Intramyocardial bone marrow stem cell treatment for myocardial regeneration
1 Department of Cardiac Surgery, Klinik und Poliklinik für Herzchirurgie, Medizinische Fakultät, University of Rostock, Schillingallee 35, 18057 Rostock, Germany
2 German Heart Center Berlin, Berlin, Germany
* Corresponding author. Tel: +49 381 494 6101; fax: +49 381 494 6102. E-mail address: gustav.steinhoff{at}med.uni-rostock.de
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Abstract |
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Transplantation of stem cells has been shown by substantial experimental evidence as well as by initial clinical studies to improve cardiac function in patients with post-infarction myocardial injury. Both angiogenic and myogenic properties of bone-marrow-derived stem cells have been evidenced to be involved in its beneficial effect on heart function after transplantation into area of ischaemic injury. This paper summarizes the current knowledge on the mechanisms involved in regenerative potential of bone-marrow-derived stem cells, with special attention to the clinical experience with cell transplantation during cardiac surgery.
Key Words: Stem cells • Angiogenesis • Myogenesis • Cardiac surgery • Heart failure
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Introduction |
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TopAbstractIntroductionBone marrow cells and...Bone marow cells and...Combination of (stem) cell...Bone marrow mononuclear cellsBone marrow stem cellsClinical results of...ConclusionReferences |
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Cell therapy for myocardial regeneration is an exciting new field of medical research that has the potential to revolutionize cardiovascular medicine. Despite significant improvements in emergency treatment, myocardial infarction leads to a net loss of contractile tissue in many patients with coronary artery disease. Often, this is the beginning of a downward spiral towards congestive heart failure and life-threatening arrhythmia. Other than heart transplantation with its obvious limitations, current therapeutic means aim at preventing further episodes of myocardial ischaemia and at enabling the organism to survive with a heart that is working at a fraction of its original capacity. They are far from representing a cure. In this situation, it is understandable that cardiac stem cell therapy attracts considerable attention and raises many hopes. In order to adequately judge both the potential benefits and the limitations of cardiac cell therapy, some understanding of the mechanism and the consequences of myocardial infarction and its current treatment concepts is needed.
In the setting of acute myocardial infarction, several studies have shown a functional benefit of intracoronary infusion of bone marrow cells compared with the standard treatment alone,1–3 but patients with chronic ischaemic heart disease and impaired heart function may require a different approach. Therefore, our group developed a protocol for the injection of purified CD133+ bone marrow stem cells directly into the diseased myocardium at the time of coronary artery bypass surgery. Based on the encouraging results in the first six patients,4 we completed a dose-escalation safety trial and then conducted a controlled study to determine efficacy compared with the standard coronary artery bypass grafting (CABG) operation. Figure 1 is depicting current strategies of bone marrow stem cell transplantation in the heart.
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Bone marrow cells and angiogenesis |
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During embryonic development, the primary vascular plexus is formed by haemangioblasts, stem cells capable of generating both haematopoietic progeny and endothelial cells, in a process termed vasculogenesis. Further blood vessels are generated by both sprouting and non-sprouting angiogenesis, finally leading to the complex functional adult circulatory system.5 Until recently, only two mechanisms of post-embryonic vascular remodelling have been recognized. Angiogenesis, the proliferative outgrowth of local capillaries, is one way to reinforce perfusion. Angiogenesis can occur under various conditions, including ischaemia. In case of myocardial ischaemia due to the occlusion of a coronary artery, pre-existing small collateral vessels also bear the capacity to enlarge in a process termed arteriogenesis. It has long been assumed that both mechanisms are mainly due to local proliferation of resident cells. The advent of cellular therapy of ischaemic organ damage has introduced neo-angiogenesis (sometimes also termed vasculogenesis) due to immigrating stem cells and progenitors as a third possible mechanism operative to improved perfusion of the adult damaged heart. Accumulating evidence indicates that immigrating (stem) cells can truly differentiate along endothelial lineage but also provide paracrine support in these three courses of action during regenerative vascular remodelling.6–8
