Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions.

The medical community is currently experiencing a wave of enthusiasm for clinical trials in which adult stem/progenitor cells are used to repair tissues. The enthusiasm is based on promising results in animal models for a variety of diseases and the encouraging reports from some initial clinical trials.1-6 It is also driven by the prospect that stem/progenitor cells may offer new hope for patients with end-stage diseases for which there are no therapies. In the wave of enthusiasm, however, several essential precautions are not being fully addressed. Therefore, there is a great danger that potentially important new therapies will be discarded prematurely because of poorly designed clinical trials. In theory, adult stem/progenitor cells may provide a therapy for an almost unlimited number of serious and currently untreatable diseases. Their potential derives from their normal role as cells that repair injured tissues.1,7 It is now known that essentially every tissue and organ in the body contains such cells for tissue repair. After the stem/progenitor cells in a tissue are exhausted by severe or chronic injury, they can be supplemented by similar cells that flow through the blood stream from the bone marrow. Both the stem/progenitor cells found in most tissues and the similar cells from bone marrow can differentiate into most cellular phenotypes and thereby replace damaged cells. It was recently made known, however, that the cells can repair injured tissues by a variety of other mechanisms, some of which are still poorly defined. The cells are a rich source of chemokines and cytokines, as is well known from the use of confluent layers of the stem/progenitor cells referred to as marrow stromal cells as feeder layers for culture of hematopoietic cells. The chemokines and cytokines can stimulate regeneration of cells by inhibiting apoptosis, suppressing immune reactions, and increasing angiogenesis. The cells can also enhance proliferation and differentiation of tissue-endogenous stem/ progenitors cells as indicated by recent experiments in which human stem/progenitor cells were infused into the hippocampus of immunodeficient mice.8 In addition, they may rescue cells with nonfunctioning mitochondria by transfer of either mitochondria or mitochondrial DNA, as was recently observed in coculture experiments.9 To some extent, they may also repair tissues by cell fusion.1,10 Recent observations, in fact, suggest that we may have unnecessarily confused ourselves by referring to them as adult stem cells. They can more properly be referred to as reparative cells, or some catchier name. Despite the great promise, it is clear that development of new therapies with cells that repair tissues will not be a linear sequence of events. As with most dramatically new therapies, the data from basic studies and from animal models are never as conclusive as one would like. The best one can say is that the data are encouraging enough to justify carefully controlled trials in patients in whom the risks can be fully justified. The molecular events of tissue repair remain a mysterious and complex process, perhaps one of the most complex processes in all of biology and medicine. Therefore, as researchers proceed, the current clinical trials must be examined carefully and used as a basis for further research to improve the therapies. The situation is analogous to the development of bone marrow transplantation in which the first long-term successes11 were not achieved until nearly a decade after the first trials in patients with end-stage hematologic malignancies.12 The first clinical trials with adult stem/progenitor cells to repair nonhematopoietic tissues were carried out with the plastic adherent cells from bone marrow referred to in the hematologic literature as marrow stromal cells, but first defined as fibroblastoid colonyforming units, then as mesenchymal stem cells, or most recently as multipotent mesenchymal stromal cells (MSCs).1,13 The cells can readily be isolated from a small sample of marrow and rapidly expanded so as to generate large numbers of cells for autologous therapies. The initial clinical trials with MSCs were in patients with severe osteogenesis imperfecta2 and then in patients with mucopolysaccharidoses.3 Subsequently, trials were initiated for graft-versushost disease that capitalize on the ability of the cells to suppress immune reactions.4,5 Currently, the largest number of clinical trials is in patients with heart disease. Here, a confusing variety of cells and strategies for different syndromes have been tested (Table 1).14-43 One approach was to mobilize bone marrow cells by subcutaneous administration of G-CSF. Another was to isolate unfractionated mononuclear cells from autologous bone marrow and infuse the cells either into a coronary artery or into the border region of myocardial infarcts. Still another approach was to isolate CD34 or CD133 cells from marrow or CD34 -enriched cells from peripheral blood after mobilization and then to infuse the cells into a coronary artery or the borderline of infarcted areas. Still other approaches were to use the same routes of infusion with either isolated endothelial progenitor cells or MSCs. To date, only a limited number of adverse effects have been attributed to any of the different therapies. In contrast, an earlier trial in which skeletal myoblasts were infused into the myocardium produced a high incidence of arrhythmias. Most of the trials using bone marrow cells have reported improvements in cardiac function. However, the number of patients enrolled in well-controlled trials is still limited. As these trials proceed, it seems imperative that we address some of the potential dangers that have frequently been ignored. One potential danger is that the clinical trials will be performed without appropriate controls or without well-defined end points. The danger seems particularly apparent in trials such as those in acute myocardial infarction in which there is great variability in the size and