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European Journal of Heart Failure 2008 10(2):119-124; doi:10.1016/j.ejheart.2007.11.009
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© 2008 European Society of Cardiology

Impact of different bone marrow cell preparations on left ventricular remodelling after experimental myocardial infarction

Stefan Frantza, Duttu Vallabhapurapub, Jochen Tillmannsa, Nikos Brousosb, Helga Wagnera, Kristina Heniga, Georg Ertla, Albrecht M. Müllerb,1 and Johann Bauersachsa,*,1

a Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg Germany
b Institut für Medizinische Strahlenkunde und Zellforschung, Julius-Maximilians-Universität Würzburg Germany

* Corresponding author. Medizinische Klinik und Poliklinik I, Universitätsklinikum der Julius-Maximilians-Universität Würzburg, Josef Schneider-Str. 2, 97080 Würzburg, Germany. Tel.: +49 931 201 0; fax: +49 931 201 36135. E-mail address: bauersachs_j{at}medizin.uni-wuerzburg.de (J. Bauersachs).


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Bone marrow (BM)-derived haematopoietic stem cells have been proposed as a potential cell source to functionally engraft the myocardium and to improve cardiac function after myocardial infarction (MI). However, experimental and clinical data are inconsistent. Since the specific characteristics of different BM cell subsets could influence their therapeutic potential we determined the effect of different BM cell populations on left ventricular remodelling after MI.

Methods and results: MI was induced in female mice by coronary artery ligation. Surviving mice were randomised to receive either: total BM, mature Lin+ or primitive Lin– cells from male mice, or saline, via intracardiac injection. Injected cells were detected in the infarct and border zone by PCR for Y-chromosomal sequences. Serial transthoracic echocardiography was performed 1, 21, and 42 days after MI. Over a period of 6 weeks, mortality was not different between the groups. After MI, animals exhibited left ventricular dilatation, as expected. Left ventricular remodelling was not influenced by Lin+ or Lin– BM cells but was partially improved by unfractionated BM cell injection. Paracrine secretion of cytokines (e.g. IL-6, GM-CSF) was differentially regulated in supernatants of cultured BM cells.

Summary: Treatment with unfractionated BM cells, but not Lin+, or Lin– cells partially improved cardiac remodelling and function after MI. This may be mediated by paracrine effects.

Key Words: Myocardial infarction • Remodelling • BM cell injection • Cytokine

Received June 29, 2007; Revised October 25, 2007; Accepted November 12, 2007


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure remains one of the most frequent causes of death in industrialized countries, despite advances in the management of acute myocardial infarction (MI) and limitation of progressive left ventricular remodelling by blockade of the renin-angiotensin-aldosterone-system [1]. The therapies currently in use are not effective enough to prevent left ventricular deterioration in many patients. Regeneration of functional myocardium by cell-based therapies may contribute to a causal therapy for heart failure after MI. Different strategies have been suggested based on the developmental potential of progenitor and stem cells to restore cardiac myocytes. Embryonic stem cells, myoblasts, or BM-derived stem cells have been analysed as potential cell sources for heart repair. Some reports claim that haematopoietic stem cells can differentiate into a wide variety of cell types including cardiomyocytes [2]. Indeed, Orlic et al. [2] reported that after MI locally delivered BM cells differentiate into cardiomyocytes and improve cardiac function. Moreover, CD34+ cell transplantation has been shown to dose-dependently improve vasculogenesis and cardiomyogenesis [3]. The underlying mechanisms of myocardial improvement however are still elusive. Whereas some authors favour the hypothesis of direct transdifferentiation of BM cells into cardiomyocytes, others suggest that BM cells do not differentiate to unrelated cell types and that paracrine effects originating from the transplanted cells could be responsible for the protective effects [4]. Inspired by the surprising reports that injection of BM cells into infarcted hearts improves heart function, several clinical trials were initiated. The first trials indicated that intracoronary transfer of BM cells was not only safe, but also enhanced regional wall motion [5-7]. However, experimental as well as clinical reports have been contradicted by further analyses which did not produce evidence of haematopoietic stem cells acquiring a cardiac phenotype [8,9]. In addition, these analyses could not detect clinical improvement after MI [10]. Thus, it remains unclear, whether progenitor cells from various sources can prevent cardiac remodelling. Also, the cell type for optimal cardiac repair is still a matter of debate.

