Bone marrow mononuclear cells and acute myocardial infarction.Stem Cell Research & Therapy 2012, 3:2

Review
Bone marrow mononuclear cells and acute myocardial infarction

Samer Arnous1, Abdul Mozid1, John Martin1 and Anthony Mathur2*

* Corresponding author: Anthony Mathur a.mathur@qmul.ac.uk

Author Affiliations

1 Department of Cardiology, London Chest Hospital, Bonner Road, London E2 9JX, UK

2 Department of Cardiology, London Chest Hospital, Queen Mary University of London, Barts and the London NHS Trust, Bonner Road, London E2 9JX, UK

For all author emails, please log on.

Stem Cell Research & Therapy 2012, 3:2 doi:10.1186/scrt93

The electronic version of this article is the complete one and can be found online at: http://stemcellres.com/content/3/1/2

Published: 17 January 2012

© 2012 BioMed Central Ltd

Abstract

Stem cell transplantation is emerging as a potential therapy to treat heart diseases. Promising results from early animal studies led to an explosion of small, non-controlled clinical trials that created even further excitement by showing that stem cell transplantation improved left ventricular systolic function and enhanced remodelling. However, the specific mechanisms by which these cells improve heart function remain largely unknown. A large variety of cell types have been considered to possess the regenerative ability needed to repair the damaged heart. One of the most studied cell types is the bone marrow-derived mononuclear cells and these form the focus of this review. This review article aims to provide an overview of their use in the setting of acute myocardial infarction, the challenges it faces and the future of stem cell therapy in heart disease.
Introduction

Despite the recent advances in percutaneous intervention, drug and device therapy, patients with acute myocardial infarction (AMI) and resulting left ventricular impairment have 13% mortality at 1 year [1]. Following the loss of over one billion cardiomyocytes in a functionally significant MI, the overloaded surviving cardiomyocytes undergo abnormal remodelling, eventually leading to heart failure. This condition, a leading cause of death and disability in the developed world, is associated with 5-year mortality rates of up to 70% in symptomatic patients [2]. Current conventional therapies do not correct underlying defects in cardiac muscle cell number [3].

The only therapeutic option that currently addresses cardiomyocyte loss is heart transplantation. However, due to stringent selection criteria and chronic shortage of donor hearts, the vast majority of patients are deemed unsuitable or never receive a transplant. Therefore, preventing this progression post-MI is a major challenge requiring novel therapeutic strategies such as stem cell transplantation to improve the prognosis and quality of life for these patients.

The traditional view that the heart is a terminally differentiated organ has been challenged by the discovery of differentiation of stem cells into cardiomyocytes in animal and human hearts [4-7]. This in turn has led to the exciting possibility for regenerative therapy for cardiomyocyte loss after a MI. The demonstration of functional recovery of myocardium through cardiomyogenesis and neoangiogenesis in AMI in murine models by Orlic and colleagues [8] generated tremendous interest in the potential of bone marrow-derived stem cells. Since then, the cardiomyogenic ability of these cells has been challenged. However, studies continue to demonstrate improvement in cardiac function and reduction in infarct size. It should be noted that progenitor cells also contribute to cardiac repair by mechanisms beyond the growth of new cardiomyocytes and as such may offer an ‘indirect’ benefit.
Animal and human trials

The most promising and obvious cell type for the growth of new cardiomyocytes is the embryonic stem cell; however, considerable technical and ethical issues exist with these cells, which must be overcome before their successful use in humans. Adult stem cells are an attractive option to explore for transplantation as they are autologous, but their differentiation potential is more restricted than embryonic stem cells. Currently, the major sources of adult cells used for basic research and in clinical trials originate from the bone marrow. The bone marrow mononuclear subset is heterogeneous and comprises mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. The differentiation capacity of different populations of bone marrow-derived stem cells into cardiomyocytes has been studied intensively. The results are rather confusing and difficult to compare, since different isolation and identification methods have been used to determine the cell population studied. To date, only mesenchymal stem cells seem to form cardiomyocytes, and only a small percentage of this population will do so in vitro or in vivo. Pragmatically, the translation of the basic science into clinical research has followed a common pathway: injection of bone marrow-derived mononuclear cells (BMMNCs) as a source of stem cells into the heart. Table 1 provides a summary of clinical trials using BMMNCs in patients with acute MI.

