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Eur J Cardiothorac Surg 2005;28:318-324
© 2005 Elsevier Science NL

Review

Stem cell research and cell transplantation for myocardial regeneration

Matthias Siepe a , * , Claudia Heilmann a , Patrick von Samson a , Philippe Menasché b , Friedhelm Beyersdorf a

a Department of Cardiovascular Surgery, University Clinic, Albert-Ludwigs-University Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany
b Department of Cardiovascular Surgery, Hôpital européen Georges Pompidou, Paris, France

Received 1 January 2005; received in revised form 1 March 2005; accepted 9 March 2005.

* Corresponding author. Tel.: +49 761 270 2818; fax: +49 761 270 2550. (Email: matthias.siepe{at}web.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Route of delivery
 3. Autologous adult stem...
 4. Future perspectives
 References
 
Several human organs are not capable of functional regeneration following a tissue defect and react with scar formation. In stem cell transplantation, undifferentiated or partly differentiated precursor cells are applied to defective tissue for therapeutic regeneration. After promising preclinical investigations, the transplantation of autologous stem cells for myocardial infarction treatment is being transferred to clinical use. Mesenchymal stem cells and endothelial precursor cells derived from the bone marrow or circulating blood as well as skeletal myoblasts are employed in clinical trials. Furthermore, indications for cell transplantation and delivery routes vary considerably throughout current investigations. Initial results suggest a potential for restoration of cardiac function in stem cell-treated patients; however, the mechanisms are not fully understood. This overview will focus on objectives, recent achievements, and future perspectives of diverse stem cell transplantation approaches.

Key Words: Cell transplantation • Mesenchymal stem cells • Endothelial precursor cells • Skeletal myoblasts • Regeneration • Myocardium • Heart failure


   1. Introduction
Top
 Abstract
 1. Introduction
2. Route of delivery
 3. Autologous adult stem...
 4. Future perspectives
 References
 
Stem cells are undifferentiated or partly differentiated precursor cells possessing the inherent capacity to proliferate on demand and to differentiate to mature cell type(s). Stem cells can be categorized by their potency or by developmental origin. As a fundamental example of pluripotent competence, embryonic stem cells account for the generation of human organs in the early stages of our development. In contrast, most fetal and adult stem cells (e.g. mesenchymal stem cells) are considered to be multipotent and therefore capable of producing a small range of differentiated cell lineages appropriate to their location. Finally, some adult stem cells or progenitor cells with the least differentiation potential such as skeletal myoblasts (SM), endothelial precursor cells (EPC) or epidermal stem cells in the basal layer of the skin are designated as unipotent. Adult stem cells are activated on demand either locally (e.g. SM) or by mobilization from the bone marrow. The latter cells circulate in the blood and can home to the specific organ.

Several human organs—and the heart is one of them—lose most of their regeneration capacity during development and react with scar healing when damaged. In contrast, lower species can regenerate complex defects: e.g. the flatworm reacts to a cut in the head by regenerating a second and fully functional head, and amphibians can regenerate functional cardiac tissue [1]. The natural mechanisms of those remarkable capacities are not fully understood, but the plasticity is thought to be a result of (I) differentiation of pluripotent stem cells to various cell types according to necessity, (II) fusion of host and stem cells, (III) de-differentiation and re-differentiation of stromal cells, and/or (IV) the existence of multiple stem cell types for one specific organ [2]. In amphibians, de-differentiation and re-differentiation seem to be the leading mechanism [3].

Stem cell transplantation was initially employed to treat hematopoetic disorders. Recently, scientists and physicians have started to use the potential of stem cells for tissue-defect repair. The principle of obtaining, expanding, and administering stem cells applies to many areas, such as scar healing in reconstructive surgery [4], cartilage-defect repair in traumatology [5], and the treatment of diabetes [6] or neurological disorders [7,8]. Stem cell transplantation is particularly interesting for myocardial regeneration, since human myocardium is not (or barely) able to replace ischemic defects with functional tissue.

The ideal cell type for cardiac stem cell transplantation should be capable of proliferation and differentiation into contractile cells, should connect to neighboring cells electromechanically, should be easy to obtain in sufficient numbers, and should not be burdened with immunological or ethical problems. However, no ideal stem cell type meeting these demands has been identified so far; the stem cells used in current clinical transplantation trials represent an approximation only.

