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Original Articles: Adult Cardiac

Role of Tumor Necrosis Factor Receptor 1 in Sex Differences of Stem Cell Mediated Cardioprotection

^a Clarian Cardiovascular Surgery, Indiana University School of Medicine, Indianapolis, Indiana
^b Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
^c Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana
^d Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Accepted for publication December 5, 2008.

^_* Address correspondence to Dr Meldrum, 635 Barnhill Drive, Van Nuys Medical Science Bldg., Rm. # 2017, Indianapolis, Indiana 46202 (Email: dmeldrum{at}iupui.edu).

	Abstract

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Background: Mesenchymal stem cells (MSCs) hold great therapeutic potential for the repair and regeneration of ischemic tissue, possibly through the release of beneficial paracrine factors. Sex differences have been observed in the paracrine function of MSCs. Female stem cells produce lower proinflammatory cytokines and higher levels of growth factors compared with their male counterparts. Ablation of tumor necrosis factor receptor 1 (TNFR1) increases protective growth factor production by male, but not by female, MSCs. We therefore hypothesized the following: (1) that female MSCs would improve myocardial recovery compared with male MSCs after ischemia-reperfusion injury (I/R); and (2) that MSCs isolated from TNFR1 knock out male, but not female, mice, would improve postischemic myocardial recovery compared with their wild type (WT) counterparts.

Methods: Male adult Sprague-Dawley rat hearts were subjected to I/R by Langendorff isolated heart preparation. The MSCs were harvested from adult mice and cultured under normal conditions. Immediately prior to ischemia, one million MSCs were infused into the coronary circulation. Cardiac functional parameters were recorded continuously.

Results: Pretreatment with MSCs from either sex significantly increased postischemic myocardial recovery as evidenced by improved left ventricular developed pressure, contractility, and rate of relaxation. Infusion with female MSCs was associated with a greater degree of myocardial recovery after I/R compared with male MSCs. The TNFR1 deficiency increased the degree of myocardial recovery associated with male MSCs, but not with female MSCs. No additional cardioprotection was observed when TNFR1 was ablated in female MSCs.

Conclusion: Sex differences influence the cardioprotective effects of both WT and TNFR1 ablated MSCs.

	Introduction

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Myocardial ischemia remains a leading cause of morbidity and mortality worldwide [1, 2]. Ischemia-mediated myocardial injury can be worsened after restoration of coronary flow (reperfusion). Oxygen radicals generated at the time of reperfusion cause further cellular death as well as microvascular and endothelial injury [3]. Mesenchymal stem cells (MSCs) represent a novel treatment modality for myocardial ischemia and reperfusion (I/R) injury [4]. Although the mechanisms behind stem-cell-mediated cardioprotection remain poorly understood, stem cells appear to mediate their beneficial effects in part by producing cytoprotective paracrine factors. These cytoprotective factors have been shown to reduce inflammation, decrease apoptotic cell death, and improve overall myocardial function [5–9].

Tumor necrosis factor alpha (TNF-) is a proinflammatory cytokine that is produced by a variety of cell types. An elevated level of TNF- is typically noted after myocardial I/R injury [10]. The effects of TNF- are mediated by TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) [10]. The activation of TNFR1 has been reported to suppress neural progenitor proliferation [11], decrease MSC growth factor production [12], generate reactive oxygen species (ROS), and induce apoptosis [13]. In contrast, TNFR2 does not contain a death domain and cannot transmit apoptotic signals [13]. The activation of TNFR2 leads to persistent, PI3K-dependent nuclear factor-B activation, which could be essential for cell survival, proliferation, and growth factor production [14–16].

