Fat is not all bad: how to make good use of adipose tissue.

Myocardial infarction (MI) continues to represent a major health problem. Improved healing and/or regeneration of infarcted myocardium by injection of progenitor cells has been proposed as a promising approach to prevent cardiac remodelling or even restore myocardial tissue. Several adult stem cell types have shown efficacy in the preclinical setting, including skeletal myoblasts, umbilical cord cells, bone marrow-derived mononuclear cells, and, more recently, adipose tissue-derived stem cells. Although the debate as to which cell type (or combinations thereof) is best suited for the treatment of acute MI continues, the mesenchymal stem cell (MSC) is particularly interesting. Thus, MSCs have been shown to be multipotent, to be capable of homing to infarcted myocardium, inducing angiogenesis and differentiating into myogenic cells, can be easily expanded ex vivo, and are possibly immune privileged. MSCs can be isolated from several organs, including bone marrow, umbilical cord blood, and adipose tissue, of which subcutaneous fat appears most easily and repeatedly accessible for high yield MSC isolation. Bone marrow-derived MSCs have already shown significant benefit in animal models of MI-induced left ventricular dysfunction. For example, in swine with MI produced by a 30 min coronary artery occlusion, allogenic bone marrowderived MSCs injected into the coronary artery 3 days after reperfusion resulted in a reduction in infarct size and improvement of left ventricular function at 4 weeks follow-up. More recently, adipose tissue-derived MSCs have also shown potential in rodent studies. Thus, in models of permanent coronary artery ligation, MSC application (either as a grafted monolayer or via intramyocardial injection), administered either immediately or 3–4 weeks after induction of MI, resulted in improved left ventricular geometry and function another 4–8 weeks later. Although these studies are encouraging, they differ significantly from the clinical setting in terms of animal model, the type of infarction, and route of cell administration. Valina et al. have compared the effects of intracoronary injections of adipose tissue-derived or bone marrow-derived autologous MSCs on left ventricular remodelling, function, and perfusion after an acute transmural MI produced by a 3 h coronary artery occlusion followed by reperfusion in swine. Their main conclusions are that both cell types reduced infarct size and improved global left ventricular function at 30 days follow-up. The study is important for several reasons. First, Valina et al. applied clinically relevant procedures in a large animal model, employing intracoronary cell injection following an ischaemia–reperfusion protocol that resulted in transmural infarction. This approach is clinically more relevant than the intramyocardial or systemic cell injections following permanent ligation, commonly used in rodents. Secondly, the authors performed a detailed analysis of global left ventricular geometry and function and regional perfusion, in conjunction with MSC cell tracking and phenotype analysis at 4 weeks follow-up. Although the results of this study, together with other preclinical studies on MSCs, warrant investigation of the clinical usefulness of MSC therapy, several questions remain to be addressed. The optimal methodology of cell therapy remains insufficiently understood. For example, the optimal timing of cell administration in reperfused myocardium remains incompletely understood. There is evidence from clinical studies to suggest that injection at 5–10 days after reperfusion is optimal, at least in the case of injection of the mononuclear cell fraction of bone marrow. Somewhat disparate from current clinical practice, with regards to the bone marrow-derived mononuclear cell fraction, Valina et al. injected MSCs, expanded ex vivo for 13+5 days, already after 15 min of reperfusion, which they based on the notion that stromal-derived factor 1 (required for recruitment of progenitor cells) is upregulated immediately following myocardial injury. Future studies should address the effect of timing of MSC injection on cell retention in The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.