PRECLINICAL STUDY: EDITORIAL COMMENT
Skeletal Muscle-Derived Stem Cell TransplantationAngiogenesis Is Required for Improved Left Ventricular Function*
H. Kirk Hammond, MD*
Department of Medicine, University of California at San Diego, and Veteran’s Administration San Diego Healthcare System, San Diego, California.
* Reprint requests and coorespondence: Dr. H. Kirk Hammond, VA San Diego Healthcare System (111A), 3350 La Jolla Village Drive, San Diego, California 92161. (Email: khammond{at}ucsd.edu).
In 2001, reports in animal models of acute myocardial infarction (MI) indicated that that cell-based therapy could be used to regenerate cardiac myocytes and thereby improve cardiac function (1). The delivery of bone marrow-derived cells, endothelial progenitor cells, embryonic or mesenchymal stem cells, and skeletal muscle-derived stem cells, to mention a few, were associated with favorable effects on left ventricular (LV) function and remodeling in a variety of preclinical studies (1–3), although questions regarding the importance of cardiac myocyte regeneration as the mechanism for improvement in LV function have been raised (4,5). The general approaches and challenges of cell-based approaches to facilitate cardiac repair and the results of preclinical and clinical studies were presented recently in excellent reviews (6–8).
Initial uncontrolled clinical trials of bone marrow-derived cell therapy in acute MI showed consistent small increases in LV ejection fraction (LVEF) (9), but subsequent randomized controlled clinical trials showed variable results (10–14). For example, the BOOST (Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration) trial showed increases in LVEF 6 months after treatment (9) which were not still present 12 months later (10). The ASTAMI (Autologous Stem Cell Transplantation in Acute Myocardial Infarction) trial found a decrease in LVEF in the treatment group (11), whereas a study by Janssen et al. (12) found no change in LVEF, although infarct size was reduced and regional function increased by treatment, despite absence of changes in regional myocardial perfusion. The REPAIR-AMI (Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction) trial investigators found that LVEF increased more in treated patients than in control subjects. Although the change was small (5.5% vs. 3.0%), clinical events indicating recurrent ischemia were reduced 12 months after treatment (13). A randomized controlled clinical study that examined the usefulness of granulocyte colony-stimulating factor to mobilize bone marrow cells in the setting of acute MI failed to show a favorable effect on LVEF (14).
Recently, a randomized controlled clinical trial of cell-based therapy for the treatment of chronic ischemia was reported (15). Patients were enrolled 3 months after acute MI if they had an open vessel perfusing a dysfunctional region of myocardium. Only one-third of patients had class 3 or 4 congestive heart failure (CHF) symptoms, but pretreatment LVEFs ranged from 30% to 43%. Three months after intracoronary infusion of bone marrow-derived cells, patients had an increase in mean LVEF from 41% to 43%, which was better than the patients who received no cell therapy or cell therapy derived from circulating blood (p > 0.001) (15). A subsequent registry report of 121 patients (including those just mentioned) with chronic myocardial ischemia who received intracoronary infusion of bone marrow-derived mononuclear progenitor cells showed a reduction in serum natriuretic peptide levels 19 months later. Patients that received bone marrow cells with higher (vs. lower) functional capacity showed increased survival (16). These data support the initiation of a larger randomized controlled clinical trial of cell-based therapy for patients with frank CHF with evaluation for sustained benefits of therapy.
The mechanism for beneficial cardiac effects remains uncertain. Cardiac regeneration is a possibility (1,3), but it has been difficult to confirm (4,5). In some clinical trials, LV functional improvement has been associated with an increased regional myocardial perfusion, suggesting that cell-based therapy may evoke myocardial angiogenesis (17–19). But how robust are data showing that the mechanism for beneficial effects is angiogenesis?
In the current issue of the Journal, Payne et al. (20), injected skeletal muscle-derived stem cells (MDSC) in the hearts of animals directly after coronary occlusion. Saline injection was compared with 3 types of MDSC injection: MDSC alone and MDSC engineered to express vascular endothelial growth factor (VEGF) or soluble Flt1 (a VEGF antagonist). Cardiac function and LV remodeling were then serially evaluated by echocardiography, and angiogenesis was assessed using histologic methods. Injection of MDSC, whether engineered to express VEGF or not, was associated with increased LV function, reduced adverse LV remodeling, and increased angiogenesis. Furthermore, animals that received MDSC engineered to secrete Flt1 did not show beneficial effects even though cell engraftment was established (20). In vitro studies showed that MDSC released VEGF in vitro when stimulated with hypoxia and cyclic stretch.
This study indicates that angiogenesis was required for the favorable effects associated with MDSC transplantation in a clinically relevant animal model of cardiac dysfunction. By inference, many of the favorable effects seen in clinical trials may reflect angiogenesis rather than cardiac myocyte regeneration. This in itself, while not a new concept, has not previously been so clearly demonstrated. Furthermore, because angiogenesis associated with cell-based therapy may be due to direct incorporation of progenitor cells into new vessels, or associated with chemoattraction and cytokines, the current studies focus on the paracrine release of VEGF as a dominant mechanism. Payne et al. have performed a convincing a priori test of the role of angiogenesis in cell-based therapy for myocardial dysfunction.
