While the ability of embryonically derived stem cells to generate multiple cell types has long been appreciated, stem cell biology began in the 1950s with the discovery of bone marrow progenitors capable of reconstituting the hematopoietic system. Remarkably, the discovery of endothelial progenitor cells (EPCs)1 capable of homing to sites of ischemia was made only a decade ago, nearly 40 years after the identification of the hematopoietic stem cell. Despite this, the use of EPCs for the treatment of vascular disease has accelerated from pre-clinical studies to clinical application within a short period of time, with resulting debate about the need for further pre-clinical work2 as opposed to acceleration of clinical trials in this field.³

More recently, attention has also been focused on other adult stem cells, including mesenchymal stem cells derived from bone marrow stroma, myoblasts derived from autologous peripheral muscle, and cardiac stem cells grown from myocardial biopsies. Each of these sources lacks the ethical constraints that define the field of embryonic stem cell research, and represents a vigorous area of pre-clinical and clinical research.

Evidence for Progenitor-cell-mediated Repair
The presence of circulating progenitor cells1 capable of differentiating into EPCs and homing to sights of ischemia where they increase neovascularization led to the realization that the state of the vasculature reflects a delicate balance between damage and repair.⁴ Several creative avenues of research have indicated that stem-cell-mediated repair is an active and ongoing process in both the myocardium and the vasculature. Pre-clinical and human studies demonstrated that foreign bodies implanted in continuity with the vasculature become endothelialized with cells of bone marrow origin.^5,6 The potency of progenitor-cellmediated vascular repair has been demonstrated in both atherosclerotic mice7 and in human radiation injury.8 The presence of gendermismatched organs after cardiac transplantation has offered investigators the opportunity to probe myocyte generation by cells of host origin.^9,10

Although the frequency and extent of myocardial renewal varies among studies, the common observation that a small fraction of myocytes contain chromosomes of host origin points to the existence of stem-cellmediated innate myocardial regenerative capacity in humans. Additionally, vascular regeneration as determined by similar identification of host cell differentiation into mature EPCs and smooth muscle cells occurs at a higher rate, suggesting that progenitor-cell-mediated vascular repair represents a more active and dynamic process.^10,11 This concept has also been explored after bone marrow transplantation, in which terminally differentiated smooth muscle, epithelial, and hepatic cells— this time of donor origin—were demonstrated.^12,13

Cellular repair mechanisms may be relatively quiescent until end organ
injury occurs. For instance, myocardial infarction (MI) may stimulate expansion of a resident cardiac stem cell population¹⁰ or recruitment of circulating cells capable of myocardial regeneration.¹⁴ Similarly, EPCs, when infused into ischemic animals, home to the site of ongoing vascular injury.¹