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Cardiovascular Research 2002 56(3):404-410; doi:10.1016/S0008-6363(02)00597-7
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Host cell-derived cardiomyocytes in sex-mismatch cardiac allografts

Antoni Bayes-Genisa, Marta Salidob, Francesc Solé Ristolb, Mireia Puiga, Vicens Brossaa, Marta Campreciósa, Josep M Corominasb, Mª Luïsa Mariñosob, Teresa Barób, Mª Carmen Velab, Sergi Serranob, Josep M Padróa, Antoni Bayes de Lunaa and Juan Cincaa,*

aServei de Cardiologia, Hospital de la Santa Creu i Sant Pau, C/San Antonio Mª Claret 167, 08025 Barcelona, Spain
bLaboratori de Citogenètica i Biologia Molecular, Departament de Patologia, Hospital del Mar, IMAS, Barcelona, Spain

* Corresponding author. Tel.: +34-93-291-9294; fax: +34-93-291-9424. jcinca{at}hsp.santpau.es

Received 12 March 2002; accepted 1 July 2002


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Mesenchymal precursor cells are able to respond to tissue signals and differentiate into a phenotype characteristic of mature cells of that tissue. We sought to investigate whether adult human cardiomyocytes can be derived from recipient precursor cells in sex-mismatched cardiac allografts. Methods: We studied four male patients who received hearts from female donors, and four female patients who received an allograft from a male donor. Four sex-matched transplant patients, two of each sex served as controls. Combined fluorescence in situ hybridization with probes specific for X- and Y-chromosomes and immunohistochemistry with {alpha}-actin was used to identify cardiac muscle cells 4 and 12 months after transplantation. Slides were examined with a fluorescence microscope to detect the presence of male cells with one X and one Y signal in the nucleus, and female cells containing two X signals. Results: Mature cardiomyocytes from the host (1–2%) were found in five endomyocardial biopsy specimens at 4 months, and in three specimens at 12 months. In addition, recipient cells negative for cytoplasmic {alpha}-actin were also identified (1–21% per slide). The number of infiltrating recipient cells was not associated with the degree of rejection of the sample or with the number of prior rejection episodes. Echocardiographic evaluation showed no improvement in cardiac performance in hearts from patients with more than 10% chimeric recipient cells. Conclusions: Our data confirm the existence of mature cardiomyocytes derived from host cells, likely mesenchymal precursors, in the adult cardiac allograft in vivo.

KEYWORDS Remodelling; Stem cells; Myocytes; Transplantation; Ventricular function

This article is referred to in the Editorial by H. Sauer, J. Hescheler and M. Wartenberg (pages 357–358) in this issue.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
One of the most common mechanisms of heart failure is the injury and loss of myocardial tissue [1,2]. Depending on the extent of myocardial injury, the remaining myocytes are unable to successfully support adequate cardiac output [3]. The great clinical impact of heart failure and the scarcity of donor hearts for cardiac transplantation have led several investigations to examine transplantation of different types of cells into the heart in an attempt to achieve structural repair and thus restore cardiac function [4–6].

Evidence suggests that mesenchymal stem cells are able to respond to signals from their host tissue microenvironment and differentiate to a phenotype characteristic of the mature cells of that tissue [7,8]. A recent report showed that purified human mesenchymal stem cells from adult bone marrow engrafted in the adult murine myocardium and differentiated to a cardiomyocyte phenotype [9]. Liechty et al. reported that human mesenchymal stem cells demonstrate cardiomyocyte differentiation after in utero transplantation in sheep [7]. Also, a murine mesenchymal stem-cell-like cell line was shown to express cardiac differentiation markers and exhibit spontaneous membrane depolarization in vitro after treatment with 5-azacytidine [10]. Thus, mesenchymal stem-cells have the ability to integrate and undergo cardiac muscle differentiation in the heart.

