Novel avenues for cell therapy in acute myocardial infarction.

It has now been more than a decade since clinical scientists began to explore a potential beneficial effect of administering cells to the ischemically injured heart. Stimulated by pioneering experimental studies that showed that bone marrow–derived cells (BMCs) might regenerate infarcted myocardium,1 clinicians quickly translated this concept into clinical application.2,3 Although it was prudent for the initial clinical application to use mononuclear BMCs, on the basis of more than 20 years of experience with these cells by our colleagues in hematology for reconstitution of bone marrow, with demonstrated excellent safety with respect to adverse cardiovascular effects (which is of paramount importance), it became obvious during subsequent experimental studies that the capacity of these cells to form cardiomyocytes by transdifferentiation was very limited.4 Nevertheless, despite the lack of significant transdifferentiation of the applied cells to cardiomyocytes, the contractile function of experimentally infarcted hearts improved to a significant extent. These insights advanced the concept that BMCs administered to the heart release soluble factors that mediate cardiac repair, neovascularization, and cytoprotection.5 Indeed, more recent studies supported this paracrine hypothesis by demonstrating that bone marrow–derived c-Kit cells stimulated endogenous cardiogenic progenitor activity and new cardiomyocyte formation even in the absence of transdifferentiation of the administered BMCs.6 Likewise, increased capillary density and improved blood flow recovery after ischemia are well established to occur after BMC administration into ischemic animal models, although very few of the transplanted cells are incorporated into the vasculature.7 Finally, in an attempt to decipher the functional relevance of the cell fate of administered BMCs, Yoon et al8 infected cells with inducible suicide genes under the control of cardiovascular cell–specific promoters, thus enabling the selective depletion of the individual cell lineage acquired by the administered undifferentiated BMCs. The observation that elimination of endotheliumand vascular smooth muscle–committed but not cardiac-committed cells was associated with an abrogation of improved contractile recovery after myocardial infarction indicated that BMC administration preferentially targeted the vasculature, and improved cardiac function may be secondary to enhanced perfusion and microvascular function. Indeed, it was shown 25 years ago that an inadequate adaptation of the capillary vasculature is the major determinant of the compensatory reserve capacity of the infarcted heart.9 Although these experimental studies have significantly enhanced our understanding of the potential mechanisms underlying a beneficial effect of BMC administration in acutely ischemic hearts, the clinical trials running in parallel during the last decade have provided rather heterogeneous results thus far.10 Although all clinical trials reported the remarkable safety of intracoronary administration of BMCs in patients with acute myocardial infarction, the overall effect on improvement in ejection fraction has been modest and significantly less persuasive than the expectations raised by the results with preclinical animal models. What could be the reasons for these discrepancies? First, the use of autologous BMCs for clinical application may affect the potency of the cellular product, because it is well known that age and risk factors for coronary artery disease impair both the functional capacity and the paracrine activity of isolated BMCs.11 Second, efficient cell therapy requires recruitment and retention of the applied cells into the targeted region of the heart. Indeed, recent data demonstrate a direct relationship between the number of cells retained acutely and the recovery of cardiac function after ischemia in animal models.12 Cell isolation procedures and storage conditions interfere majorly with the signaling mechanisms responsible for recruitment of BMCs after infusion into the infarct-related artery, the current method of choice for cell administration in patients with acute myocardial infarction.13 Timing of BMC administration after acute ischemic injury may compromise cell retention by altering the signals that emanate from the niche in the peri-infarct target region of the heart. Finally, microvascular obstruction may even prevent access of the intra-arterially administered BMCs to the infarct region and thus limit recruitment of the cells. All of these mechanisms likely contribute to the heterogeneous results of different clinical trials using different cell preparation methods, different timing of cell administration, and lack of controls for the presence of microvascular obstruction. As reported in this issue of Circulation Research, Penn and coworkers14 now embark on fresh ground in 2 ways: First, by using an allogeneic bone marrow–derived stem cell product, and second, by using a catheter-based microneedle adventitial delivery system to eliminate some of the uncontrolled variables discussed above in patients 2 to 5 days after primary percutaneous coronary intervention for acute myocardial infarction. The strategy of injecting an allogeneic cell product should eliminate the heterogeneity inherent to all autologous The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Germany. Correspondence to Andreas M. Zeiher, MD, Division of Cardiology, Department of Medicine III, Goethe University Frankfurt, Theodor Stern Kai 7-60590 Frankfurt, Germany. E-mail [email protected] (Circ Res. 2012;110:195-197.) © 2012 American Heart Association, Inc.