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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Percutaneous bone-marrow-derived cell transplantation: clinical observations

Pedro L. Sánchez1, Adolfo Villa2, José Alberto San Román2, Teresa Cantero2, María Eugenia Fernández3 and Francisco Fernández-Avilés1,*

1 Hospital Universitario Gregorio Marañón, C Doctor Esquerdo 46, 28007 Madrid, Spain
2 ICICOR (Instituto de Ciencias del Corazón), Hospital Clínico Universitario de Valladolid, Valladolid, Spain
3 IBGM (Instituto de Biología Molecular), Valladolid, Spain

* Corresponding author. E-mail address: faviles{at}secardiologia.es


   Abstract
Top
 Abstract
Introduction
 Bone-marrow-derived stem cells
 Clinical aplications
 Clinical safety
 The near future
 References
 
Different types and routes of stem cell delivery have been used in clinical practice to repair infarcted or ischaemic myocardium. Of these, percutaneous administration of bone-marrow-derived progenitors represents the most optimal method to date, as it allows the evaluation of the cells' effects independent of revascularization and the application of multiple administrations over time. Two different percutaneous catheter-based methods have been used in clinical trials to deliver bone-marrow-derived stem cells: intracoronary infusion and transendomyocardial delivery through a left ventricle catheter. Despite the clinical scenarios investigated (acute myocardial infarction, chronic ischaemia with no revascularization option, and ischaemic cardiomyopathy), in general percutaneous bone-marrow-derived stem cell therapy is feasible, relatively safe (with unresolved concerns regarding arrhythmias, restenosis, and atherosclerosis progresion), and could exert a benefit upon ventricular function and perfusion. At this point, intermediate-size, randomized trials are aimed to well establish the efficacy of this therapy that analyses surrogate endpoints: either perfusion or left ventricular function based on the clinical scenario tested.

Key Words: Bone marrow • Stem cells • Myocardial infarction • Myocardial ischaemia • Ischaemic cardiomyopathy


   Introduction
Top
 Abstract
 Introduction
Bone-marrow-derived stem cells
 Clinical aplications
 Clinical safety
 The near future
 References
 
After overcoming the classical dogma that denied the renewal capacity of the adult heart, an increasing amount of data has been obtained to suggest that it is possible to encourage its intrinsic regenerative capacity by stimulating resident stem cells or transplanting extracardiac progenitors.

Different types and routes of stem cell delivery have been used in clinical practice to repair infarcted or ischaemic myocardium.1 Of these, percutaneous administration of bone-marrow-derived progenitors represents the most optimal method to date, as it allows the evaluation of the cells effects independent of revascularization and the application of multiple administrations over time.2 Two different percutaneous catheter-based methods have been used in clinical trials to deliver bone-marrow-derived stem cells: intracoronary infusion and transendomyocardial delivery through a left ventricle catheter.

This article reviews clinical considerations of current evidence using percutaneous bone-marrow-derived stem cell transplantation in the heart.


   Bone-marrow-derived stem cells
Top
 Abstract
 Introduction
 Bone-marrow-derived stem cells
Clinical aplications
 Clinical safety
 The near future
 References
 
Bone marrow stem cells include several cell subpopulations with different morphologic and phenotypic characteristics. Experimental works have showed their capacity to transdifferentiate into mature cells belonging not only to the same germ layer tissues but also to other germ layers, a property named plasticity. Bone marrow stem cells can be collected easily, expanded in vitro if necessary, and implanted in patients by different routes. Bone marrow can be applied by using an unfractioned solution that includes not only several stem cell populations but also other mononuclear cells. Instead, it can be purified in order to choose the type of cells regarded as beneficial.