A new hope for more suitable donor cells may rise from adult cardiac stem cells [9–11], if future studies verify their existence and if they can be isolated and multiplied to sufficient numbers in adults. Fetal cardiomyoblasts are able to form new functional tissue in animal experiments [12,13], but their clinical use is rejected due to the immunosuppression required, ethical considerations, and the shortage of quantity. The same concerns affect the use of pluripotent embryonic stem cells (ESC), even though they possess remarkable potential for functional myocardial scar healing in preclinical studies [14–16]. Most significantly, the fear of neoplastic transformation limits the use of such pluripotent ESC [17].

Due to these limitations, adult autologous stem cell types are preferred in clinical investigations. This issue is addressed more specifically below.


   2. Route of delivery
Top
 Abstract
 1. Introduction
 2. Route of delivery
3. Autologous adult stem...
 4. Future perspectives
 References
 

(I) Direct intramyocardial stem cell injection (Fig. 1 ) can be performed during surgical revascularization procedures [18–23]. In a non-surgical approach, direct intramyocardial cell injection is implemented via endoventricular catheters and guided by electromechanical mapping [24–27]. A significant percentage of cells dies during the injection process due to tissue hypoxia and physical stress [28–31]. Strategies that enhance graft survival are thus mandatory to optimize the benefits of this procedure.
(II) Intracoronary injection via percutaneous coronary intervention catheters is less invasive than intramyocardial injection and may allow homogeneous homing of cells into areas bordering the infarction zone. Initial reports suggest successful realization of this approach using either bone marrow-derived stem cells or skeletal myoblasts [32–39]. However, cell quantity and infusion characteristics need to be precisely determined to avoid the risk of additional myonecrosis [38,39].
(III) Intravenously infused progenitor cells colonize infarcted hearts more intensely than infarction-free hearts [40–42]. The infusion of stem cells seems a promising approach for practical and economical reasons, since it is the least invasive method. However, the homing process of injected stem cells solitarily to the targeted organ needs to be investigated in detail. The risk of side effects from homing to non-cardiac organs limits this approach [40,41].
(IV) Tissue-engineered constructs can function as a vehicle to apply either huge amounts of functional cells or of an entire myocardial tissue to a scar. Zimmermann et al. engineered circular contracting elements using fetal cardiomyoblasts without scaffolds and applied them on myocardial infarctions in a rat model [43]. Also, scaffold-based, bioengineered grafts from fetal cardiomyoblasts can spontaneously contract and regenerate heart function in animal models [44,45]. Yet, it will be impossible in near future to use tissue-engineering products made of these heterologous cell types for ethical reasons. Our own experiments focused on scaffold-based application of autologous myoblasts to a myocardial infarction area (Fig. 2 ). One of the mechanisms relevant in autologous cell transplantation is, at least in part, paracrine attenuation of the surrounding tissue and the release of cytokines that can migrate to the scar.



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  		Fig. 1. Intramyocardial transplantation of 150µl myoblast suspension by micro-injections using an insulin syringe in a rat myocardial infarction model.

 


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  		Fig. 2. In contrast to the intramyocardial injection, a polyurethane scaffold (Artelon®, Artimplant, Sweden) was permanently implanted on the outer surface of a myocardial scar in rats. These highly porous (>90%) scaffolds were seeded with 5 million cultured skeletal myoblasts and incubated for 2 weeks prior to implantation to allow cell attachment and proliferation. When examined 4 weeks after the implantation procedure, cells remained undifferentiated and embedded in a dense structure surrounding the infarction zone. No cell migration into the scar was detected. Functional assessment identified this approach to be as effective as direct intramyocardial myoblast injection (data not shown).

 

   3. Autologous adult stem cells and their application for myocardial regeneration
Top
 Abstract
 1. Introduction
 2. Route of delivery
 3. Autologous adult stem...
4. Future perspectives
 References
 
3.1. Bone marrow-derived stem cells (BMSC)
Bone marrow-derived stem cells (BMSC) contain different species of stem cells such as hematopoetic and mesenchymal stem cells. It has been demonstrated that BMSC are able to differentiate into cardiomyocytes, endothelial cells, smooth muscle cells, and others [10,46–48]. Alternatively to bone marrow samples, stem cells of all types can be mobilized from the bone marrow by granulocyte-colony stimulating factor in sufficient numbers and can be collected peripherally from the blood. These stem cells can be used for transplantation to defective myocardium [21,35].

Initially, Orlic et al. proved the therapeutic potential of intramyocardial injection of bone marrow-derived cells that expressed no hematopoetic differentiation marker (lin –), but carried c-kit, the receptor for the stem cell factor [49]. They observed not only a functional benefit, but also de novo myocardium in the scar area. This investigation prompted other work, suggesting that different populations of BMSC are able to repair hearts after myocardial infarction by differentiating into cardiomyocytes, by fusing with host cells, and/or by neovascularization [10,47,50,51].