Table 1. Clinical trials using autologous bone marrow mononuclear cells in patients with acute myocardial infarction
Trials with no sham bone marrow harvest or intracoronary re-infusion in the control group

In the first human trial, Strauer and colleagues [9] re-infused intracoronary BMMNCs 7 days after myocardial infarction (MI). The mean number of mononuclear cells was 2.8 × 107. There was a significant improvement in myocardial perfusion and a reduction in the infarct region in the cell therapy group. The Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) investigators randomised patients into intracoronary infusion of BMMNCs or ex vivo expanded circulating progenitor cells 4 days after MI [10]. There was a significant improvement in global and regional left ventricular (LV) function in both groups and a beneficial effect on the post-infarction remodelling process manifest by a profound improvement in wall motion abnormalities in the infarct area and a significant reduction in end-systolic LV volume at 4 months post-MI. The LV ejection fraction (LVEF) further improved at 12 months, resulting in a total increase of 9.3% at 1 year [11]. Of interest, there was no difference between the two active treatment groups. The mean number of infused cells was 245 × 106, which contained haematopoietic progenitor, mesenchymal and stromal cells. However, a major limitation of both of these trials was the lack of a control group receiving sham bone marrow harvest or intracoronary re-infusion.

Another trial in which there was no sham procedure is the Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial, which included only patients with acute anterior MI. The intracoronary re-infusion of BMMNCs 4 to 8 days after infarction did not have a beneficial effect on LVEF compared to percutaneous coronary intervention (PCI) alone at 6 months [12]. This lack of beneficial effect may be explained by the different cell processing protocols used in this trial. Cell processing protocols may have a significant impact on the functional capacity of bone marrow-derived stem cells [13]. Comparison of different isolation protocols revealed a vastly reduced recovery of mononuclear cells and nullification of the neovascularisation capacity when the ASTAMI cell isolation and storage protocol was used [13].

The Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration (BOOST) trial, a slightly larger trial, included 60 patients that were randomised to receive intracoronary BMMNCs or standard therapy 4.8 days after successful PCI following AMI. There was a significant improvement in global LVEF in the cell treatment group at 6 months without an effect on LV remodelling [14]. However, this improvement was not maintained at 18 months. The mean number of bone marrow cells that were infused contained 9.5 × 106 CD34+ and 3.6 × 106 haematopoietic colony-forming cells. The improvement in LVEF did not correlate with the number of CD34+ cells or haematopoietic colony forming cells. Again, a major limitation of the BOOST trial is that the control group did not undergo a sham bone marrow harvest or intracoronary infusion.

The first long-term study involving 62 patients who underwent intracoronary BMMNC transplantation 7 days post-AMI not only resulted in an early significant improvement in ejection fraction (EF) and infarct size, but there was also a significant reduction in mortality and improvement in exercise capacity compared to controls at 5 years [15].
Randomised controlled trials

The Transcatheter Transplantation of Stem Cells for Treatment of Acute Myocardial Infarction (TCT-STAMI) trial, which included a control group receiving a placebo infusion, showed a significant (approximately 5%) improvement in LVEF of patients receiving intracoronary BMMNCs at 6 months [16].

Intracoronary bone marrow derived progenitor cells in acute infarction (REPAIR-AMI), a large randomized double-blind controlled trial that included over 200 patients, showed an improvement in the primary endpoint in the treatment group that was an absolute change in global LVEF from baseline to 4 months, as measured by quantitative left ventricular angiography [17]. Furthermore, the pre-specified cumulative endpoint of death, MI, or revascularisation was significantly reduced, and this benefit was maintained at one year follow-up [18]. The mean increase in LVEF in the BMMNC group was 2.5% and there was an inverse relationship between the baseline EF and the degree of improvement. For example, patients with a baseline EF below the median value (48.9%) had an absolute increase in global EF that was three times higher than that in the placebo group. In contrast, the improvement in LVEF in patients with a baseline EF that was above the median value was non-significant (0.3%). The timing of cell infusion post-PCI also had an effect on the primary endpoint. Patients in whom the cells were infused ≥5 days post-PCI were the only ones who derived benefit.

By contrast, the LEUVEN-AMI study by Janssens and colleagues [19] showed that intracoronary re-infusion of BMMNCs within 24 hours of reperfusion was associated with a greater reduction in infarct size and improved regional systolic function, but no overall improvement in global left ventricular function compared to controls.
Trials that used two different cell populations

More recently, the Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) trial, which included patients with anterior MI, uniquely compared two cell types. Patients were randomized to receive intracoronary infusion of unselected (n = 80) or selected CD34+CXCR4+ (n = 80) BMMNCs, or to the control group (n = 40) [20]. Although patients in the treatment group had a 3% improvement in LVEF, this did not reach statistical significance. However, the primary endpoint analysis included 5 hours) may be more likely to have significant improvement of LVEF following the BMMNC infusion [20].