Sex differences exist in the paracrine actions of MSCs. As we reported previously, female MSCs produce more beneficial growth factors (more vascular endothelial growth factors [VEGF]), less proinflammatory cytokines (TNF and interleukin [IL]-6), and undergo less apoptotic death in response to hypoxia and lipopolysaccharides (LPS) than their male counterparts [17–19]. Interestingly, TNFR1 deficiency increased VEGF production, decreased IL-6 and TNF production in male MSCs, but not in female MSCs after exposure to hypoxia and LPS [19]. It is unknown whether sex differences in TNFR1-deficient MSCs affect cardioprotection during myocardial I/R. We hypothesized the following: (1) that female MSCs would improve myocardial recovery to a greater degree compared with male MSCs after I/R; and (2) that MSCs isolated from TNFR1 deficient male, but not female, mice would improve postischemic myocardial recovery compared with their wild type (WT) counterparts.

	Material and Methods

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Animals
Normal adult male Sprague-Dawley rats were obtained from Harlan (200 to 250 g; Indianapolis, IN). Wild type C57BL/6J mice and TNFR1-deficient mice (6 to 8 weeks old) on a background of C57BL/6J were obtained from Jackson Laboratory (Bar Harbor, ME). Mice that are homozygous for TNFR1 allele are viable, normal in size, and do not display any gross physical abnormalities. Animals were fed a standard diet and acclimated in a quiet quarantine room for 1 week before the experiments. The animal protocol was reviewed and approved by the Indiana Animal Care and Use Committee of Indiana University. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication No. 85-23, revised 1985).

Preparation of Mouse Bone Marrow Stromal Cells
A single-step stem cell purification method using adhesion to cell culture plastic was employed as previously described [20]. Briefly, adult mouse bone marrow stem cells were collected from bilateral femurs and tibias after sacrifice by removing the epiphyses and flushing the shaft with complete media (Iscove's Modified Dulbecco's Medium; Invitrogen, Carlsbad, CA) and 10% fetal bovine serum (GIBCO Invitrogen, Carlsbad, CA), using a syringe with a 26G needle. Cells were disaggregated by vigorous pipetting several times, and were passed through a 30-µm nylon mesh to remove remaining clumps of tissue. Cells were washed by adding complete media, centrifuging for 5 minutes at 300 x g at 24°C, and removing the supernatant. The cell pellet was then resuspended and cultured in 75 cm² culture flasks with complete media at 37°C in 5% CO₂ in air. The MSCs preferentially attached to the polystyrene surface; after 48 hours, nonadherent cells in suspension were discarded. Fresh complete media was added and replaced every 3 or 4 days thereafter. When the cultures reached 90% of confluence, the stem cell culture was passaged; cells were recovered by the addition of a solution 0.25% trypsin-ethylenediaminetetraacetic acid (GIBCO Invitrogen, Carlsbad, CA) and replated in flasks. The MSCs were negative for the hematopoietic markers CD34 (95%) and CD45 (94%), and were positive for the mesenchymal stem cell marker CD44 (96%) [21]. Cells were utilized for experimentation between passages 3 and 7.

Isolated Heart Preparation (Langendorff)
Rats were anesthetized (sodium pentobarbital, 60 mg/kg intraperitoneal [i.p.]) and heparinized (500 U i.p.), and hearts were rapidly excised by median sternotomy and placed in 4°C Krebs-Henseleit solution (119 mM sodium chloride, 20.8 mM sodium bicarbonate, 11 mM dextrose, 12 mM calcium chloride dihydrate, 47 mM potassium chloride, 11.7 mM magnesium sulfate heptahydrate, and 11.8 mM potassium dihydrogen phosphate). The aorta was cannulated and the heart was perfused under constant pressure (mean 75 mm Hg) with oxygenated (95% O₂/5% CO₂) Krebs-Henseleit solution (37°C). A left atrial resection was performed prior to insertion of a water-filled latex balloon through the atrium into the ventricle. The balloon was initially adjusted to a desired mean end diastolic pressure (EDP) of 5 mm Hg and hearts were allowed to equilibrate for 15 minutes. Pacing wires were fixed to the atrium and hearts were paced at approximately 6 Hz, 3V, 2 ms (350 beats per minute) during equilibration and reperfusion to ensure a standard heart rate between groups. A three-way stopcock above the aortic root was used to create warm global ischemia, during which the heart was placed in a 37°C degassed organ bath. After 25 minutes of ischemia, hearts were reperfused for 60 minutes. The left ventricular developed pressure (LVDP), EDP, rate of contraction (delta pressure/delta time [+dp/dt]), and rate of relaxation (–dp/dt) were continuously recorded using a PowerLab 8 preamplifier/digitizer (AD Instruments Inc., Milford, MA) and an Apple G4 PowerPC computer (Apple Computer Inc., Cupertino, CA).