There are several issues to consider regarding clinical application of this approach. 1) Arrhythmia: injection of MDSC into failing human hearts has been associated with an increased incidence of subsequent sustained ventricular tachycardia (VT) (21). Owing to low expression of connexin-43 gap junction protein, engrafted MDSCs do not exhibit optimal electrophysiological integration, which may be the mechanism for arrythmogenesis (21). Injection of cells into viable hibernating rather than infarcted regions may reduce the incidence of VT (7). 2) Brief engraftment: preclinical studies indicate that engrafted cells remain in the heart very briefly, a few days at most (7). If paracrine-related angiogenesis is the mechanism for improved LV function, sustained secretion of angiogenic proteins may be required. Although the authors cite a report indicating that engrafted MDSCs secrete VEGF for 12 weeks (22), brief-duration engraftment is a widely recognized shortcoming of the approach (6,7). 3) Delayed treatment: the preparation of autologous MDSCs will make immediate treatment for MI impossible. Logically, early intervention would be expected to yield better results, even when the infarct-related artery is opened by percutaneous coronary intervention, because the targeted area is the infarct border region that, owing to dysynergic contraction, suffers from sustained ischemia and is thereby prone to adverse remodeling (23).
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Implications
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The principal finding of Payne et al. (20) is that the beneficial effects of MDSC injection result from paracrine secretion of an angiogenic growth factor. Is cell transplantation the optimal means to obtain paracrine-related secretion of angiogenic factors? The use of virus vectors encoding VEGF could be injected immediately after MI and could elaborate VEGF for sustained periods, without presenting the heart with a heterogeneous electrophysiological substrate, thereby circumventing 3 of the problems associated with MDSC transplantation. Although cardiovascular gene transfer is bedeviled with its own struggles, data from preclinical models of acute and chronic myocardial ischemia demonstrated favorable effects on LV function (24) similar to those described with cell-based therapy.
Payne et al. (20) provides a simple and elegant study indicating that transplanted MDSCs provide favorable effects through paracrine release of VEGF and subsequent angiogenesis. If this is the sole mechanism of benefit, elements likely to improve results in clinical trials may include identification of the cell and delivery method that provides persistent and efficient cardiac engraftment. Engineering these cells to express angiogenic factors (alone or in combination) whose expression is governed by biological signals (ischemia/hypoxia) may provide additional advantages. That cell-based treatment of acute MI advanced from the first preclinical observation (1) to completion of the first randomized clinical trial (9) in 3 years is impressive but explains, perhaps, why there is so much potential for improvement.
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Footnotes
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Dr. Hammond is supported by National Institutes of Health grants 5P01HL066941 and HL081741 and a merit grant from the Department of Veteran’s Affairs.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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Autologous stem cell transplantation in acute myocardial infarction: the ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005;39:150-158.[CrossRef][Web of Science][Medline] 12. Janssen S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial Lancet 2006;367:113-121.[CrossRef][Web of Science][Medline] 13. Schächinger V, Erbs S, Elsässer A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction N Engl J Med 2006;355:1210-1221.[CrossRef][Medline] 14. Engelmann MG, Theiss HD, Hennig-Theiss C, et al. Autologous bone marrow stem cell mobilization induced by granulocyte colony-stimulating factor after subacute ST-segment elevation myocardial infarction undergoing late revascularization: final results from the G-CSF-STEMI (Granulocyte Colony-Stimulating Factor ST-Segment Elevation Myocardial Infarction) trial J Am Coll Cardiol 2006;48:1712-1721.[Abstract/Free Full Text] 15. Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction N Engl J Med 2006;355:1222-1232.[CrossRef][Medline] 16. Assmus B, Fischer-Rasokat U, Honold J, et al. Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure: results of the TOPCARE-CHD registry Circ Res 2007;100:1234-1241.[Abstract/Free Full Text] 17. Perin EC, Dohmann HF, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy Circulation 2004;110:II213-II218.[Web of Science][Medline] 18. Tse HF, Kwong YL, Chan JK, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation Lancet 2003;361:47-49.[CrossRef][Web of Science][Medline] 19. Fazel S, Cimini M, Chen L, et al. Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines J Clin Invest 2006;116:1865-1877.[CrossRef][Web of Science][Medline] 20. Payne TR, Oshima H, Okada M, et al. A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts J Am Coll Cardiol 2007;50:1677-1684.[Abstract/Free Full Text] 21. Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J Am Coll Cardiol 2003;41:1078-1083.[Abstract/Free Full Text] 22. Oshima H, Payne TR, Urish KL, et al. Differential myocardial infarct repair with muscle stem cells compared to myoblasts Mol Ther 2005;12:1130-1141.[CrossRef][Web of Science][Medline] 23. Zheng W, Weiss RM, Wang X, et al. DITPA stimulates arteriolar growth and modifies myocardial postinfarction remodeling Am J Physiol 2004;286:H1994-H2000.[Web of Science] 24. Losordo DW, Dimmeler S. Therapeutic angiogenesis and vasculogenesis for ischemic disease. Part I: angiogenic cytokines. Circulation 2004;109:2487-2491.[Free Full Text]
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