Putative progenitors for therapeutic angiogenesis have been isolated from adult human peripheral blood based on their expression of CD34, a marker molecule shared by microvascular endothelial cells and haematopoietic stem cells.9 The same group provided the proof of concept by transplantation of genetically marked mouse bone marrow into recipient mice that were subsequently subjected to five distinct models of vascular remodelling including myocardial ischaemia.10 In this particular system, transgenic mice constitutively expressing beta-galactosidase under the transcriptional regulation of an endothelial cell-specific promoter were used as donors to replace the bone marrow in the recipient animals. Definitively, bone marrow-derived endothelial (progenitor) cells were found in reproductive organ tissues as well as in healing cutaneous wounds one week after punch biopsy. Marrow-derived endothelial progenitor cells were found to incorporate into capillaries among skeletal myocytes in an additional test for peripheral post-ischaemic regeneration after hindlimb ischaemia, as well as into foci of neovascularization at the border of an infarct after permanent ligation of the anterior descending artery.10 Most importantly, direct injection of the bone marrow mononuclear cell fraction in rat models of myocardial ischaemia increased the capillary density.11,12 Analysis of the effects of blood and bone marrow mononuclear cell implantation into ischaemic myocardium in pigs further revealed that the stem cell effects are not limited to angiogenesis and improved collateral perfusion, but also include the supply of regulatory cytokines.13,14 However, concerns exist regarding limited efficiency owing to the minute numbers of stem cells in small sample volumes of non-enriched blood and blood marrow that are delivered intra-myocardially and the risk of foreign tissue differentiation following local stroma cell injections. Kocher et al.15 circumvented this problem by using positively selected CD34+/133+ cells from human donors after stem cell mobilization with G-CSF for intravenous injection after permanent ligation of the left anterior descending coronary artery in nude rats, resulting in a five-fold increase in the number of capillaries compared with control. As a result of the stem-cell-mediated angiogenesis, which was attributed to the content of marrow-derived angioblasts, the authors also found an approximately 20% increase of left ventricular ejection fraction (LVEF) and cardiac index together with a reduced severity of ventricular remodelling in human CD34-treated, compared with control ischaemic animals.15
Another candidate cell population for the regeneration of ischaemic cardiac muscle and vascular endothelium are CD45+ haematopoietic CD34LOW/–/c-kit+, so called side population stem cells with a specific Hoechst 33342 DNA dye efflux pattern.16,17 Orlic et al.18 used an alternative method to enrich putative regenerative stem cells for local application by depleting unwanted cell lineages prior to enrichment for the expression of the stem cell factor receptor c-kit from murine bone marrow. Thus, concentrated cells, considered to represent haematopoietic stem cells, were observed to incorporate not only into vascular structures but dominantly led to myocardial regeneration.18 Subsequent experiments by this group employed mobilization of stem cells by G-CSF prior to experimental myocardial infarction that also led to a significant increase in vascular density within the scar, a reduction in mortality, and a significant reduction in infarct size.19
Although the evidence that angiogenesis occurs in ischaemic myocardium is convincing, this new therapeutic option also has a potential for serious side effects.20 Most importantly, bone-marrow-derived endothelial cells were found as part of the tumor neo-vasculature in experimental colon cancer.10 This finding might suggest a risk to trigger the growth of silent tumors by systemic use of pro-angiogenic stem cell therapy.
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Bone marow cells and myogenesis |
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Although the pro-angiogenic effect of marrow-derived stem cells appears to be well established, stem-cell-mediated myogenesis remains a matter of debate. The traditional view implies that ischaemic damage to the myocardium can only be compensated by hypertrophy, not hyperplasia, of surrounding cardiomyocytes. This dogma has recently been challenged, and intra-myocardial as well as extra-myocardial sources of regenerating contractile cells have been suggested.21 Cardiomyocyte proliferation has been described, although only with minute frequency.22,23 Furthermore, the existence of cardiomyocytes of non-cardiac origin has been suggested by chimerism analyses after transplantation,24–26 but the biologic relevance of some of these data has been questioned.27,28
The notion that bone marrow cells can regenerate infarcted myocardium led to great excitement. In their landmark paper, Orlic et al.29 described that injection of genetically labelled murine LinNEG/c-kit+ stem cells (isolated from mouse bone marrow by depletion of committed cells, and further enriched for expression of c-kit) led to the formation of new myocardium, occupying two-thirds of the infarct region within 9 days. This paper initiated a wave of enthusiasm, but also critical discussion. The data were interpreted to indicate trans-differentiation of adult haematopoietic stem cell by crossing lineage boundaries.30 However, the fact that cells are derived from bone marrow does not necessarily prove that they are haematopoietic in origin, especially in the light of growing knowledge about mesenchymal, non-haematopoietic stem cells within the marrow. The recognition of cell fusion as a common phenomenon in some artificial transplant models for regeneration of ischaemic tissue has added to the controversy.31,32 From the clinicians' point of view this was no surprise, since cell fusion is an intrinsic characteristic of contractile cells. Multinucleated skeletal myotubes are a classic example of cell fusion, and cardiomyocytes have long been known to form a large syncytial union.