In order to further analyse whether BM cells can directly or indirectly improve cardiac repair, we treated post-MI mice with either unfractionated BM cells, progenitor-enriched (Lin–) or mature (Lin+) BM subpopulations. We hypothesized that injection of BM cell subsets into the infarcted heart could improve left ventricular dilatation in mice.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Animals and surgery
Female C57Bl6 mice, 8 to 12 weeks old, with a body weight of 20-25 g, underwent left coronary artery ligation to induce MI, as described before [11]. After 24 h 112 animals with estimated infarct sizes over 30% were randomised to receive either total BM, Lin–, Lin+ cells from male mice (5x105 cells in 50 µl phosphate buffered saline (PBS)), or PBS via intracardiac injection. For intracardiac injection, animals were intubated and ventilated, the chest was re-opened and the cells injected into the left ventricle under direct sight. The Standing Committee on Animal Research of our institution approved the study protocol. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

2.2. Imaging procedure
Echocardiographic studies were performed under light anesthesia with spontaneous respiration using isoflurane, as recently described [12]. Echocardiographic acquisition (Toshiba Aplio and a 15 MHz transducer) and analyses were performed by a single researcher experienced in rodent echocardiography who was blinded to the treatment groups, as recently described [12].

2.3. Sample collection and determination of infarct size
Mice were sacrificed after the haemodynamic study. Hearts were excised and the right and left ventricles were separated. The left ventricle was cut into three transverse sections: apex, middle ring and base as previously reported [13]. From the middle ring, 5 µm-sections were cut and stained with picrosirius red. Infarct size was determined by planimetric measurement using a digital image analyser and calculated by dividing the sum of endocardial and epicardial circumferences of infarct areas by the sum of the total endocardial and epicardial circumferences. Only animals with a histological infarct size over 30% were included in further analyses.

2.4. Cell preparation
BM cells were obtained from the tibiae and femora of C57/Bl6 male mice. Fc receptors on the BM cells were blocked using Fc block (mAB 2.4G2). BM cells were surface stained using rat IgG specific for B220, Gr-1, Mac-1, CD4, CD8 and Ter119, to mark lineage positive BM cells, followed by magnetic labelling of cells with goat anti-rat IgG microbeads (Miltenyi Biotec). Labelled cells were loaded onto a column and cell separation was achieved under a magnetic field. The labelled lineage positive cells were retained in the column while the unlabelled lineage negative cells ran through the column and were collected as the lineage negative fraction. For isolation of the lineage positive BM fraction, the column was removed from the magnetic field and the cells were eluted.

2.5. Y chromosome detection
Genomic DNA was isolated from infarcted and non-infarcted ventricles and from the remaining heart tissue. For analysis of male donor contribution, conventional (T3 Thermocycler, Biometra, Göttingen, Germany) and real time PCRs (RG-3000, Corbett Research, Mortlake, Australia; ABsolute QPCR SYBR Green Mix, ABgene, Epsom, UK) were performed with primers specific for Y-chromosomal (YMT2/B) or myogenin sequences [14].

2.6. Paracrine secretion of cytokines
MACS-sorted Lin–, Lin+ or total BM cells were cultured for 24 h in triplicates of 200 µl volume with 1x105 cells/sample. In addition, medium alone without cells was taken as a control, to study background cytokine profiles in the medium. Cytokines [interleukin (IL)-1{alpha}, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12(p70), IL-17, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN) {gamma}, keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP) 1{alpha}, RANTES, tumour necrosis factor (TNF)-{alpha}] were measured with Bio-plex cytokine assays (Bio-Rad, Munich, Germany; Immumed GmbH, Munich, Germany) according to the manufacturer's protocol.

2.7. Real Time PCR of Myosin heavy chain (MHC)
RNA was isolated as previously described (11). Real time PCR was performed (iCycler, Bio-Rad, Munich, Germany) with commercially available TaqMan probes for 18S (Applied Biosystems, Foster City, CA, USA), and murine myosin heavy chain (12). PCR parameters were used as recommended for the TaqMan universal PCR master mix kit (Applied Biosystems, Foster City, CA, USA). RNA samples were normalized to 18S rRNA.

2.8. Statistical analysis
All replicate data are presented as mean and standard error of mean. Mortality rates were compared using a log rank test. Absolute differences among groups were compared using a Mann-Whitney test for the comparison of two groups and a Wilcoxon test for the comparison of time dependent differences. Statistical significance was achieved when two-tailed p≤0.05. Statistical analyses were carried out using the StatView statistics program (Abacus Concepts, Inc., Berkley, CA).


