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1. Use ofMesenchymal Stem Cells In Myocardial Infarction Treatment
2. Challenging the Dogma It has always been believed that the heart is composed of terminally differentiated cardiac myocytes but research has shown that stem cells are capable of myocardial regeneration and they can prevent and even reverse necrosis and scarring of cardiac tissue.
3. Stem Cells Totipotent: capable of developing into any cell of an organism
eg: zygote
Pluripotent: capable of developing into most tissues except the placenta
eg: embryonic stem cells
Multipotent: capable of developing into a limited number of tissues
eg: adult stem cells
4. Adult Stem Cells Different types of adult stem cells:
Hematopoietic stem cells
Mesenchymal stem cells (MSCs)
Skeletal myoblasts
Resident cardiac stem cells
5. Steps in Stem Cell Treatment Extraction of MSCs: They are extracted from the bone marrow of the donor.
Expansion of MSCs in culture medium : This is done using off the shelf products like enrichment cocktails and growth mediums.
Delivery of the MSCs to the site of the infarct.
Homing and differentiation of MSCs: Once in the system the MSCs migrate to the site of the infarct and differentiate into myocytes under the influence of cytokines and paracrine agents.
6. Routes of Delivery Two main routes of delivery
Transvascular: This includes intravenous infusion and intracoronary infusion. Intracoronary infusion is done using percutaneous coronary intervention (PCI).
Direct injection into the myocardium: In this approach the MSCs are directly injected into the myocardium at the borders of the site of the infarct (endocardial) using a needle catheter during a PCI or (intramyocardial) as an adjunct to a coronary bypass graft (CABG)
7. Routes of Delivery Intravenous
Least invasive
More effective in acute settings
More systemic exposure
Intracoronary
Intermediate
More effective in acute settings
Less systemic exposure
High rate of engraftement at the site of infarct
Direct Myocardial injection
Most invasive
Can be used later as compared to intravascular approaches
Least systemic exposure
High rate of engraftment at the rite of infarct
8. Homing and Differentiation Myocardial necrosis causes release of inflammatory signals which induce mobilization and homing of MSCs to the site of the infarct. Some of these include
Stem cell factor (SCF) and c-kit
CXCR4 and stromal cell derived factor-1(SDF-1)
Vascular endothelial growth factor (VEGF) and VEGF receptor-2.
9. Allogenic vs. Autologous MSCs are considered to be immune privileged since they evade allorejection. This is the result of three mechanisms
Hypoimmunogenicity: MSCs lack MHC-II protein and thus evade recognition by T cells and they also lack co stimulatory factors CD40, CD40L,CD80 and CD86 required for T cell activation
Affect dendritic cells and natural killer cells: MSCs prevent maturation and migration to the lymph nodes of dendritic cells and natural killer cells. They also decrease secretion of TNF-a by dendritic cells and IFN-? by natural killer cells and increase secretion of IL-10 by dendritic cells.
Suppress T cell proliferation and generate a local immunosuppressive milieu: MSCs produce nitric oxide which inhibits stat5 phosphorylation which is essential for T cell proliferation. MSCs also produce hepatocyte growth factor (HGF), PGE2 and transforming growth factor-ß1(TGF-ß1) which create a local immunosuppressive environment.
10. Conduction After the MSCs undergo differentiation it is essential that they also acquire the electrical properties of cardiac myocytes. Electrical conduction through the differentiated MSCs is attributed to the development of gap junctions, which are seen at the interfaces between the MSCs themselves and between the MSCs and cardiac myocytes.
MSCs have a resting potential of -30 to -40mV.They express a small fraction of L-type Ca channels and they are considered inexcitable which results in slower conduction velocity in-vitro, in a co-culture of MSCs and myocytes as compared to only myocytes. But the conduction velocity in a co-culture of MSCs and myocytes is still faster than that observed in a co-culture of fibroblasts and myocytes, which would be seen in the case of an MI.
Resynchronization of two separately beating fields has been seen within 24 to 48 hours of transplantation.
11. Risks vs. Benefits Benefits:
Clinical trials have shown improvement of both systolic and diastolic function after transplant of MSC
Increase in left ventricular ejection fraction (LVEF)
Decrease in the area of functional defect
Increase in the wall movement velocity of the infarcted area
No significant changes in the left ventricular dystolic diameter (LVDd)
No significant changes in E/A ratio
Small increase in isovolumic relaxation time (IVRT)
Risks:
Highly invasive procedures except for IV infusion
Susceptible to re-entrant arrhythmias
Risk of propagating genetic defects
Tumors
12. Provacel FDA has approved Phase I clinical trial for Provacel an interventional therapy using MSCs to prevent heart failure resulting from an acute myocardial infarction, sponsored by Osiris Therauptics Inc. 53 patients were admitted in this double-blind, placebo-controlled, dose escalating, multicenter, randomized trial and were treated using allogenic MSCs which were delivered through a standard IV line within 7 days of suffering from a first MI. These patients are going to be followed for a period of two years to demonstrate the safety of the product and to evaluate preliminary efficacy data.
13. Conclusion Preclinical and human trials have showed short term benefits of using MSCs post MI that include improvement in LVEF, reduction of scar tissue, absence of hypertrophy and improvement in in contractility and conduction but it is also essential to study long term effects. Further studies are warranted to help design treatments that are best suited to individual needs depending on the location of the infarct, time elapsed since the MI and hemodynamic stability of the patient.
Thus although MSC transplants have a long way to go from the laboratory to the patient’s bedside, they do show promise, that their use will help improve the quality of life of the patients and reduce progression to heart failure.
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