More serious concerns were produced by two publications, which could not reproduce the promising in vivo trans-differentiation data. Using a modified Lin+ depletion protocol for stem cell enrichment in an otherwise similar myocardial ischaemia model, Balsam et al.33 found abundant GFP+ cells in the myocardium after 10 days that nearly disappeared until day 30. The remaining donor cells lacked cardiac tissue-specific markers, and instead adopted only haematopoietic fates as indicated by the expression of CD45. Murry et al.34 used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to follow murine LinNEG/c-kit+ stem cells after transplantation into healthy and injured mouse hearts, and could not find evidence for relevant differentiation into cardiomyocytes. In defence of the initial paper some have argued that (i) the cell isolation protocols were not completely identical, and (ii) both groups nevertheless observed some functional improvement in cell-treated hearts. However, it cannot been denied that the evidence for myogenesis based on haematopoietic adult stem cells myogenesis is extremely controversial.21,35–37 Very recently, a direct side-by-side comparison of human CD133+ bone marrow cells and human skeletal myoblasts in a myocardial ischaemia model in immunoincompetent rats demonstrated similar functional improvement in both groups, although only the myoblasts reached robust engraftment. Our own studies underline the angiogenic capacity of CD133+ stem cells from adult human bone marrow and cord blood in a Scid-mouse myocardial infarction model.38 Moreover, both cell preparations had beneficial effect on post-infarction mortality and apoptosis. Only adult bone marrow preparations contained a higher c-kit population and caused cardiac functional restoration in echocardiography. These findings underscore our limited understanding of how stem cells can elicit an improvement of heart function.
In contrast, the myogenic potential of stroma cell-derived mesenchymal stem cells is much better documented. Stroma cells are usually isolated based on their ability to adhere to plastic, not by selection for expression of certain surface markers. Their number in primary marrow aspirates is low, but they readily multiply for numerous cycles in culture, without apparent genotypic and phenotypic changes. Several years ago, Wakitani et al.39 reported the in vitro development of myogenic cells from rat bone marrow mesenchymal stem cells exposed to the DNA-demethylating agent 5-azacytidine, and Makino et al.40 isolated a cardiomyogenic cell line from murine bone marrow stromal cells that were treated with 5-azacytidine and screened for spontaneous beating. Those cells connected with adjoining cells, formed myotube-like structures, and beat spontaneously and synchronously. They expressed various cardiomyocytes-specific proteins, had a cardiomyocyte-like ultrastructure, and generated several types of sinus node-like and ventricular cell-like action potentials. When isogenic marrow stromal cells are implanted in rat hearts, they appear to become integrated in cardiac myofibres, assume the histologic phenotype of cardiomyocytes, express connexins, and form gap junctions with native cardiomyocytes.41,42 Again, epigenetic modification with 5-azacytidine is believed to facilitate differentiation towards a cardiomyocyte phenotype in vivo.43 Human mesenchymal stem cells derived from the marrow of volunteers have also been injected in hearts of immunodeficient mice, and again it was observed that they assume cardiomyocyte morphology and express various cardiomyocyte-specific proteins.44
Under different cultivation conditions, mesenchymal stem cells readily assume an osteoblast, chondrocyte, or adipocyte phenotype. In fact, preclinical research on regeneration of skeletal components is much more advanced than that on cardiovascular applications. It is therefore no surprise that, when unmodified mesenchymal stem cells are implanted in the heart, they may form islets resembling chondrogenic or osteogenic tissue. To date, there is very little, if any, information on stroma cell surface markers that might be helpful in identifying subpopulations with a particular potential for myogenic differentiation. It is therefore still unclear whether unmodified stroma cells that were expanded in vitro following simple isolation by plastic adherence will ultimately be useful in clinical protocols, whether a certain pro-myogenic subpopulation will be identified, or whether epigenetic re-programming prior to implantation will be necessary for functionally relevant myocardial regeneration in humans.
