Mesenchymal Stem Cells: Future Source for Reparative Medicine

Bhatia et al.1 succinctly reviewed the updated information on the bone marrow-derived mesenchymal stem cells (MSCs) as the source for reparative medicine, focusing on their use for myocardial regeneration, thus ameliorating impaired cardiac function and prevent-ing its progression to congestive heart failure. Although early clinical trials with this approach are being undertaken, many challenges remain in our pre-clinical knowledge, which are needed to optimize their therapeutic application. Some of such issues have been discussed in this review; however, crystallizing the major questions we face could allow us to focus our efforts in addressing them. The premise for using MSCs to repair damaged tissue is that they are pluripo-tent stem cells, which can trans-differentiate into various phenotypes to replace the lost cells. A fundamental challenge to this thesis has been raised, which is the concept that the new cell thought to be derived from an MSC is in fact due to fusion of the implanted MSC with a native cell in the host, thus forming a polyploid hybrid cell. Murray et al.,2 who reported on the cell fusion, asked the ultimate question: “Regenerating the Infracted Heart: Holy Grail or Wholly Fiction?” Even the notion that hematopoietic stem cells could undergo pluripotent differentiation in vivo is being questioned.3 Findings contradicting these pessimistic views have also been reported, thus a clear resolution of this controversy is urgently required.4 Perhaps such conflicting findings could be related to the particular cell population studied or to the experimental conditions employed, since the incidence of cell fusion reported vary widely. We also need to know more about the functional contribution of such hybrid cells, if any, and the optimal conditions to induce desired trans-differentiation in vivo. The definition of a stem cell is its ability for self-renewal as well as its capacity for multi-lineage differentiation. For any cell therapy approach, precise characterization of the donor cell population is of paramount importance. For differentiated cells, various surface cell markers displayed are highly useful; however, in stem cells, the cell markers may reflect their stage of differentiation rather than as the hallmarks of distinct cell populations. For example, CD34 positive stem cells in bone marrow are taken to identify “hematopoietic stem cells,” while the CD34 negative cells are thought to represent “marrow stromal stem cells.” There is evidence, however, that long-term repopulating activity of the hematopoietic stem cells reside in the CD34 negative cells, so that CD34 expression in fact is a marker for stem cell activation and mobilization.5 Another good illustration of this issue is how to identify true “embryonic stem (ES) cells.” Presently, there are no reliable markers that can distinguish truly pluripotent ES cells, such that a group of US and Canadian biologists, hoping to set standards for experimentation with ES cells, proposed using the functional capabilities of the specific cells to identify them. The true ES cells, when implanted into a recipient tissue in vivo, will form teratomas; while ES cells injected into a developing animal embryo should turn up in all its tissues. Both in ES cells and in adult stem cells, mapping the various genes that are turned on or off at various times in culture may thus lead to a better understanding of the role of these cell markers, while providing important insight into the properties that confer their “sternness.”6 Our current extensive use of cell markers to identify stem cell populations needs to be viewed in this perspective. The recruiting of MSCs and circulating stem cells, as well as their homing to the injured myocardium, have been discussed in this review by Bhatia et al.1 The signaling molecular mechanisms for this process are being investigated vigorously. There is evidence that molecular signals associated with inflammatory response following tissue injury may play important roles. We have observed that MSCs, which can migrate and target to the acutely injured site, may lose such capability in chronic scar tissue where inflammatory response has subsided.7 Such findings are of clinical interest since less invasive systemic infusion of MSCs may be considered in patients with acute myocardial infarction, while for patients with stable myocardial scar, local delivery of the donor cells may be mandatory. In patients with various nonischemic cardiomyopathies, whether such homing mechanism exist or not has not been fully investigated. How a limited number of cells implant-ed within a scar tissue, without apparent integration and connection with native myocardium, could contribute to the improvement in ventricular function as reported in many experimental and clinical studies remains perplexing.8,9 A number of alternate mechanisms, unrelated to the direct contractile contribution of the implanted cells, have been proposed, but none had been confirmed. On a related subject, the dose-response relationship between the quantity of cells implanted and survived vs. the magnitude of improvement in left ventricular function have not been established either. To undertake proper clinical trials, such preclini-cal data would be very important. The surprising findings of MSCs tolerating allo-transplant or even xeno-transplant without immunosuppression has also been described by Bhatia et al.1 Further confirmation of such findings10 and understanding of the possible immunological mechanisms involved would be highly desirable, since clinically the implication is the potential for them being used as “universal donor cells.”11 The logistic advantage of using universal donor cells clinically as compared with the use of autologous cells is obvious. The senescent or debilitated patients with dysfunctional MSCs could conceivably receive allogeneic MSCs from younger and healthier donors. Thus, in spite of the great promise of stem-cell therapy for myocardial repair, many challenges remain with this approach. Investigations at both experimental and clinical levels are being pursued vigorously, and it is hoped that this fascinating therapeutic approach could benefit our patients in the near future.

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