Colonization of cardiac allografts by mesenchymal cells from the recipient (cardiac chimerism) may occur in transplanted hearts and may have functional consequences [11]. Evidence supporting this hypothesis has been afforded very recently by Quaini et al. [12], who demonstrated substantial cardiac chimerism in hearts obtained at autopsy from female donors transplanted into male recipients. However, since fetal cell microchimerism has been evidenced after pregnancy in women with male progeny [13,14], a definite confirmation that recipient cells differentiate into cardiomyocytes in the donor heart require the demonstration of cardiac chimerism in allografts of male donors implanted in female recipients. We studied cardiac chimerism in endomyocardial biopsies of living patients with sex-mismatched cardiac allografts. We used combined simultaneous hybridization for both the X- and Y-chromosomes and immunohistochemistry for {alpha}-actin. In addition, we tried to correlate the level of cardiac chimerism with the presence of transplant cellular rejection, and left ventricular function assessed by echocardiography.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Patients and biopsies
Twelve patients receiving a cardiac allograft were selected for this study. Eight sex-mismatched patients were studied: four male patients receiving hearts from female donors, and four female patients receiving allografts from male donors. Four sex-matched patients served as controls: two female patients who received hearts from female donors served as negative controls for Y-chromosome, and two male patients with cardiac allografts from male donors were Y-chromosome positive controls. Patients were followed during 1 year, and clinical, echocardiographic, and histopathologic studies were performed in accordance with our institutional guidelines. All patients gave informed consent.

Endomyocardial biopsy specimens for this study were obtained 4 months and 12 months after transplantation from the right ventricular apex with the Cordis biotome (Cordis, Miami, FL) inserted through the right internal jugular vein. Five to eight endomyocardial biopsy specimens measuring 2–3 mm in diameter were obtained and immersed in buffered 4% formaldehyde [15]. After fixation, 4-µm-thick sections were excised and subsequently paraffin-embedded. Slides were deparaffinized in xylene three times for 10 min each and rehydrated in a graded ethanol series alcohol 100°, alcohol 90°, and alcohol 70°. Tissue sections were hydrated with deionized water. One section was stained with hematoxylin–eosin (HE), and both immunohistochemistry and fluorescent in situ hybridization were carried out in another section.

The diagnosis of transplant rejection was performed in blinded fashion and was based on the recommendations of the ISHLT 7-grade scoring system [16]. All patients were treated with conventional immunosuppresive therapy after heart transplantation and were clinically stable at the time of biopsy.

2.2 Combined immunohistochemical analysis and in situ hybridization
2.2.1 Immunohistochemistry
Immunohistochemical analysis was made using a monoclonal antibody against {alpha}-actin (clone 1A4, prediluted 069D, Biomeda, Foster City, CA, USA) as a marker for cardiac muscle, and the EnVisionTM+ system (DAKO, Denmark). Proteinase K was used to unmask the antigen of the tissue sections to be recognized by the antibody. The TechMate 500 (DAKO, Denmark) was used for immunohistochemical staining. After pretreatment, two slides were paired face-to-face in a washing buffer and loaded into the slide holder. Horseradish peroxidase and 3,3'-diamino-benzidine tetrahydrochloride (DAB) were the enzyme and chromogen employed, respectively. The endogenous peroxidase activity was blocked by 3% hydrogen peroxide for 15 min.

2.2.2 Fluorescence in situ hybridization (FISH)
We used the probe of Vysis (Downers Grove, IL, USA) consisting of two different probes, one with {alpha}-satellite DNA specific to the centromere region Xp11.1-q11.1 directly labeled with Spectrum Green, and the other with {alpha}-satellite DNA specific to the centromere region Yp11.1-q11.1 directly labeled with Spectrum Orange. Immunohistochemical-stained sections were treated with a solution of proteinase K for 18 min at 37 °C to digest cytoplasmatic membrane proteins. Slides were subsequently post-fixed in buffered formalin. Pretreated tissue sections were denatured in 70% formamide/2xSSC, pH 7.0 at 74 °C for 5 min and then dehydrated in a series of ethanol. Hybridization was carried out overnight at 37 °C under a coverslip in a moist chamber. Washes were performed at 72 °C in a solution of 2xSSC/0.3% NP-40 for 2 min. Tissue sections were counterstained with 10 µl of 4,6-diamino-2-phenylindole (DAPI counterstain) (Vysis) [17].

In this study, a minimum of 100 nuclei per slide were studied by two observers blind to the gender of donor and recipient. Results were analyzed in a fluorescent Nikon (Eclipse 600) microscope using the Cytovision software. Tissue sections were scanned at low magnification (100x) with DAPI excitation to localize those areas whose histopathological characteristics had been established by examining the immunohistochemical staining against {alpha}-actin. Simultaneous hybridization for both the X- and the Y-chromosomes definitely identified cells as either being of male or female origin. Two dots were identified within the nucleus: the hybridization signal for the Y-chromosome consisted of a reddish-orange dot, and the signal for the X-chromosome consisted of a green dot.