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Combination of (stem) cell treatment with CABG surgery |
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CABG patients were among the first to be included in clinical trails of cell therapy for myocardial regeneration. The most obvious reason is that the infarcted myocardium can be readily accessed during the operation, a unique opportunity to delivery cells in the centre or the border zone of the infarcted tissue by rather simple means.
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Bone marrow mononuclear cells |
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TopAbstractIntroductionBone marrow cells and...Bone marow cells and...Combination of (stem) cell...Bone marrow mononuclear cellsBone marrow stem cellsClinical results of...ConclusionReferences |
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Probably the simplest approach to myocardial cell therapy in the clinical setting is the transfer of bone marrow mononuclear cells into the myocardium. The proponents of this approach argue that by using unmodified marrow or unselected mononuclear cells, the ‘ideal’ cell for myocardial regeneration, which has not yet been identified, is not lost during the preparation process. Conversely, opponents argue that the vast majority of the bone marrow mononuclear cells are blood cells of all lineages and their immediate progenitors, whereas only few cells formally meet the stem cell criteria. Whether the local concentration of relevant stem or progenitor cells will surpass the hypothetical threshold for induction of regeneration processes remains unclear. Indubitably, marrow mononuclear cells can be easily collected and prepared during a standard CABG operation, which is an obvious and important logistic advantage.
The first such report came from Yamaguchi University, Japan. Hamano et al.45 described five patients who underwent CABG with simultaneous bone marrow collection from the iliac crest. The mononuclear cell fraction was prepared using a commercially available apheresis system, and between five and 22 injections of 5x107 to 1x108 cells were performed in the ischaemic myocardium that was not directly revascularized by bypass grafting. In three of those five patients, improved perfusion of the cell-treated tissue was noted post-operatively. No complications such as arrhythmia or local calcification were noted, but no statement was made with respect to LV function. In a similar trial, Galinanes et al.46 from Leicester University, UK, collected marrow by sternal bone aspirate at the time of CABG surgery. This was diluted with autologous serum and injected into LV scar tissue. Post-operatively, regional contractility in LV wall segments that did or did not receive marrow cells was assessed by dobutamine stress echocardiography, and only the segmental wall motion score of the areas injected with bone marrow and receiving a bypass graft in combination improved upon dobutamine stress. Most likely, many more patients have been subjected to similar treatment protocols elsewhere, but very little or no information as to the functional outcome is available. Most importantly, no controlled trial has so far demonstrated the superiority of CABG and mononuclear cell injection over CABG alone.
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Bone marrow stem cells |
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TopAbstractIntroductionBone marrow cells and...Bone marow cells and...Combination of (stem) cell...Bone marrow mononuclear cellsBone marrow stem cellsClinical results of...ConclusionReferences |
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Our own group has focused on the intramyocardial injection of purified haematopoietic bone marrow stem cells since 2001.47 We chose not to simply inject an unmodified mononuclear bone marrow cell suspension, because the large number of leukocytes and their progenitors may primarily induce local inflammation, rendering the actual stem cell effects insignificant. Instead, we prepare a purified stem cell suspension using clinically approved methods. Two monoclonal antibodies are currently available for clinical selection of bone marrow stem cells, anti-CD34, and anti-CD133. Approximately 60–70% of the CD34+ bone marrow cells co-express the CD133 antigen, and 70–80% of the CD133+ cells are CD34+ as well. The CD133+ bone marrow cell population contains a small proportion of clonogenic cells that have a very high potential to induce neoangiogenesis.48 Furthermore, there is accumulating evidence that the CD133+/CD34– subpopulation includes multipotent stem cells with a significant potential for differentiation into mesenchymal and other non-haematopoietic lineages. Between 2001 and 2003, we conducted a formal phase-I safety and feasibility trial in 15 patients, including a dose-escalation protocol. Since 2003, an open-label controlled phase-II trial is being undertaken, that will eventually include 100 patients. Fifty patients will undergo CABG and intramyocardial stem cell delivery, and 50 patients with comparable characteristics will have CABG alone. The inclusion criteria