15. Cardiac Cell Therapy - Mixed Results from Mixed Cells. Rosenzweig, A. N Engl J Med 2006 355: 1274-1277.

Experiments in animals have suggested that the transfer of cells derived from bone marrow (BMC) could dramatically improve cardiac function after infarction through regeneration of the myocardium or neovascularization. Such studies have generated tremendous excitement and stimulated clinical studies such as those reported in the September 21, 2006 issue of the N Engl J Med. These studies provide a realistic perspective on this approach while leaving room for cautious optimism and underscoring the need for further study.

Schächinger et al. (citation 17) report that at 4 months, the absolute improvement in left ventricular ejection fraction (LVEF), measured by angiography, was greater among patients treated with BMC than among those given placebo (5.5% vs. 3.0%, P=0.01). This double-blind and fully controlled trial provides the best evidence yet for beneficial effects of BMC after acute myocardial infarction. Enthusiasm is tempered somewhat by the modest size of the effect and by a recent report from the Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial that the relative improvement in LVEF after infusion of BMC at 6 months, as compared with no infusion, was no longer significant at 18 months, suggesting that the main effect was an acceleration of recovery.

Ultimately, the validation of cardiac cell therapy will require demonstration of benefit with regard to clinical outcomes --- as was the case with reperfusion. Studies performed to date have not been designed or powered to evaluate clinical outcomes. Nevertheless, it is encouraging that the investigators found the rate of adverse clinical events to be significantly lower at 1 year among patients receiving BMC than among those receiving placebo. Given the relatively small number of events, this result will require replication in larger cohorts. However, it reinforces the message that BMC infusion is not only feasible but also safe, and it raises the possibility that clinical benefits may exceed the modest improvement seen in ventricular function. Data on ventricular function at 1 year are not available.

In contrast, in the smaller Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial involving three noninvasive imaging methods, Lunde et al. (citation 16) did not find a significant improvement in LVEF at 6 months in the mononuclear BMC group, as compared with the control group. Janssens et al. (Lancet 2006; 367: 113-121) also did not detect an improvement in global ventricular function at 4 months in the BMC group as compared with the control group, although infarct size was reduced and regional wall motion was improved in the BMC group. The identification of features of BMC preparations and of patients that are predictive of a favorable response should help to resolve these discrepancies and to focus future trials.

Assmus et al. (citation 18) evaluated the effects of BMC or progenitor cells derived from circulating blood (CPC) in patients with chronic ventricular dysfunction. In this randomized, crossover trial, the absolute change in LVEF was significantly greater among patients receiving BMC than among those receiving CPC. The groups received the other type of cell in the next phase of the trial, but the result was independent of the order in which the cells were given, suggesting that the BMC effect is somewhat specific. Although the benefit observed after BMC infusion was modest (an increase in LVEF by 2.9 percentage points), it is remarkable that any benefit was seen in these patients, who were studied on average more than 6 years after infarction and who were already receiving optimal medical care. The trial suggests that BMC can have effects beyond simple acceleration of healing after infarction.

Although the prospect of regeneration of cardiac tissue provided an initial stimulus for cell-based therapies, subsequent work in animals has questioned the ability of BMC to effectively generate cardiomyocytes, and clinical studies have suggested that only 1.3 to 2.6% of infused BMC are retained in the heart. Functional benefits may also be mediated through paracrine secretion of growth factors or cytokines, which could indirectly promote survival of cardiomyocytes, mobilization of endogenous progenitor cells, or neovascularization. Do these distinctions matter? There is no doubt that the ultimate success or failure of cell therapy will rest on its ability to show clinical efficacy rather than on the imputed mechanism. However, understanding whether these effects are mediated directly by the transplanted cells or indirectly through involvement of other cells, would enable targeted delivery of essential components and is likely to be a critical step in the full realization of the potential of this therapeutic approach.

Patients should be treated with cells only as part of randomized, controlled trials and only after they understand that neither the efficacy nor the long-term risks of this approach are established. Future trials should be powered to examine clinical end points and patients should be followed over the long term and for both beneficial and adverse effects. Simultaneously, we must continue to support basic and translational research that can help guide clinical investigation.

Recent randomized studies of cell therapy for heart disease represent a milestone in this rapidly developing field while serving as a cogent reminder that many important clinical and fundamental questions have yet to be addressed. We should guard against both premature declarations of victory and premature abandonment of a promising therapeutic strategy. The ultimate success of this strategy is likely to depend on continued and effective coordination of rigorous basic and clinical investigations.

16. Intracoronary Injection of Mononuclear Bone Marrow Cells in Acute Myocardial Infarction. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Egeland T, Endresen K, Ilebekk A, Mangschau,A, Fjeld JG, Smith HJ, Taraldsrud E, Grogaard HK, Bjornerheim R, Brekke M, Müller C, Hopp E, Ragnarsson A, Brinchmann JE, Forfang K. N Engl J Med 2006 355: 1199-1209.

The authors conducted a randomized, controlled trial to investigate the effects of intracoronary injection of autologous cells derived from bone marrow in the acute phase of myocardial infarction.

