Christopher Morin

 Introduction: Development of myocardial infarction (MI) occurs when a maturing plaque fissures and exposes its lipid rich core to components of circulating blood. The process ends with formation of an acute thrombus over the plaque with closure of the vessel¹. Initially it was thought that cardiomyocytes were not able to divide and scars formed, however recent studies have shown that myocytes can undergo mitosis and regenerate following MI². Mesenchymal stem cells (MSC) can differentiate into cardiac and vascular lineages, and intra-coronary, intra-venous, and epicardial delivery are being used for enhancing post-MI cardiac repair^2-3. Studies have shown that MSCs demonstrate cardio-protective and regenerative abilities by secreting cytokines and growth factors including IL-1β, TNFα, Akt, PDGF-D, MCPIP1, and Rap1³. The absence of NUCKS can augment paracrine activity⁴. These findings suggest paracrine activity on MSCs can promote cardiac repair and angiogenesis, and forms the basis for novel therapeutic research. Methods: The studies used rat or murine model systems to test the effects of MSC cytokine secretion, MSC response to stimulation by cytokine administration, and recombinant viral vectors to introduce knockout genes into mice. The primary measure used to assess cardiac function was most often assessed using two-dimensional echocardiography. MSC adhesion ability was measured with flow cytometry, adhesion assays, qPCR, and western blot analysis. Angiogenesis was assessed using capillary-like tube formation assays. Results: Studies showed that stimulation of MSCs with a combination of TNFα and IL-1β promoted expression of VCAM-1 and improved cardiac function recovery following MI⁵. Animals treated with Akt-Exo showed increased cardiac function, accelerated endothelial cell proliferation and angiogenesis in vivo⁶. Transduction of MCPIP1 for overexpression into BM-MSCs increased angiogenesis and promoted MSC differentiation into functional cardiac cells post-MI⁷. After administration of Rap1 and Terf2IP into mice via a lentivirus recombinant packaging system, studies showed that Rap1 has a critical inhibitory role in regulating the paracrine effects of MSC-mediated heart repair through the NFκβ signaling pathway⁸. Additionally studies showed that depletion of nuclear casein kinase and cyclin-depending kinase substrate 1 (NUCKS) was beneficial for increasing the therapeutic efficacy of BM-MSCs for cardiac repair following MI⁴. Conclusions: Studies have found that modulating the paracrine effects on bone marrow-derived mesenchymal stem cells can provide an efficacious method for increasing angiogenesis, cardio-protective effects and function following myocardial infarction. In models, increasing the levels of IL-1β, TNFα, Akt, MCPIP1 and decreasing NUCKS and Rap-1 can be used to develop therapeutics in post-MI patients.

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