Several human trials on BMSC transplantation into damaged myocardium followed, using unselected or differently characterized types of progenitor cells and diverse delivery routes for various indications and end points [20–22,24,25,32,35,36]. Initial randomized studies have been published recently or are underway to investigate a possible functional benefit. Wollert et al. [38] applied unselected bone marrow-derived progenitor cells to 30 patients with acute myocardial infarction via catheter approach during percutaneous coronary intervention (PCI). The control group (n=30) received PCI and best medical treatment alone. In the patients receiving cell transplantation, the ejection fraction (EF) measured by MRI improved significantly (from 50.0±10 to 56.7±12.5%, P=0.0026) after 6 months as compared to baseline, while ventricular size was not significantly affected. However, the rise in EF was not significant in the subgroup of patients with poor EF values before the treatment, even though these patients obviously need restoration of function more urgently.

Throughout the various studies on BMSC transplantation, researchers use different ways to select the applied cells. In some investigations, surface marker antigens (e.g. CD 44) are used to identify mesenchymal stem cells (MSC) from the pool of collected cells, because this subpopulation is suggested to differentiate into cardiomyocytes [46,52]. A drawback is that stem cells also need to be defined functionally, since they can change the surface marker setting during the culture passage [48]. Also, the mixed pool of BMSC transplanted potentially can hide the underlying mechanisms; e.g. most researchers cannot exclude co-transplantation of EPCs together with MSC.

Still, little is known about the fate of the transplanted stem cells and their mode of action in augmenting cardiac function. Current controversies mainly concern the differentiation potential of bone marrow stem cells to regenerate cardiomyocytes [9–11]. Some authors used a stem cell pretreatment with 5-azacytidine to increase the percentage to take a cardiomyocyte-differentiation pathway, but the significance of this approach is not yet clear [53–55]. More recent studies suggest that the percentage of bone marrow-derived stem cells taking this differentiation pathway is quite low [56].

Other possible explanations for improved cardiac function may be to a certain extend neovascularization or a paracrine effect of the injected cells [57]. In future, more studies with specific control groups and clearly defined cell typing must be conducted to assess this problem. In addition, we should be wary of prematurely promoting BMSC transplantation for widespread clinical practice, since the risk of neoplastic transformation has not been entirely excluded.

3.2. Endothelial progenitor cells (EPCs)
EPCs develop from hematopoetic stem cells and are released from the bone marrow when required [58]. They can be isolated from the leukocyte fraction of circulating blood in various adult animal species [59–62] and in human adults [63], however, in small numbers. Human EPCs are characterized by combined expression of CD34, AC133, and VEGF-receptor 2 (Flk-1) [60,64,65]. Other ways to identify EPCs are to show endocytosis of acetylated low-density lipoprotein (acLDL) and/or binding of Ulex europaeus aggulutinin-1 in combination with typical endothelial cell markers [58,63]. These cells differentiated into vascular endothelium, in vitro [66] and have been shown to incorporate into sites of active neovascularization [37,67,68] (see Fig. 3 ). Revascularization of ischemic myocardium is, therefore, one of the possible mechanisms that could explain functional benefit from EPC transplantation. Recently, investigators have found evidence that EPC even differentiate into cardiomyocytes in vitro. Cultured EPCs needed cell-to-cell contact to rat cardiomyocytes for transdifferentiation, but cell fusion was not observed [69].



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  		Fig. 3. EPCs were injected in myocardial infarction areas in rats. Transplanted EPCs are labeled with ac-LDL-Dil in red, endothelium is marked by Isolectin B4 in green, and DAPI marks all cellular nuclei. Triple staining marks incorporation of injected EPCs into vascular endothelium.

 
Despite promising applications for tissue regeneration, the limited endogenous pool, functional impairment of EPCs associated with higher age or diabetes, and the finite number of replications of EPCs for ex vivo expansion constitute important liabilities for autologous transplantation [65]. For instance, Rupp showed that EPC from patients suffering from coronary artery disease displays impaired transdifferentiation capacity. An improvement of this situation has been achieved by statin therapy in these patients [70]. Gene transfer to EPCs could present another possibility to overcome the problem of cellular senescence and functional impairment [71,72].