Patients with acute ST-elevation infarction of the anterior wall treated with percutaneous coronary intervention were randomly assigned to the group that underwent intracoronary injection of autologous mononuclear bone marrow cells or to the control group, in which neither aspiration nor sham injection was performed. Of the 50 patients assigned to treatment with mononuclear bone marrow cells, 47 underwent intracoronary injection of the cells at a median of 6 days after myocardial infarction. There were 50 patients in the control group.

The mean (±SD) change in left ventricular ejection fraction (LVEF) between baseline and 6 months after infarction for all patients was 7.6±10.4 percentage points. The effect of bone marrow cells on the change in LVEF was an increase of 0.6 percentage points, an increase of 0.6 percentage points on echocardiography, and a decrease of 3.0 percentage points on MRI.

The authors concluded that, with the methods used, they found no effects of intracoronary injection of autologous mononuclear bone marrow cells on global left ventricular function.

17. Intracoronary Bone Marrow–Derived Progenitor Cells in Acute Myocardial Infarction. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG., Hamm CW., Suselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, for the REPAIR-AMI Investigators. N Engl J Med 2006 355: 1210-1221.

In a multicenter trial, the authors randomly assigned 204 patients with acute myocardial infarction to receive an intracoronary infusion of progenitor cells derived from bone marrow or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy.

At 4 months, the absolute improvement in the global left ventricular ejection fraction (LFEV) was significantly greater in the bone marrow cell group than in the placebo group (mean [±SD] increase, 5. 5±7. 3% vs. 3. 0±6. 5%; P=0.01). At one year, intracoronary infusion of bone marrow cells was associated with a reduction in the prespecified combined clinical end point of death, recurrence of myocardial infarction, and any revascularization procedure (P=0.01).

The authors concluded that intracoronary administration of bone marrow cells is associated with improved recovery of left ventricular contractile function in patients with acute myocardial infarction and that large scale studies are warranted.

18. Transcoronary Transplantation of Progenitor Cells after Myocardial Infarction. Assmus B, Honold J, Schächinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM. N Engl J Med 2006 355: 1222-1232.

The authors studied the effects of intracoronary transplantation of progenitor cells derived from bone marrow or circulating blood in patients with healed myocardial infarction.

75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously were randomly assigned, in a controlled crossover study, to receive either no cell infusion (n=23) or infusion of circulating blood cells (n=24) or bone marrow progenitor cells (n=28) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive circulating blood or bone marrow cells, and the patients who initially received bone marrow cells or circulating blood cells were crossed over to receive circulating blood cells or bone marrow cells, respectively, at 3 months’ follow-up.

The absolute change in left ventricular ejection fraction was significantly greater among patients receiving bone marrow cells (+2.9 percentage points) than among those receiving circulating blood cells (-0.4 percentage points, P=0.003) or no infusion (-1.2 percentage points (P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of bone marrow cells. The crossover phase of the study revealed that intracoronary infusion of bone marrow cells was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to bone marrow cells or from blood cells to bone marrow cells.

The authors concluded that intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of bone marrow cells is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.

19. Biology of cord blood cells and future prospects for enhanced clinical benefit. Broxmeyer HE. Cytotherapy. 2005;7:209-18.

This is an authoritative review by one of the pioneers in the field who has maintained a high level of continued research in CB. The review covers the biology of hematopoietic stem (HSC) and progenitor (HPC) cells, efforts to expand these cells ex vivo for enhanced clinical utility that has thus far not been very successful, and recent studies on attempts to enhance the homing and engrafting capability of HSC as an alternative means for more effective use of the limited numbers of CB cells collected. This review also highlights the presence in CB of mesenchymal stem cells, unrestricted somatic stem cells, endothelial progenitor cells and immune cells. The presence and biology of these non-HSC/HPC may open up future possibilities for additional clinical benefit of CB.

The author points emphasizes that CB contains numerous cell types, although in some cases quite are, in addition to the HSC and HPC that have been used for transplantation. These other CB cell types can likely be cryopreserved and thus, the clinical effectiveness of CB may have greater impact than thus far been utilized. These non-HS/HPC cells and modulation of their functional activities ex vivo and in vivo offer the possibility of additional benefits.

20. Adult stem cell lines in regenerative medicine and reconstructive surgery. Conrad C, Huss R. J Surg Res. 2005;124:201-8.

The authors state that multipotent adult stem cells seem to be almost comparable to embryonic stem cells with respect to their ability to differentiate into various tissues in vitro and in vivo, a function that has been termed "stem cell plasticity". In vivo experiments in rodents have shown that adult stem cells participate in tissue and organ regeneration in almost all lesions.

The term "adult" is used to distinguish any multipotent cell from embryonic stem (ES) cells or primordial germ cells. Previously, most of the published data with respect to the differentiation of precursor cells used already predetermined progenitor cells. However, there is a growing scientific interest in the potential of adult stem cells derived from other sources, like the bone marrow, umbilical cord, or peripheral blood. The is evidence from a variety and increasing number of different studies that tissue progenitors can differentiate into committed cells of other tissues, a feature defined as plasticity.

