Mesenchymal Stem Cells in Cardiac Repair
Introduction: Myocardial Infarction (MI) is a major public health problem that results in cardiac remodeling and resulting impaired heart function. Current treatment aims to prevent maladaptive pathways, but not seek to compensate for the loss of myocardium1. The use of Mesenchymal Stem Cells (MSCs) has proven to be a beneficial therapy to prevent pathological remodeling of the cardiac tissue though various mechanisms, such as angiogenesis2-5 paracrine stimulation3-6, and to a lesser extent, differentiation into cardiomyocytes, and activation of endogenous cardiac stem cells5. Methods: MSCs were transduced to overexpress CXCR43 (MSCCX4) and HIF-1α2 (HIF-MSC) in different experiments. In addition, Nuclear casein kinase and cyclin-dependent kinas substrate (KNUCKS) knockout MSCs (NUCKS-/- MSCs) were collected under hypoxic conditions and assessed both with molecular techniques (Western Blot, real time PCR), and histological staining with trichome stain4. Aside from transplanted MSCs and cultivated MSC media, delivery of MSCs via pericardial-stem cell-loaded patches was performed5, as well as the direct action of coculture of BMSCs with cardiomyocytes6. Results: HIF-MSCs showed a higher content of Jagged1 loaded exosomes (vesicles loaded with biological material), which is primordial in the NOTCH signaling pathway (which among its many actions, coordinates angiogenesis), as well as expression of miRNA-312. MSCCX4 also showed an increase in the number of tube-like structures via paracrine stimulation with VEGF3; in addition, MSCCX4 medium played an important role in mobilization of MSC toward ischemic tissue, as well as induced proliferation of adult rat cardiomyocytes3. NUCKS -/- MSCs had angiogenic effects via VEGF and IL-10; and also, showed cardio protective roles by inhibiting apoptosis of ischemic cardiomyocytes4. MSCs delivered via pericardial patches showed activation of epicardial cells Wt1 which have potential to differentiate further into endothelium, VSM, and cardiomyocytes; in addition, the levels of c-kit+ cells was also increased5. Coculture of BMSCs with cardiomyocytes, inhibited the hypertrophic growth of cardiomyocytes mainly by the heightened release of VEGF6. Conclusion: Studies have shown that MSCs have the potential to reduce the ischemic area after a myocardial infarction by stimulation of angiogenesis, as well as supportive paracrine stimulation. Overall these actions resulted in enhanced contraction of the left ventricle as well as increased ejection fraction when compared to control groups5. In addition, the infarction size was reduced, and the thickness of the ventricular wall was increased, with further prevention of malignant hypertrophy; ultimately, all these events result in an enhancement of cardiac contractility3-5.
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- Gonzalez-King HCA, García NA, Ontoria-Oviedo I, Ciria M, Montero JA, Sepúlveda P. Hypoxia inducible factor-1 alpha potentiates Jagged 1-mediated angiogenesis by mesenchymal stem cell-derived exosomes. Stem Cells. March 2017. doi:10.1002/stem.2618.
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- Zhang Y, Chiu S, Liang X, Chai Y-H, Qin Y, Wang J. Absence of NUCKS augments paracrine effects of mesenchymal stem cellsmediated cardiac protection. ELSEVIER. April 2017:1-11. doi:http://dx.doi.org/10.1016/j.yexcr.2017.04.012.
- Wang Q-II, Wang H-J, Li Z-hua, Wang Y-II. Mesenchymal stem cell-loaded cardiac patch promotes epicardial activation and repair of the infarcted myocardium. Journal of Cellular and Molecular Medicine. 2017;XX(X):1-16.
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