3.3. Skeletal myoblasts (SM)
SM are myogenic progenitor cells and capable of reacting upon peripheral muscle trauma by proliferation. They then differentiate and fuse to form myotubes and fibers. Myoblasts are considered possible donor cells for myocardial regeneration because they have an inherent potential for contractility. In addition, they can be harvested autologously by simple muscle biopsy, isolated, and expanded ex vivo in great numbers [73]. They are resistant to ischemia, and do not raise immunologic and ethical concerns. In animal models, injection of cultured SM resulted in the formation of functional myotubes within the scar and, in particular, in an effective regeneration of cardiac function in severely failing hearts [28,30,74]. We learned from human studies using SM injection during assist device implantation that the implanted cells fuse to form myotubes. This observation was confirmed by immunohistochemistry when the hearts were excised during cardiac transplant procedure later on [75].

Menasché et al. established the technique of cardiac myoblast transplantation in patients during surgical revascularization [18]. In addition to an increase in regional function and wall thickening, investigators noticed ventricular dysrhythmias as a possible side effect of the intervention. Others reported similar findings using surgical [19,23] or transcatheter approaches [33,34] in phase I trials. A current randomized phase II study (MAGIC II trial) is assessing the functional outcome of patients after SM transplantation. This clinical trial also involves implantation of a defibrillator in all patients. The procedure should make it possible by interpretation of Holter data, to really assess whether myoblast transplantation increases the risk of arrhythmias beyond that related to the underlying heart failure substrate. Preliminary data from the safety analysis suggest that this is not the case.

Yet again, the mode of action is still to be determined. Even though a previous investigation postulated the possibility of electromechanical coupling between skeletal and cardiac muscle [76], more recent experiments revealed no electrical integration of skeletal myofibers in surrounding cardiac tissue [77]. Thus, transplanted myoblasts (as well as MSC) might exhibit a paracrine effect influencing the surrounding tissue [77,78].

Experiments comparing the effect of SM and BMSC transplantation—a study conducted in rabbits and two studies in rats—observed no significant difference between the two cell types regarding their potential to restore function [79–81]. A combination of SM and BMSC restored ventricular function even better than either of the two cell types alone [81]. The mechanism of this synergistic effect is unclear and needs further investigation.


   4. Future perspectives
Top
 Abstract
 1. Introduction
 2. Route of delivery
 3. Autologous adult stem...
 4. Future perspectives
References
 
Unless researchers will establish ways to expand human cardiomyocytes or cardiomyoblasts in sufficient numbers, the focus will remain on the autologous cell types EPC, MSC, and SM for clinical cell transplantation. However, their mode of action to regenerate myocardium is not understood in detail. Obviously, more basic research is needed to enhance the potential for improvement. For example, exact identification of the subpopulation of MSC or EPC that might differentiate to cardiac muscle, and of the specific signaling and activation pathways, could optimize cell transplantation considerably. Cord blood cells were recently suggested to be a new source of immature cells for transplantation. Kogler et al. demonstrated a high-differentiation potential of cord blood stem cells, including transdifferentiation to cardiomyocytes [82]. The question arises whether cord blood cell banks should be established for autologous replacement purpose or if we can even use these stem cells heterologously.

Other techniques to regenerate the damaged myocardium have been proposed. Gene therapy, growth factor application, and tissue engineering in combination with stem cell transplantation are thought to improve the effectiveness of stem cells. By means of gene therapy, cells could be directed into cardiac differentiation in vitro (e.g. by transfecting skeletal myoblasts with connexin-43, [83]) to allow better functional integration into the myocardium. Moreover, stem cells transfected with specific genes to augment cardiac function (ß-adrenergic receptor kinase, for example) or angiogenesis (e.g. VEGF) can serve as a permanent delivery device for the gene products [84,85]. However, the uncontrolled expression of cytokines and growth factors could pose an additional risk for tumorigenesineoplastic transformation.

We are still at the beginning of cardiac stem cell therapy. If more randomized clinical studies confirm the safety and effectiveness of cardiac stem cell transplantation, its potential application will be far-reaching. In future research, we must ascertain the accurate selection of stem cells for the accurate indication, using the accurate delivery route (Tables 1 and 2 ).


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  		Table 1. Different delivery routes for stem cell transplantation
 


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  		Table 2. Selection of stem cells and their specific characteristics for cell transplantation
 


   Acknowledgments
 
Dr Matthias Siepe was supported by the German Research Foundation (DFG), Kennedyallee 40, 53175 Bonn, Germany. Figures 1 and 2 were obtained from investigations performed by Matthias Siepe in the Department of Cardiovascular Surgery of the University Hospital in Bern, Switzerland.


   Footnotes
 
{star} This work was presented at the Postgraduate Course of the joint 18th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 12th Annual Meeting of the European Society of Thoracic Surgeons, Leipzig, Germany, September 12–15, 2004.


   References
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 1. Introduction
 2. Route of delivery
 3. Autologous adult stem...
 4. Future perspectives
 References
 

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