Some authors claim that the injection of bone marrow-derived cells into the heart may lead to the differentiation of progenitor cells into cells with a cardio-myoblast-like phenotype, although these results are currently an issue of controversy. Others have reported that hematopoietic stem cells also can differentiate in vitro into neural progenitors, myogenic tissue progenitors, and that dystrophin expression can be restored after hematopoietic stem cell transplantation in dystrophin-deficient mdx mice, leading to the suggestion that adult stem cells from different sources and of almost any tissue phenotype can "trans-differentiate" into other tissue progenitors depending on appropriate conditions.

The authors review available data regarding osteogenic differentiation, cardio-myogenic differentiation, neuronal differentiation and discuss applications in regenerative medicine. They point out that, despite all of the cumulative experimental in vitro and in vivo evidence on the plasticity of adult murine and human stem cell lines, the question remains whether this might be relevant for the regeneration of tissue and organ function in mammals and human beings. Indeed, the function of "transdifferentiation" of stem cells has been questioned. Nevertheless they state that there is reason to assume that circulating progenitor cells and stem cells recruited from the bone marrow are involved in tissue repair and the maintenance of organ function in vivo.

21. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, Liedtke S, Sorg RV, Fischer J, Rosenbaum C, Greschat S, Knipper A, Bender J, Degistirici O, Gao J, Caplan AI, Colletti EJ, Almeida-Porada G, Muller HW, Zanjani E, Wernet P. J Exp Med. 2004; 19;200:123-35.

The authors state that cord blood (CB) provides a definite advantage for the development of cell therapeutics in regenerative medicine. In contrast to adult BM, the stem cell compartment in CB is less mature. This has been documented for the hematopoietic stem cells, which in CB are more abundant than in BM and have a higher proliferative potential associated with an extended life span and longer telomeres. Besides this biological superiority, CB is abundantly available, is routinely harvested without risk to the donor, and infectious agents such as CMV are rare.

The authors report that they have identified a rare, CD45 and HLA class II–negative stem cell candidate displaying robust in vitro proliferative capacity without spontaneous differentiation but with intrinsic and directable potential to develop into mesodermal, endodermal, and ectodermal cell fates. They termed the primary population unrestricted somatic stem cell (USSC).

The authors provide detailed experimental results and discuss the significance of their data by stating that they have demonstrated that an adherent CD45-negative unrestricted stem cell population from human placental CB was shown to be pluripotent. In contrast to other data from CB identifying mesenchymal cells that differentiated only into osteoblasts, chondrocytes, adipocytes, or neural progenitors in vitro, this is the first time that an adherent cell population has been identified, which after ex vivo expansion allows directed differentiation into bone, cartilage, hematopoietic cells, neural, liver, and heart tissue in vivo in various animal models.

Although the USSCs described have a very low primary frequency in CB, they can be expanded to at least 10¹⁵ cells and maintain a normal karyotype. In contrast to MSCs from BM, the USSCs have a wider differentiation potential and differ in immunophenotype and in their mRNA expression profile. The potential to generate hematopoietic cells as shown here from USSCs in vitro and in vivo has not been described for human MAPC.

The authors conclude that, on the basis of their pluripotency and expansion under GMP conditions into large quantities, USSC, when pretested for infectious agents and matched for the major transplantation antigens, may serve as a universal allogeneic stem cell source for the future development of cellular therapy for tissue repair and tissue regeneration.

22. Tissue-specific engraftment after in utero transplantation of allogeneic mesenchymal stem cells into sheep fetuses. Schoeberlein A, Holzgreve W, Dudler L, Hahn S, Surbek DV Am J Obstet Gynecol. 2005;192:1044-52.

The authors point out that the fetal sheep is an established animal model for in utero transplantation of stem cells. The anatomic, physiologic, and immunologic similarities between sheep and human fetal development make it a valuable tool for the evaluation of the clinical applications of in utero therapy. Human mesenchymal stem cells (MSCs) have been successfully transplanted into fetal sheep where they differentiated into multiple lineages.

In this study the authors addressed the short-tem engraftment capacity of allogeneic fetal liver-derived MSCs in different organs. Sheep fetal liver-derived MSC selected by adherence culture (passage 1) were transplantated into the fetal peritoneal cavity with ultrasound-guidance (mean gestational age, 59 days). After 14 days recipient fetuses were analyzed by fluorescence-activated cell sorting (FACS), real-time polymerase chain reaction (PCR), and immunohistochemistry.

Fetuses (n = 11) were transplanted with 7.7 x 10(6) MSCs (mean). All surviving fetuses (n = 5) showed engraftment with mean levels of 3.2% (lung), 0.8% (spleen), 0.6% (liver, brain), 0.4% (bone marrow), 0.1% (blood, thymus), and <0.1% (kidneys) by flow cytometry. Immunohistochemistry showed organ-specific distribution.

The authors concluded that in utero transplantation of allogeneic MSC results in low level, multiorgan engraftment at 14 days post transplant. This supports the potential of in utero MSC transplantation for the treatment of nonhematopoietic genetic disorders of the fetus.

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