2.3 Statistical analysis
Results are presented as mean±S.D. The significance of differences between two measurements was determined by Student's t-test. Associations among recipient cells with the number of prior episodes of rejection, and the ISHLT rejection grade of the studied sample were assessed by Pearson correlation coefficient.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Study patients
Eight sex-mismatched and four sex-matched heart transplanted patients were studied. The underlying primary diseases for transplantation were idiopathic dilated cardiomyopathy in seven patients, ischemic cardiomyopathy in one, valvular cardiomyopathy in one, alcoholic cardiomyopathy in one, intraventricular myxoma in one, and hypertensive cardiomyopathy in one. Table 1 shows patient age at transplantation, sex of donor and sex of recipient. Endomyocardial biopsy specimens were examined 4 and 12 months after transplantation with different degrees of transplant rejection using the standardized ISHLT classification [16]. During the first 4 months after transplantation the mean number of rejection episodes per patient was 6.9±1.9; 28 of these were mild rejection episodes consistent with ISHLT grades 1A or 1B, and 27 were moderate cellular rejection episodes consistent with ISHLT grades 2, 3A, or 3B. Between 4 and 12 months after transplantation the mean number of rejection episodes per patient decreased to 2.5±2.1; 11 of these were mild cellular rejection episodes, and nine were moderate rejection episodes.


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  		Table 1 Histopathology of endomyocardial biopsy specimens from sex-mismatched heart transplant patients 4 and 12 months after transplantation

 
3.2 Immunohistochemical and in situ hybridization analysis
Morphologic examination of the tissue samples identified {alpha}-actin in the cytoplasm of cardiac cells. We did not identify cells morphologically recognizable as myofibroblasts.

3.2.1 Sex-matched specimens
The hybridization signal for both the X- and Y-chromosomes was detected in 75% of cells in specimens from male donor allografts transplanted into male recipients (Fig. 1A). In 15% of cells, only the X-chromosome was identified, and in 10% of cells only the Y-chromosome was present. Inevitably, during the process of cutting 4-µm-thick sections for hybridization, nuclei are also sectioned and portions of nuclei lost. In cardiac allograft specimens in which both the donor and the recipient were female, the Y-chromosome body was always absent, and in 86% of cells the two X chromosomes were identified (Fig. 1B).


Figure 1
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  		Fig. 1 Fluorescence in situ hybridization for X-chromosome (green nuclear signal) and Y-chromosome (red nuclear signal) bodies in sex-matched controls (x500). Panel A is a biopsy specimen from a male recipient (XY) receiving a heart from a male donor (XY), and panel B is a specimen from a female recipient (XX) receiving a heart from a female donor (XX). In both panels the blue areas show the DAPI staining in nuclei.

 
3.2.2 Sex-mismatched specimens at 4 months
The results are summarized in Table 1. In endomyocardial biopsy specimens from four female patients with allografts from male donors, we found clear evidence of infiltration of the cardiac allograft by cells of recipient (female) origin. Two X-chromosome bodies were clearly distinguishable in 8.9±2.2% of cells. Host cell-derived cardiomyocytes containing two X signals surrounded by cytoplasmic {alpha}-actin were identified in 1.5±0.6% of cells (Fig. 2). In addition, 7.4±1.9% of recipient cells were identified but did not stain for {alpha}-actin. Recipient cells morphologically recognizable as infiltrating lymphocytes and macrophages were identified in biopsy specimens with ISHLT rejection grades 3A or 3B.


Figure 2
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  		Fig. 2 Combined immunostaining for cardiac muscle {alpha}-actin and double in situ hybridization for X-chromosome (green nuclear signal) and Y-chromosome (red nuclear signal) bodies in an endomyocardial biopsy specimen of a cardiac allograft from a male donor (XY) implanted in a female recipient (XX) (x1000). Panel A shows light microscopy of {alpha}-actin immunohistochemistry of cardiac muscle with the typical cardiomyocyte morphology. In panel B, fluorescence microscopy of the same section shows a recipient cell identified by the presence of two green dots in the nucleus (XX bodies). Arrows highlight the recipient's chimeric cell. In panel B the blue areas show the DAPI staining in nuclei.

