Paracrine-Mediated Systemic Anti-Inflammatory Activity of Intravenously Administered Mesenchymal Stem Cells: A Transformative Strategy for Cardiac Stem Cell Therapeutics.

Abstract

Stem cell therapy as a treatment option for acute myocardial infarction or heart failure caused by ischemic or nonischemic cardiomyopathy has focused on direct cardiac delivery of stem cells to facilitate cardiac engraftment. Once engrafted, it was believed that these cells would either transdifferentiate into new functioning myocytes or stimulate the expansion of resident myocardial stem cells. However, a sea change in thinking about cell therapy in cardiovascular disease has occurred as mounting evidence indicates that (1) inflammation is a major mechanism contributing to the progressive myocardial dysfunction seen in patients post-acute myocardial infarction and in patients with cardiomyopathy, and (2) systemic paracrine-mediated anti-inflammatory effects of stem cells can drive beneficial cardiac effects in these diseases. These concepts lead to a potentially transformative strategy that intravenous delivery of stem cells, through systemic anti-inflammatory mechanisms, improves myocardial function and thereby obviates the need for invasive methods of stem cell delivery. Until recently, the prevailing view of the mechanism responsible for any potential benefit of stem cells in patients with acute myocardial infarction (AMI) or with heart failure (HF) caused by ischemic or nonischemic cardiomyopathy (ICM/NICM) was that benefit derived from local effects—once engrafted in damaged myocardium, the stem cells either transdifferentiate into functional myocardium, stimulate resident myocardial stem cells to expand, and repopulate the heart with functioning myocytes or secrete substances leading to myocardial healing. This mechanistic perspective implied that the greater the number of engrafted cells in the myocardium, the greater the cardiac benefit. Because few intravenously administered stem cells engraft in injured myocardium, invasive strategies providing direct delivery of stem cells to the heart were uniformly adopted. This necessarily involved either catheter-based delivery (intracoronary or transendocardial injection) or surgical delivery (direct intramyocardial injection). A transformative concept relating to stem cell treatment of patients with AMI or ICM/NICM has recently …