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Intracardiac injection
BM cells from male donor mice were isolated and injected under direct visualisation 24 h after MI into female recipients (see Fig. 1A). As tested by semi-quantitative PCR for Y chromosome-specific sequences 6 weeks after injection, male donor cells were detected in the infarcted myocardium of 75% of female recipient mice (Fig. 1B). Right ventricular or non-infarcted myocardium was negative in qPCR analyses. The frequency of donor cells was in the range of 1 donor cell/100,000 recipient cells. This indicates engraftment after cell transplantation albeit at low levels.


Figure 01
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  		Fig. 1 Protocol and donor-specific PCR analysis on genomic DNA of heart tissues after transplantation. Animals were injected with either total BM, enriched (Lin–) and not enriched (Lin+) BM population or PBS (A: design of the protocol with timing of experimental MI, cell injection, echocardiography imaging studies, and sacrifice). Genomic DNA from right ventricle, infarcted and non-infarcted left ventricle were prepared. The donor contribution was analysed by male donor-specific YMT 2/B PCR with normalization by myogenin. Female and male genomic DNAs served as positive and negative controls. A representative Southern blot is shown (B).

 
3.2. Mortality and organ weights
In order to analyse whether BM cells can directly or indirectly improve left ventricular remodelling we injected either, freshly prepared total BM cells, Lin– or Lin+ BM subpopulations, or PBS, after experimental MI. Survival curves after coronary artery ligation did not differ between the 4 groups at 42 days (Fig. 2), although there was a trend to better survival in the BM and Lin+ group.


Figure 02
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  		Fig. 2 Survival analysis. Coronary artery ligation was performed in mice with subsequent injection of either total BM cells, of Lin– or Lin+ BM populations, or PBS. Postoperative survival was not different between the groups using a log rank test.

 
Body weights were similar in both groups (Table 1). Heart weight to body weight ratio increased post-MI, this was significantly reduced after treatment with total BM cells, but not with other cell populations. This result was confirmed by molecular markers of myocardial hypertrophy: βMHC/{alpha}MHC ratio was significantly increased after MI, and ameliorated by injection of total BM, but not of Lin– or Lin+ cells (see Table 1). Right ventricular weights were not affected by cell treatment. Infarct size determined 6 weeks after MI was comparable in all groups (see Table 1, BM vs. Lin– vs. Lin+ vs. PBS, p=n. s.). Thus, with respect to survival and infarct size no cell treatment was clearly superior to PBS injection. However, BM cell but not Lin– or Lin+ cell injection significantly improved left ventricular hypertrophy.


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  		Table 1 Organ weights

 
3.3. Echocardiographic measurements
To serially analyse left ventricular remodelling, animals underwent echocardiography at days 1, 21, and 42 post-injection. All measurements were recorded at two levels: at the apical level, which shows changes within the infarcted region, and at the mid-papillary level, which shows changes in the dimensions of the surviving uninfarcted myocardium. As expected, infarcted ventricles dilated significantly over time (see Fig. 3). Cell treatment with Lin– or Lin+ cells did not prevent left ventricular dilatation. However, left ventricular remodelling especially on the papillary level was diminished by treatment with total BM when compared to PBS treated animals (see Table 2). Therefore, only total BM cell injection improved left ventricular remodelling after MI.


Figure 03
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  		Fig. 3 Left ventricular dilatation following myocardial infarction (MI). The development of left ventricular dilatation at the mid-papillary level over 6 weeks is illustrated. Hearts dilated significantly over time following myocardial infarction ({dagger}p≤0.05, {dagger}{dagger}p≤0.01 day 1 vs. day 42). Treatment with BM-derived cells, but not with Lin–, or Lin+ cells improved left ventricular dilatation when compared to PBS treated MI mice (*p≤0.05).

 


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  		Table 2 Echocardiographic measurements week 6

 
3.4. Secretion of cytokines
BM-derived cells secrete cytokines which could protect the ischaemic myocardium through paracrine effects [15]. Therefore, we measured the levels of various cytokines in conditioned medium of BM, Lin–, or Lin+ cells in triplicate. Whereas some cytokines were equally secreted by all cells (IL-1β, IL-2, IL-3, IL-5, IL-10, IL-17, MIP-1{alpha}, RANTES, KC, and TNF-{alpha}), other cytokines were differentially produced in a time and cell type-dependent manner (Table 3 and Fig. 4). Supernatants of BM or Lin– cells contained significantly more IL-1{alpha}, IL-4, IL-6, IL-12, GM-CSF, and IFN{gamma} than medium or supernatants of Lin+ cells after 24 h of incubation. Cytokine levels of medium and Lin+ cells were not different with the exception of IL-12 which was significantly more secreted by Lin+ cells. Together these findings indicate that several cytokines were differentially secreted in vitro by the different BM cell types.