were defined as follows: (i) documented transmural myocardial infarction more than 10 days and less than 3 months prior to admission for surgery; (ii) presence of a localized area of akinetic LV wall without paradoxical systolic movement that corresponded with the infarct localization; (iii) the infarct area should not be amenable to surgical or interventional revascularization; (iv) elective CABG indicated to bypass stenoses or occlusions of coronary arteries other than the infarct vessel; (v) absence of severe concomitant disease (i.e. terminal renal failure, malignoma, debilitating neurological disease). Patients who underwent emergency operation for unstable angina, reoperations, concomitant valve procedures, or had a history of significant ventricular arrhythmia are excluded. In our experience, it proved rather time-consuming to recruit patients who met the inclusion criteria (approximately 10 patients per year), probably because the modern rapid catheter interventions in acute myocardial infarction prevent the development of completely akinetic LV wall areas in many patients.49
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Clinical results of intramyocardial CD133+ bone marrow stem cell transplantation with CABG surgery after myocardial infarction (Rostock trial) |
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Safety trial
All 15 patients included in the dose-escalation safety trial tolerated the operation well and has a post-operative course without major complications. The dose escalation ranged from 0.5 to 5x106 CD133+ bone marrow stem cells for intramyocardial transplantation. Minor complications were a rethoracotomy for bleeding from the internal mammary artery on the day of surgery and a respiratory tract infection in two patients. Otherwise, the in-hospital reconvalescence was uneventful, and all patients were referred to a cardiac rehabilitation program during the third post-operative week. Follow-up time currently ranges between 30 and 50 months and encompasses a total of 625 patient months (31 December 2005). No relevant ventricular arrhythmia was recorded at any time point by online telemetric monitoring or Holter ECG, and the reported exercise tolerance improved in all patients. A 75-year-old patient with cerebrovascular disease was lost to follow-up 9 months after surgery. He died of a stroke at later term (no autopsy available). All other patients were alive and well at the time of submission of the paper. The echocardiographic data of the safety trial patients are depicted in Figure 2. Overall, the average LVEF rose from 39.0±8% to 50.1±9% at 6 months and 48±6% at 18 months (P=0.001), and LVEDV decreased from 147.9±38% to 126.4±29 and 127.2±18%, respectively (P=0.1). Myocardial perfusion was assessed by Thallium SPECT scans. The activity in the area at risk—expressed as the quotient post-operative-to-pre-operative activity—demonstrated improved perfusion in the previously non- or hypo-perfused infarction zone in 13 patients. The average perfusion ratio after CABG and CD133+ cell injection was 1.15±0.1 at 2 weeks (P=0.0001), 1.14±0.2 at 6 months (P=0.02), and 1.14±0.288 at 18 months (P=0.07). Figure 3 depicts representative perfusion scans from a patient who received 5x106 CD133selected/CD34+ cells in the border zone of a posterior transmural myocardial infarction, where no bypass graft could be placed. It is evident that at the time of discharge there was no relevant improvement, but perfusion of the ischaemic tissue had virtually normalized 4 months later. This secondary gain in tissue blood supply might be attributed to the cell injection.
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Efficacy trial
Forty patients were randomly assigned to undergo either CABG and cell injection or CABG only. All but one patient who remained in the study had an uneventful post-operative course. The only early post-operative complication was a low cardiac output syndrome with acute renal failure in one patient, requiring medium-dose catecholamnie treatment and temporary haemofiltration. This patient recovered completely and was transferred to the ward on post-operative day 6. During the follow-up period, no major adverse events (death, myocardial infarction, or cardiac re-intervention) were reported, and all patients were alive and well at most recent follow-up (31 December 2005).
The echocardiographic data on LV function summarized in the data relevant for the primary outcome parameter, ‘LVEF at 6 months’ are depicted in Figure 4. The average LVEF rose from 37.4±8% to 47.1±8% at 6 months in patients receiving CABG and cell injection (P=0.005), and from 37.9±10% to 41.3±8% in patients undergoing CABG only (P=0.47). As required by the study protocol, direct comparsion of the primary outcome parameter (average LVEF at 6 months) achieved a P-value of 0.04. Within the range of probablity defined by the statistical power, the null hypothesis is therefore rejected, indicating that CABG and cell injection resulted in better LVEF than CABG only. The average change in LVEF was +9.7% in CABG and cell injection patients, and +3.4% in CABG-only patients (P=0.0009).
