Abstract 711: Intracoronary Injection of Autologous Mesenchymal Stem Cells (MSCs) Increases the Myocardial Localization of CD133+ Hematopoietic Stem Cells (HSCs) in Swine with Hibernating Myocardium
Background: We previously demonstrated that mesenchymal stem cells (MSCs) improve function without altering coronary flow in swine with hibernating myocardium. Since we did not identify myocytes that were derived from MSCs, we tested the hypothesis that MSCs effect cardiac repair by mobilizing cardiac precursors to the myocardium from bone marrow derived HSCs.
Methods: Swine (n=17) with hibernating myocardium from a chronic LAD occlusion were studied 4-months after instrumentation in the closed-chest sedated state (propofol). Autologous MSCs expanded ex vivo (44x106 cells, n=10) were injected into the major coronary arteries. We assessed regional flow and function 2 weeks (n=6) and 4 weeks (n=4) after MSCs vs. untreated hibernating myocardium (n=7) and sham controls (n=5).
Results: LAD wall thickening increased from 2.3 ± 0.4 mm in untreated to 4.4 ± 0.6 mm after MSCs (p<0.05) with no change in resting (0.96 ± 0.11 ml/min/g in untreated to 1.07± 0.12 ml/min/g in MSCs, p-ns) or vasodilated adenosine flow (1.11 ± 0.16 ml/min/g in untreated to 1.26± 0.16 ml/min/g in MSCs, p-ns). Immunohistochemical staining (Table⇓) was performed to evaluate the frequency of myocytes in the growth phase of the cell cycle (Ki-67), myocardial HSCs (CD133+) and co-localization of GATA-4 with CD133+ cells using confocal microscopy. MSCs increased Ki-67 positive myocytes in parallel with CD133+ cells with values peaking at 2 weeks and falling 4 weeks after MSCs. After i.c. MSCs, 4.8 ± 1.4% of myocardial CD133+ cells co-expressed GATA-4. There was a prominent increase in myocyte number (nuclear density) with a reduction in myocyte diameter as compared to untreated hibernating animals.
Conclusion: These data indicate that intracoronary MSCs induce HSCs to home to the heart. MSCs lead to an increase in myocytes in the cell cycle, a reduction in myocyte size and an increase in myocyte nuclear density. This raises the possibility that MSC mediated cardiac repair is effected by the mobilization of HSCs.