The timing of cell infusion may also play a role on the derived benefit. Although the REPAIR-AMI trial suggests that the enhanced improvement of the LVEF was confined to patients who were treated ≥5 days after primary PCI, the investigators of the HEBE and REGENT trials showed no interaction between the timing of cell infusion and derived benefit. The meta-analysis by Martin-Rendon and colleagues [22], however, showed that the benefit of stem cell therapy was even greater when the BMMNCs were infused >7 days after MI. The effect of timing on the beneficial effects of BMMNC administration is further supported by the study by Lai and colleagues [31] that showed that intracoronary BMMNC administration provided cardio-protection in a fashion similar to ishaemic preconditioning. This benefit was only seen when the myocardium had not been preconditioned by other means. An ongoing study at our centre, the REGENERATE-AMI (ClinicalTrial.gov NCT00765453), is designed to study the delivery of BMMNCs at very early time points (within 6 hours of PCI). The purpose of this design is to replicate the animal models where very early interventions lead to a significant (40%) improvement in cardiac function [8].

The dose of infused BMMNCs has varied between different trials with variable results. There appears to be a dose-dependent improvement in EF, with the benefit of BMMNCs only seen when doses higher than 108 are administered [22].
Direct (transdifferentiation) and indirect (paracrine and angiogenesis) effects of stem cells

To date, there is no direct clinical evidence that cellular cardiomyogenesis in fact occurs in the human heart after transplantation of progenitor cells, and over the past few years, various experiments using different types of stem cells have shown that 4 days after reperfusion (based on available evidence). Furthermore, given the seemingly small improvements that these trials have shown, the cost-effectiveness of cell therapy will also need to be addressed.

Two ongoing randomised controlled trials (TIME and late TIME studies) may help us understand whether the timing of cell administration plays an important role. The TIME study (Clinicaltrials.gov NCT00684021) is a trial designed to assess the effect of timing (3 versus 7 days) of BMMNC administration versus placebo in patients with acute MI. The LATE TIME study (Clinicaltrials.gov NCT00684060) will assess the effect of BMMNC administration 2 to 3 weeks after a MI.
Future cells

Animal and human studies have clearly shown that stem cell engraftment into the myocardium is associated with improvement in cardiac function; however, the quest for the optimal population of cells remains a challenge [85,86]. Embryonic stem cells are able to transform into cardiomyocytes and can replicate indefinitely, although ethical issues – their potential to form teratomas and the need for immunosuppressive therapy – have hindered their use in clinical trials. Furthermore, one of the major limitations of adult stem cells, including skeletal myoblasts and bone marrow-derived stem cells, is their limited ability to cross their lineage boundaries.

Fat tissue-derived multipotent stem cells [87], multi-potential cells from bone marrow or skeletal muscle [88,89], somatic stem cells from placental cord blood [90], and cardiac-resident progenitor cells [32,91] all show promising pre-clinical and some clinical applications.

Ultimately, cells that more closely resemble embryonic stem cells in their regenerative potential without the ethical issues provide an important future direction. A cell type that comes close, and is on the horizon of being tested for potential clinical application, is the inducible pluripotent stem cell (iPSC). iPSCs can be generated from adult human somatic cells by retroviral transduction [92], have similar differentiation potential and may provide an alternative to pluripotent embryonic stem cells.
The future of bone marrow stem cells

For the time being, it is important to establish whether the simple unfractionated bone marrow cell approach has clinical benefit, given the large number of studies that have been performed using this cell type without providing a clear answer. Meta-analysis suggests a positive effect on surrogate cardiac end-points in studies using BMMNCs to treat AMI. There is now a need to perform a large scale clinical trial using clinical hard end-points such as mortality to establish whether the positive effects seen on surrogate end-points can indeed translate to meaningful clinical benefits.
Abbreviations

AMI: acute myocardial infarction; ASTAMI: Autologous Stem-Cell Transplantation in Acute Myocardial Infarction; BMMNC: bone marrow-derived mononuclear cell; BOOST: Bone Marrow Transfer to Enhance ST-Elevation Infarct Regeneration; EF: ejection fraction; LV: left ventricular; LVEF: left ventricular ejection fraction; MI: myocardial infarction; PCI: percutaneous coronary intervention; REPAIR-AMI: Intracoronary bone marrow derived progenitor cells in acute infarction; SDF: stromal-cell-derived factor.
Competing interests

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Acknowledgements

This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Research.
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