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As determined by SPECT imaging, myocardial perfusion in the area of interest at 6 months had improved in four control patients and in 11 patients who were treated with CABG and cell injection (P<0.05 by
2 test). Overall, improvement of perfusion was greater in the CABG and cell injection group than in the CABG-only group [median (25th–75th percentile)=0.95 (0.91–1.03) for CABG only patients vs. 1.02 (0.95–1.1) for CABG and cell injection patients]. The evaluation of the effects of CD133+ bone marrow cells upon direct intramyocardial transplantation in chronically ischaemic hearts of patients undergoing CABG gives primary clinical evidence of safety and efficacy of the treatment. In the initial safety trial, no stem-cell-related complications were observed during up to 4 years of follow-up. LV function improved, but the safety trial obviously does not allow to distinguish between the effects of cell injection and bypass grafting. In the subsequent efficacy trial in 40 patients randomly assigned to undergo CABG and cell injection or CABG controls, we found that global LV systolic function at 6 months was moderately but significantly better in cell-treated patients. It therefore appears that concomitant injection of CD133+ bone marrow cells yields a functional benefit in addition to the bypass operation. Similar results were reported by Patel et al.50 in a randomized study of 20 patients with intramyocardial injection of CD34+ autologous bone marrow stem cells and OP-CABG surgery. They found a significant improvement of EF (16.7 vs. 6.5%) in the cell-treated group vs. a control group after 6 months. Catheter-based intramyocardial injection of mononuclear bone marrow cell preparations by Perin et al.,51 Fuchs et al.,52 and Tse et al.53 also have reported efficient improvement of LV function in chronic ischaemic heart disease.
Given the notion that autologous bone marrow stem cells can indeed improve the function of chronically ischaemic myocardium in addition to the beneficial effects of traditional revascularization procedures, we believe that there is room for substantial further improvement. The cell number we have used is rather small and can be increased by modifying the isolation process, and the over-night storage of the cell product might impair the biologic activity. Other cell types with a greater likelihood for true cardiomyocyte-differentiation, i.e. mesenchymal stem cell-derived cells, might ultimately prove more efficient. Strategies to precondition cells prior to implantation by pharmacologic, genetic, or physical means are also currently under evaluation. However, for the time being, clinicians have to resort to clinically available cell products, and we believe that the approach we have chosen is invaluable in this respect.
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Conclusion |
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TopAbstractIntroductionBone marrow cells and...Bone marow cells and...Combination of (stem) cell...Bone marrow mononuclear cellsBone marrow stem cellsClinical results of...ConclusionReferences |
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Based on the existing experience, it seems to be justified to conclude that transplantation of autologous bone marrow cells in the infarct border zone can be safely performed in patients with ischaemic heart disease. Whether neoangiogenesis, neomyogenesis, or both occur in the human situation remains unclear at this point, and carefully designed controlled studies are needed to further determine the efficacy of clinical cell transplantation for ischaemic heart disease. It may well be that relevant myocardial regeneration already can be induced by using adult stem/progenitor cells that have not been expanded and modified ex vivo. However, given the tremendous amount of data demonstrating functional benefits in large animal models, careful clinical studies are needed to clarify clinical safety and efficacy for every cell population. Therefore, the clinical introduction of such treatment will need both patience and public support before established treatment protocols are available. The positive initial clinical experience with intramyocardial bone marrow stem cell transplantation is raising hope for further regenerative cardiac stem cell therapies.
Conflict of interest: none declared.
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References |
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- Wollert KC and Drexler H. (2005) Mesenchymal stem cells for myocardial infarction: promises and pitfalls. Circulation 112:151–153.
- Strauer BE, Brehm M, Zeus T, Kostering M, Hernandez A, Sorg RV, Kogler G, Wernet P. (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918.
- Schachinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM. (2004) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 44:1690–1699.