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  		Table 3 Cytokine levels of total BM, Lin–, or Lin+ cell conditioned medium

 


Figure 04
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  		Fig. 4 IL-6 levels in conditioned medium of BM, Lin–, or Lin+ cells 24 h after plating. Cytokine secretion was differentially regulated in the different cell lines. (*p≤0.05 vs. medium).

 

   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The therapeutic potential of injected BM cells after MI has been ascribed to the broad developmental plasticity of adult stem cells which, according to this hypothesis, are considered to be able to transdifferentiate into unrelated cell types including cells of the heart [16]. In one study, Lin– and ckit+ primitive BM cells were isolated and injected into the border zone of acute infarcts in recipient mice. Donor cells were reported to occupy and repair the injured myocardium [2]. However, these findings have not remained un-opposed [17]: Wagers et al. [18] could not detect differentiation of haematopoietic stem cells into relevant numbers of cardiac cells, a result that has been subsequently confirmed by other groups [4,9]. Thus, it is still a matter of debate, whether progenitor cells from sources outside the heart can prevent cardiac remodelling and which cell type is optimal for cardiac repair. Therefore, in our study we compared for the first time the effects of three different, well defined BM cell populations on left ventricular remodelling. While we could not detect a beneficial effect of either Lin– or Lin+ cell transplantation after MI, left ventricular remodelling was ameliorated by treatment with total BM cells. These results are in line with a recent clinical study by Assmus et al. [19]. In this study 75 patients with stable ischaemic heart disease received either no cell infusion, infusion of circulating progenitor or total BM cells into the patent coronary artery supplying the most dyskinetic left ventricular area. Only patients receiving BM, but not control patients or patients receiving circulating progenitor cells, had a moderate improvement of regional contractility in the area targeted by the intracoronary infusion.

What could be responsible for the different effects of different cell lines? Uemura et al. recently highlighted the effect of paracrine factors on the therapeutic potential of BM-derived stem cells [15]. BM stem cells prevented left ventricular remodelling more efficiently after in vitro preconditioning. This seems to be related to an upregulation of several cytokines, growth factors, and survival proteins secreted in the immediate environment. Gnecchi et al. [20] found most of the benefit of mesenchymal stem cell transplantation in the heart was reproduced by injection of the cell-free supernatant recovered from mesenchymal stem cell cultures. For the first time we have measured secretion of certain cytokines in vitro by the different cell types. We found no clear pattern in the regulation of the cytokines in vitro. Whereas several innate immune cytokines were not regulated at all, like TNF and chemokines, other cytokines of the innate as well as adaptive immune response like IL-1{alpha}, IL-4, IL-6, IL-12, and IFN{gamma}, were upregulated. We know little about the role of IL-1{alpha}, IL-4, IL-12, and IFN{gamma} in cardiac remodelling. All of these cytokines are upregulated after MI. However, their function in healing and left ventricular remodelling is unclear at present. On the other hand, GM-CSF and IL-6 have been extensively studied. The role of IL-6 in left ventricular remodelling is limited. However, GM-CSF effectively mobilizes bone marrow-derived progenitor cells into the peripheral circulation. In addition, it has multiple direct and indirect beneficial cardiovascular effects including neovascularization of ischaemic myocardium and reducing the extent of myocardial damage after infarction [21,22]. Thus, secretion of GM-CSF might partially explain our cell type specific effects. However, it has to be emphasized that the regulation of the cytokine network is rather complex, and our in vitro results cannot be easily extrapolated to in vivo conditions. It is the complex interaction of different cytokines and growth factors which seems to be important.

Since definite myocardial regeneration by injection of progenitor cells has not been demonstrated so far, Wall et al. [23] hypothesized that changes in left ventricular remodelling after cell injection are independent of the injected material and the beneficial effects of injection may be only due to altered mechanics. Indeed, injection of non-contractile material improved left ventricular remodelling after MI. However, our data clearly refute this hypothesis since the same amount of different types of cells had differential effects on left ventricular remodelling.

In conclusion, we could not detect a beneficial effect of either Lin– or Lin+ BM cell transplantation after MI. However, left ventricular remodelling was ameliorated by treatment with total BM cells; this effect may be mediated by paracrine secretion of cytokines.


   Acknowledgements
 
This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 688, TPA10) and the IZKF Würzburg (Interdisziplinäres Zentrum für klinische Forschung, TP-D22). We thank Barbara Bayer, Vroni Hornich, and Andrea Reusch for their excellent technical support.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 Both authors contributed equally to the work. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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