The Unraveling of the Matryoshka Doll
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Significant advances have been made in the field of cardiac regenerative medicine. Investigations into the mechanism of action have identified multiple strategies of the delivery of biologics that are both cell and cell free that yield quantitatively equivalent results. Here in, we present a viewpoint of the successive layers within the cell that can be exploited to prevent or treat cardiac dysfunction.
In the beginning, it was supposed to be simple, transplant noncommitted bone marrow–derived stem cells to the myocardium, where they would migrate into the infarct zone and differentiate into cardiac myocytes, replacing the lost contractile function of the heart and limiting the risk of heart failure.1 Soon, it became evident that circulating stem cells were being signaled to home to the site of myocardial injury; whether those stem cells were exogenously infused or endogenously released from the bone marrow. These early findings led to a bifurcation of the field where clinicians performed trials trying to prevent or restore cardiac function in patients with ischemic heart disease,2 and bench scientists focused on distinct cell types and mechanisms of action.3 Sixteen years later, stem cell therapy is no closer to standard of care, but we have learned a great deal. Although our successes have been limited,4 our understanding of the physiology and biology has grown immensely:
First and foremost, we understand that adult stem cell therapy seems to be safe. Unlike the arrhythmias we observed with skeletal myoblasts, we have not seen adverse electric, mechanical, or oncogenic effects of adult stem cells.
The concept of stem cell transplantation at the time of acute myocardial infarction is not as easy as we had first thought as stem cell preparation seems to have significant consequences on whether the therapy will work4 or not.5
We have …