[Abstract/Free Full Text] - Stamm C, Westphal B, Kleine HD, Petzsch M, Kittner C, Klinge H, Schumichen C, Nienaber CA, Freund M, Steinhoff G. (2003) Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 361:45–46.[CrossRef][ISI][Medline]
- Risau W. (1997) Mechanisms of angiogenesis. Nature 386:671–674.[CrossRef][Medline]
- Kinnaird T, Stabile E, Burnett MS, Epstein SE. (2004) Bone marrow-derived cells for enhancing collateral development—mechanisms, animal data, and initial clinical experiences. Circulation Research 95:354–363.
[Abstract/Free Full Text] - Rafii S and Lyden D. (2003) Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9:702–712.[CrossRef][ISI][Medline]
- Urbich C and Dimmeler S. (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ Res 95:343–353.
[Abstract/Free Full Text] - Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967.
[Abstract/Free Full Text] - Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, Magner M, Isner JM. (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228.
[Abstract/Free Full Text] - Tomita S, Li RK, Weisel RD, Mickle DA, Kim EJ, Sakai T, Jia ZQ. (1999) Autologous transplantation of bone marrow cells improves damaged heart function. Circulation 100:II247–II256.
- Kobayashi T, Hamano K, Li TS, Katoh T, Kobayashi S, Matsuzaki M, Esato K. (2000) Enhancement of angiogenesis by the implantation of self bone marrow cells in a rat ischaemic heart model. J Surg Res 89:189–195.[CrossRef][ISI][Medline]
- Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Tsutsumi Y, Ozono R, Masaki H, Mori Y, Iba O, Tateishi E, Kosaki A, Shintani S, Murohara T, Imaizumi T, Iwasaka T. (2001) Implantation of bone marrow mononuclear cells into ischaemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 104:1046–1052.
- Kamihata H, Matsubara H, Nishiue T, Fujiyama S, Amano K, Iba O, Imada T, Iwasaka T. (2002) Improvement of collateral perfusion and regional function by implantation of peripheral blood mononuclear cells into ischaemic hibernating myocardium. Arterioscler Thromb Vasc Biol 22:1804–1810.
[Abstract/Free Full Text] - Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. (2001) Neovascularization of ischaemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 7:430–436.[CrossRef][ISI][Medline]
- Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP. (1997) Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3:1337–1345.[CrossRef][ISI][Medline]
- Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW, Entman ML, Michael LH, Hirschi KK, Goodell MA. (2001) Regeneration of ischaemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 107:1395–1402.[CrossRef][ISI][Medline]
- Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. (2001) Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann N Y Acad Sci 938:221–229.
[Abstract/Free Full Text] - Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 98:10344–10349.
[Abstract/Free Full Text] - Epstein SE, Kornowski R, Fuchs S, Dvorak HF. (2001) Angiogenesis therapy—amidst the hype, the neglected potential for serious side effects. Circulation 104:115–119.
- Mathur A and Martin JF. (2004) Stem cells and repair of the heart. Lancet 364:183–192.[CrossRef][ISI][Medline]
- Kajstura J, Leri A, Finato N, Di Loreto C, Beltrami CA, Anversa P. (1998) Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci USA 95:8801–8805.
[Abstract/Free Full Text] - Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P. (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757.
[Abstract/Free Full Text] - Quaini F, Urbanek K, Beltrami AP, Finato N, Beltrami CA, Nadal-Ginard B, Kajstura J, Leri A, Anversa P. (2002) Chimerism of the transplanted heart. N Engl J Med 346:5–15.
[Abstract/Free Full Text] - Laflamme MA, Myerson D, Saffitz JE, Murry CE. (2002) Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res 90:634–640.
[Abstract/Free Full Text] - Muller P, Pfeiffer P, Koglin J, Schafers HJ, Seeland U, Janzen I, Urbschat S, Bohm M. (2002) Cardiomyocytes of noncardiac origin in myocardial biopsies of human transplanted hearts. Circulation 106:31–35.
- Spangrude GJ, Torok-Storb B, Little MT. (2002) Chimerism of the transplanted heart. N Engl J Med 346:1410–1412.[CrossRef][ISI][Medline]
- Bianchi DW, Johnson KL, Salem D. (2002) Chimerism of the transplanted heart. N Engl J Med 346:1410–1412.[CrossRef][ISI][Medline]
- Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410:701–705.[CrossRef][Medline]
- Korbling M and Estrov Z. (2003) Adult stem cells for tissue repair—a new therapeutic concept? N Engl J Med 349:570–582.