Haematopoietic stem cells
Haematopoietic stem cells are found into the haematopoietic niches in bone marrow. These cells are haematopoietic cell precursors that enter the peripheral blood system and differentiate in mature blood cells. These early progenitors can be cultured in an appropriate microenvironment (in vivo or in vitro) to obtain mature cells. The isolation of subpopulations of haematopoietic stem cells has become achievable after surface markers were identified. The c-kit, sca-1, Thy-1 and haematopoietic lineage markers (lin) are the epitopes that best identify progenitor cells within bone marrow and allow the isolation of this type of cells out of an unfractioned solution.3 CD34, CD133, and CD117 are antigens for isolation of purified haematopoietic progenitors in humans that recognize more specific subpopulations with specific properties but, so far, no true specific antigen for haematopoietic stem cell identification has been found.4

Endothelial progenitors cells
Endothelial progenitors cells are a subpopulation present in bone marrow and peripheral blood following mobilization. These cells express CD133, CD34, and an endothelial marker named vascular endothelial growth factor receptor-2 (KDR); besides, these cells become mature endothelial cells when engraft in sites of neovascularization.5 Diverse subpopulations have been identified showing different characteristics as high plasticity, a paracrine effect consisting of release of angiogenic growth factor, secreting angiogenic factors, etc. Mobilization through cytokine treatment (G-CSF or others) may be needed to recruit a high number of these cells.

Mesenchymal stem cells
These are a rare population of cells from bone marrow stroma, isolated for their capacity of plastic adhesion and their inmunophenotype. Mesenchymal stem cells are negative for the markers of haematopoietic stem cells (CD34 and CD133); in fact, these cells lack specific surface markers and have an inmunophenotype positive for many adhesion proteins. In healthy myocardium, the mesenchymal stem cells-donor expresses cardiac markers,6 and in infarcted myocardium enhances regional wall motion and prevents remodelling of the remote non-infarcted tissue.7


   Clinical aplications
Top
 Abstract
 Introduction
 Bone-marrow-derived stem cells
 Clinical aplications
Clinical safety
 The near future
 References
 
To date, 20 percutaneous bone-marrow-derived clinical trials involving 535 patients have been published. The principal differences between these studies were the type of patients, the type of cell employed, the delivery approach, and the method of measurement.1

Three different clinical scenarios have been experimented; either in patients with acute myocardial infarction (12 trials, 379 patients treated; Table 1),8–22 in patients with myocardial ischeamia and no revascularization option (four trials, 34 patients treated; Table 2),23–27 or in patients with ischaemic cardiomyopathy and a depressed ejection fraction (four trials, 122 patients treated; Table 3).28–32


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  		Table 1 Clinical trials with catheter-based delivery of bone-marrow-derived cells following an acute myocardial infarction

 

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  		Table 2 Clinical trials with catheter-based delivery of bone-marrow-derived cells for patients with myocardial ischemia without options of revascularization

 

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  		Table 3 Clinical trials with catheter-based delivery of bone-marrow-derived cells for patients with chronic ischemic cardiomyopathy or chronic coronary occlusions

 
The types of bone-marrow-derived stem cells that had been used in clinical practice are: bone-marrow-derived mononuclear cells,8–11,13,15–16,20–23,25,26,28–30 bone-marrow-derived nucleated cells,19,24 bone-marrow-derived mesenchymal cells,12,14 bone-marrow-derived endothelial progenitor cells,9–11,14,18,30–32 and isolated CD133+17 and CD34+ progenitors (Tables 1 to 3).27

Two different percutaneous delivery approaches have been experimented: intracoronary administration of the cells and transendocardial delivery with a left ventricle catheter. Percutaneous intracoronary infusion has so far been the only catheter-based route used for stem cell administration in patients with recent myocardial infarction or ischaemic cardiomyopathy, whether cell delivery in patients with ischaemic cardiomyopathy has been performed through the endocardium with a left ventricle catheter using the NOGA mapping or intracoronarily.

Finally, regarding the method of assessment of the effects on the heart of cell repair, different imaging techniques capable of measuring perfusion or left ventricular function have been used, such as the echocardiogram with a great variability for the small differences tried to detect. One reason why, future studies should unify the measurement image technique.

After this initial clinical experience, we currently know that percutaneous bone-marrow-derived stem cell therapy is feasible with unresolved concerns regarding safety as discussed in the following section. However, we are now ruling out the efficacy of this therapy with controversial results coming from small randomized control trials (Tables 1 to 3).

At this point, experts advocate to no longer perform studies involving small number of patients, but rather to conduct intermediate-size, randomized control studies to well establish the efficacy of cell therapy that analyses surrogate endpoints.