 
In male patients who received hearts from female donors, the presence of X- and Y-chromosome bodies were identified in 12.1±9.4% of cells. In one of these specimens we found 2% of X- and Y-chromosome-positive host cells whose identity as cardiomyocytes was confirmed by their location and expression of {alpha}-actin (Fig. 3). In 11.6±8.8% of cells the hybridization signal for X- and Y-chromosomes was identified but the cells did not stain for {alpha}-actin. Again, the specimens with moderate rejection showed recipient inflammatory cells.


Figure 3
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  		Fig. 3 Combined immunostaining for cardiac muscle {alpha}-actin (brown cytoplasm) and double in situ hybridization for X-chromosome (green nuclear signal) and Y-chromosome (red nuclear signal) bodies in an endomyocardial biopsy specimen of a cardiac allograft from a female donor implanted in a male recipient (x1000). Panel A shows light microscopy of {alpha}-actin immunohistochemistry of cardiac muscle. In panel B, fluorescence microscopy of the same section shows a recipient cell identified by the presence of one X and one Y signal in the nucleus. Arrows highlight the recipient's chimeric cell. In panel B the blue areas show the DAPI staining in nuclei.

 
In this series, we did not find a statistically significant association between the percentage of infiltrating recipient cells with the number of prior rejection episodes (r = 0.14, P = 0.7), or the ISHLT rejection grade of the studied tissue sample (r = 0.4, P = 0.28).

3.2.3 Sex-mismatched specimens at 12 months
Twelve months after transplantation, we analyzed X- and Y-chromosome hybridization in biopsy specimens from the same patients. Results are shown in Table 1. The average percentage of recipient cells at 12 months was 6.5±5.4%, which represents a 38% reduction compared to recipient cells identified at 4 months, yet the difference is not statistically significant (P = 0.2). At this stage, only three biopsy specimens showed host cell-derived cardiomyocytes: one specimen with 1% of cells, and two specimens with 2% of cells each.

No association between the percentage of infiltrating recipient cells with the number of prior rejection episodes (r = 0.04, P = 0.9), or the ISHLT rejection grade of the studied tissue sample (r = 0.1, P = 0.78) was found.

3.3 Cardiac performance
Clinical and echocardiographic variables were examined during follow-up in an attempt to determine the functional consequences of the chimeric cells involved in the generation of new myocytes in sex-mismatch cardiac transplant patients. All patients remained clinically stable in NYHA class I during the 12 months of follow-up. To assess cardiac function, patients were divided into two groups according to the percentage of infiltrating recipient cells. Table 2 shows the echocardiographic variables 4 and 12 months after transplantation in hearts from patients with less than 10% of chimeric recipient cells and in hearts from patients with more than 10% of chimeric recipient cells. No statistically significant differences were observed in heart function, size, and mass during follow-up between the two groups.


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  		Table 2 Echocardiographic variables 4 and 12 months after transplantation in patients with sex-mismatched cardiac allografts

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The results of this study confirm the existence of host cell-derived mature cardiomyocytes in sex-mismatched cardiac allografts in vivo.

Cell migration from the host to a transplanted organ can be detected easily with the use of FISH for the Y-chromosome when a female donor heart is transplanted into a male patient [12,18]. This method to study chimerism may potentially overestimate the number of male cells originating from the recipient due to fetal microchimerism. Transplacentally acquired fetal progenitor cells persist for decades beyond pregnancy and lead to a state of low-grade microchimerism in the mother [19]. Microchimerism of male fetal cells during pregnancy has been described in a variety of organs [13,14], thus becoming a potential confounding source of Y-chromosome positive cells in tissue samples obtained from donor female hearts of women with male progeny. In the recent report by Quaini et al., cardiac chimerism was only studied in sex-mismatch transplanted hearts obtained from female donors (with a mean age of 43±15 years), thus male cells identified in the myocardial specimens could originate from: (a) stem cells transferred from the male recipient after cardiac transplantation, and (b) male stem cells transferred as a result of fetal-maternal transfusion during pregnancy, labour, or twin gestation. In our study, the inclusion of a group of female patients who received a heart from a male donor, and the use of simultaneous hybridization for both the X- and Y-chromosomes [20] permitted to demonstrate recipient cardiomyocytes in a situation in which fetal microchimerism is not possible. Thus, we provide compelling evidence that cells with two X signals surrounded by an actin cytoskeleton in biopsy specimens from male donors are definitely cardiomyocytes differentiated from recipient cells, likely mesenchymal precursors.

