First randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease. Nevertheless, some trials have shown that conflicting results and uncertainties remain in the case of mechanisms of action and possible ways to improve clinical impact of stem cells in cardiac repair. In this paper we will examine the evidence available, analyze the main phase I and II randomized clinical trials and their limitations, discuss the key points in the design of future trials, and depict new directions of research in this fascinating field.

Recently, the existence of a population of stem cells located in the adipose tissue has been observed. Adipose-derived stem cells are able to differentiate into multiple cell lineages including cardiac myocytes. Hence, adipose-derived cells are emerging as a new source of adult stem cells for cardiovascular repair. In this review, we discuss the basic principles of adipose-derived stem cells (types and characteristics, obtention processes, immunophenotypic characterization, and cell potency), the initial experimental studies, and the currently ongoing clinical trials.

After more than ten years of human research in the field of cardiac regenerative medicine, application of stem cells in different phases of ischemic heart disease has come to age. Randomized clinical trials have demonstrated that stem cell therapy can improve cardiac recovery after the acute phase of myocardial ischemia and in patients with chronic ischemic heart disease, and several efficacy phase III trials with clinical endpoints are on their way. Nevertheless, a complete knowledge on the mechanisms of action of stem cells still remains elusive. Of the three main mechanisms by which stem cells could exert their benefit, paracrine signaling from the administered cells and stimulation of endogenous repair are nowadays the most plausible ones. However, in this review we will define and discuss the concept of stem cell potency and differentiation, will examine the evidence available, and will depict future directions of research.

Over the last years, stem cell therapy has emerged as an inspiring alternative to restore cardiac function after myocardial infarction. A large body of evidence has been obtained in this field but there is no conclusive data on the efficacy of these treatments. Preclinical studies and early reports in humans have been encouraging and have fostered a rapid clinical translation, but positive results have not been uniformly observed and when present, they have been modest. Several types of stem cells, manufacturing methods and delivery routes have been tested in different clinical settings but direct comparison between them is challenging and hinders further research. Despite enormous achievements, major barriers have been found and many fundamental issues remain to be resolved. A better knowledge of the molecular mechanisms implicated in cardiac development and myocardial regeneration is critically needed to overcome some of these hurdles. Genetic and pharmacological priming together with the discovery of new sources of cells have led to a "second generation" of cell products that holds an encouraging promise in cardiovascular regenerative medicine. In this report, we review recent advances in this field focusing on the new types of stem cells that are currently being tested in human beings and on the novel strategies employed to boost cell performance in order to improve cardiac function and outcomes after myocardial infarction.

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