   Clinical safety
Top
 Abstract
 Introduction
 Bone-marrow-derived stem cells
 Clinical aplications
 Clinical safety
The near future
 References
 
When a new therapeutic strategy gets started, safety becomes the main goal of every single investigation testing that treatment. Undoubtedly, that stem cell therapy is safe is far from being proved. Thousands of patients have to be recruited in clinical trials and followed long enough to definitively establish its safety profile. Therefore, current ongoing randomized mechanistic intermediate-size trials on stem regenerative therapy must focus not only on remodelling and perfusion but also, and mainly, on safety. A shared database with all complications of stem cell treatment in humans should be a priority of all investigators involved in this field. Percutaneous bone-marrow-derived clinical trials undertaken so far shed light on several complications that cast doubts on regenerative therapy safety in humans.

Arrhythmias
Thus far, arrhythmias have been mainly reported in clinical trials using myoblasts for cardiac repair. However, this adverse effect could not be exclusive of them. In our ongoing experience, we have intracoronarily transplanted autologous bone marrow mononuclear cells in 72 patients following ST-elevated acute myocardial infarction. Four patients showed delayed episodes of ventricular arrhythmias and three were implanted with an internal defibrillator.33 Recently, Bartunek et al.17 intracoronarily delivering CD133+ in patients with acute myocardial infarction, have reported two patients presenting ventricular tachycardia. Such adverse events required us to be extremely cautious until future larger controlled trials assist us in identifying the risk attributable to bone-marrow-derived cell replacement therapy and to the arrhythmogenic substrate.

Restenosis
In trials using bone-marrow-derived stem cells, different from CD133+ a low restenosis rate have been obtained in initial studies with angiographic follow-up.8–16,19–22 However, a recent non-randomized matched trial in acute myocardial infarction raises concerns on this issue, though. After CD133+ cells intracoronary injection, despite a significant improvement in remodelling and perfusion parameters, unexpected rates of 37% in-stent restenosis and 11% reocclusion were found.17 The use of bare-metal stents and CD133+ cells that carry a high angiogenic potential may in part account for these apparent discrepancies.

Non-target organ seeding
Molecular imaging with radioactively labelled stem cells in animal models showed that the percentage cells homing to the heart is quite low with other organs (kidney, liver, and spleen) being the receptors of the vast majority of progenitors.34,35 Recently, a similar finding was seen in humans.36 Notwithstanding that intracoronary injection significantly increases the number of cells incorporating to the heart, radiotracer uptake still predominates in other organs.36 The clinical consequences, if any, of this unintended non-target organ homing are not known.

Accelerated atherogenesis
A fairly high proportion of the novo-lesions at non-stented arteries has been found after stem cell transplantation.16,17 The capability of stem cells on angiographically smooth arteries to induce or accelerate atherosclerosis cannot be neglected. Only randomized trials by using angiographic and intravascular ultrasound endpoints will provide information on this topic.

Impairment of microvascular perfusion
Mesenchymal stromal cells were found to bring about microinfarctions in a canine model.37 Cells used in humans are smaller. Furthermore, by means of microvascular perfusion tests, human trials have failed to demonstrate any significant microvascular dysfunction after stem cells injection.12,14 Further investigations are needed to settle this question.

Unintended cell differentiation
Initial concerns on tumorigenicity after adult stem cells therapy flawed as experimental and clinical data have been coming out with such complication not reported so far. Nonetheless, unintended differentiation was found in a single study in which extensive intramyocardial calcification after unselected bone-marrow cells transplantation was seen in the peri-infarct and infarct areas in rats.38 Whether this phenomenon occurs in humans have to be explored.


   The near future
Top
 Abstract
 Introduction
 Bone-marrow-derived stem cells
 Clinical aplications
 Clinical safety
 The near future
References
 
In the near future, experts advocate to no longer perform studies involving small numbers of patients, but rather to conduct intermediate-size, randomized, controlled trials to well establish the effects of stem cell therapy on surrogate markers.39 In this sense, the investigator must remember that safety and efficacy of the procedure should still be the primary considerations in determining whether future large clinical trials should be undertaken. Therefore, imaging techniques will be crucial tools in shedding light on these two questions. In parallel, mechanistic basic and clinical investigations will be surely undertaken by researchers in order to evaluate the ideal bone-marrow-derived population. Besides, new invasive delivery procedures will be tested.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Bone-marrow-derived stem cells
 Clinical aplications
 Clinical safety
 The near future
 References
 

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