In our study we found a decreased number of recipient cardiomyocytes at 12 months. Recent data also found the highest levels of chimerism at early stages (between 4 and 28 days after transplantation), and the lowest levels of chimerism at the long term (between 396 and 552 days after transplantation) [12]. To date the explanation of this phenomenon is merely speculative. The transplanted donor heart has to reverse the recipients’ end-stage heart failure characterized by an increased hemodynamic load. These mechanical factors most likely stretch the myocardium and may trigger the migration of undifferentiated cells from the host to optimize cardiac mass and restore function in the short term. Thus, correction of ventricular overload may lead to a reduction of cell chimerism in the long term. An alternative hypothesis is that the donor heart stimulates humoral factors at early stages, which may act as molecular signals for the chemoattraction and activation of undifferentiated cells.

In addition to host cell-derived cardiomyocytes that expressed cytoplasmic actin, we identified cells from the recipient negative for actin. Some of these cells were morphologically recognizable as infiltrating lymphocytes and macrophages in biopsy specimens with substantial inflammatory infiltrate (ISHLT rejection grades 3A or 3B). However, in this study we did not find a statistically significant association between the percentage of infiltrating recipient cells and the ISHLT rejection grade of the studied tissue sample. Thus, identification of recipient cells morphologically similar to surrounding cardiac muscle but negative for {alpha}-actin in specimens without inflammatory infiltrate (ISHLT rejection grade 0) suggests that these may be precursor cells in the process of differentiation, phenotypic maturation, and acquisition of functional competence [21]. Previous studies demonstrated that during in vivo cardiomyogenesis, myofibrils are initially distributed in sparse, irregular myofibrillar arrays, which gradually mature into parallel arrays of myofibrils and ultimately align into densely packed sarcomeres [22,23].

Cellular transplantation has emerged as a potentially new means of improving viability of damaged myocardium. The rationale underlying cellular transplantation is that exogenously supplied cells might compensate for myocyte loss and/or dysfunction and consequently improve heart function. Experiments in vitro showed that human embryonic stem cells may differentiate into spontaneously beating cardiomyocytes [24]. Moreover, myocardial colonization with fetal cardiomyocytes has been shown to improve function in experimental models of myocardial ischemia [25,26]. Interestingly, a recent report showed that cellular transplantation in mice can improve function of globally failing hearts by a mechanism that does not involve the sustained presence of transplanted cells but rather the effects of cardioprotective factors released by them [5]. These investigators found that none of the grafted cells were present in the recipient myocardium after 1 month, although heart function assessed by echocardiography was substantially improved. In our study, we did not find functional differences measured echocardiographically in hearts of patients with less than 10% of chimeric recipient cells and in those with more than 10% of chimeric recipient cells. We speculate that the lack of changes in cardiac performance can be related to: (1) limited sensitivity of transthoracic echocardiography to detect minor and local changes in contractility; (2) precursor recipient cells may not have a completely structured sarcomere; (3) the infiltrating recipient cells sparsely disseminated in the myocardium, instead of adhering to general cardiac contractility may introduce disarray in a similar manner to that of hypertrophic cardiomyopathy; and (4) it may be inaccurate to correlate the number of recipient cells of specimens obtained from the right ventricular apex with ejection fraction values obtained from the left ventricle.

In summary, we have shown the existence of a precursor host cell population capable of being instructed by the cardiac environment to yield mature cardiac muscle. This raises the possibility that precursor cells, most likely mesenchymal stem cells [7,9,10], can be isolated from a patient, cultured outside the body in vitro, and delivered in a therapeutic context to support the patient's diseased heart. Obtaining sufficient own precursor cells for clinical purposes would reduce or abolish the need of strategies to counter immune rejection. However, clinical use will require the delivery of adequate numbers of cells to specific sites for therapeutic effect. Further insight is required to better understand the process of phenotypical and functional cell differentiation in the cardiac microenvironment.

Time for primary review 34 days.


   Acknowledgements
 
We are grateful to Robert S. Schwartz for critical review of the manuscript.


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

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D. J. Prockop
Further proof of the plasticity of adult stem cells and their role in tissue repair
J. Cell Biol., March 17, 2003; 160(6): 807 - 809.
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 Cardiovasc ResHome page
H. Sauer, J. Hescheler, and M. Wartenberg
Cardiac differentiation of mesenchymal stem cells in sex mis-matched transplanted hearts: self-repair or just a visit?
Cardiovasc Res, December 1, 2002; 56(3): 357 - 358.
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