heart Association, Inc.