[Free Full Text] - Goodell MA. (2003) Stem-cell ‘plasticity’: befuddled by the muddle. Curr Opin Hematol 10:208–213.[CrossRef][ISI][Medline]
- Camargo FD, Chambers SM, Goodell MA. (2004) Stem cell plasticity: from transdifferentiation to macrophage fusion. Cell Prolif 37:55–65.[CrossRef][ISI][Medline]
- Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC. (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673.[CrossRef][Medline]
- Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664–668.[CrossRef][Medline]
- Chien KR. (2004) Stem cells: lost in translation. Nature 428:607–608.[CrossRef][Medline]
- Couzin J and Vogel G. (2004) Cell therapy—renovating the heart. Science 304:192–194.
[Abstract/Free Full Text] - Honold J, Assmus B, Lehman R, Zeiher AM, Dimmeler S. (2004) Stem cell therapy of cardiac disease: an update. Nephrol Dial Transplant 19:1673–1677.
[Free Full Text] - Ma N, Ladilov Y, Moebius JM, On LL, Piechaczek C, David A, Kaminski A, Choi YH, Li W, Egger D, Stamm C, Steinhoff G. (2006) Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model. Cardiov Res 71:158–169.
[Abstract/Free Full Text] - Wakitani S, Saito T, Caplan AI. (1995) Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 18:1417–1426.[CrossRef][ISI][Medline]
- Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S. (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:697–705.[ISI][Medline]
- Chedrawy EG, Wang JS, Nguyen DM, Shum-Tim D, Chiu RC. (2002) Incorporation and integration of implanted myogenic and stem cells into native myocardial fibers: anatomic basis for functional improvements. J Thorac Cardiovasc Surg 124:584–590.
[Abstract/Free Full Text] - Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, Chiu RC. (2000) Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 120:999–1005.
[Abstract/Free Full Text] - Bittira B, Kuang JQ, Al Khaldi A, Shum-Tim D, Chiu RC. (2002) In vitro preprogramming of marrow stromal cells for myocardial regeneration. Ann Thorac Surg 74:1154–1159.
[Abstract/Free Full Text] - Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98.
- Hamano K, Nishida M, Hirata K, Mikamo A, Li TS, Harada M, Miura T, Matsuzaki M, Esato K. (2001) Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischaemic heart disease: clinical trial and preliminary results. Jpn Circ J 65:845–847.[CrossRef][Medline]
- Galinanes M, Loubani M, Davies J, Chin D, Pasi J, Bell PR. (2004) Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans. Cell Transplant 13:7–13.[ISI][Medline]
- Stamm C, Kleine HD, Choi YH, Dunkelmann S, Lauffs JA, Lorenzen B, David A, Liebold A, Nienaber CA, Zurakowski D, Freund M, Steinhoff G. Intramyocardial delivery of CD133+ bone marrow cells and CABG surgery for chronic ischemic heart failure: safety and efficacy studies. J Thorac Cardiovasc Surg (in press).
- Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, Rafii S. (2000) Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood 95:952–958.
[Abstract/Free Full Text] - Stamm C, Kleine HD, Westphal B, Petzsch M, Kittner C, Nienaber CA, Freund M, Steinhoff G. (2004) CABG and bone marrow stem cell transplantation after myocardial infarction. Thorac Cardiovasc Surg 52:152–158.[CrossRef][ISI][Medline]
- Patel AN, Geffner L, Vina RF, Saslavsky J, Urschel HC, Kormos R, Benetti F. (2005) Surgical treatment for congestive heart failure with autologous adult stem cell transplantation: a prospective randomized study. J Thor Cardiov Surg 130:1631–1638.
- Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischaemic heart failure. Circulation 107:2294–2302.
- Fuchs S, Satler LF, Kornowski R, Okubagzi P, Weisz G, Baffour R, Waksman R, Weissman NJ, Cerqueira M, Leon MB, Epstein SE. (2003) Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease—A feasibility study. J Am Coll Cardiol 41:1721–1724.
[Abstract/Free Full Text] - Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. (2003) Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 361:47–49.[CrossRef][ISI][Medline]
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