Experimental Isolated Heart Groups
Rat hearts were divided into the following groups (n = 5 per group): (1) control; (2) male wild type (MWT) MSC infusion; (3) female wild type (FWT) MSC infusion; (4) male TNFR1KO (MR1KO) MSC infusion; and (5) female TNFR1KO (FR1KO) MSC infusion. The MSCs were treated with trypsin. Single-cell suspension was mixed with an equal volume of trypan blue (20 µl, 0.4%; Lonza, Walkersville, MD) to mark dead cells. The mixture was allowed to sit at room temperature for a few minutes (less than 10 minutes). Viable cells exclude trypan blue, while dead cells stain blue due to trypan blue uptake. Cells were loaded onto a cytometer and then counted by microscopy. One million viable cells were isolated and resuspended in 1 mL of Krebs-Henseleit solution (37°C). Over the course of one minute prior to ischemia, the solution containing 1 million MSCs was infused into the coronary circulation (infusion rate: 1 million cells/1 minute/1 mL of Krebs-Henseleit solution).

Presentation of Data and Statistical Analysis
All reported values are mean ± standard error of the mean and a p value less than 0.05 was considered statistically significant. Left ventricular developed pressure (LVDP), rate of contraction (+dp/dt), and rate of relaxation (–dp/dt) are presented as a percentage of baseline during equilibration. Data were compared using two-way analysis of variance (ANOVA) with repeated measures (RANOVA) with post hoc Bonferroni.

	Results

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Stem cells Improve Myocardial Functional Recovery After Ischemic Injury
Treatment of hearts with MSCs of either sex prior to ischemia resulted in significantly improved postischemic functional recovery as compared with vehicle controls. This was demonstrated, specifically, through improved LVDP, +dp/dt, and –dp/dt in the experimental groups as compared with controls (Figs 1A; 1B; 1E; 1F; 1G). For example, at end reperfusion LVDP was significantly higher in both the male MSC and female MSC groups compared with vehicle control (42.9 ± 2.8%, 55.2 ± 2.7%, and 30.7 ± 2.3% of baseline for the male MSC group, female MSC group, and vehicle control group, respectively; Fig 1B). Compared with male MSCs, female MSCs conferred a greater degree of myocardial protection after I/R. The hearts infused with female MSCs had significantly higher LVDP compared with those infused with male MSCs after I/R (Figs 1A and 1B).

View larger version (34K): [in this window] [in a new window]   Fig 1. Intracoronary infusion of female MSCs provided greater cardioprotection compared with male MSCs. Although MSCs of either sex improved cardiac function after ischemic injury, hearts infused with FWT MSCs had greater functional recovery. This was seen in higher LVDP, +dp/dt, –dp/dt, and lower EDP during reperfusion (A, E, G) and at the end of reperfusion (D, F). No significant differences were noted when comparing EDP among all groups (C). (A, B, E–H): data were expressed as % of equilibration. (* = p < 0.05 MWT vs vehicle control; + = p < 0.05 FWT vs vehicle control; # = p < 0.05 FWT vs MWT as determined using two-way analysis of variance with repeated measures followed by a Bonferroni post hoc analysis (n = 5). (EDP = end diastolic pressure; FWT = female wild type; LVDP = left ventricular developed pressure; MSCs = mesenchymal stem cells; MWT = male wild type; • = vehicle control; = MWT; = FWT.)

View larger version (29K): [in this window] [in a new window]   Fig 2. Stem cells isolated from TNFR1 deficient male mice demonstrated greater degree of cardioprotection compared with their WT counterparts. Hearts infused with male TNFR1 knockout MSCs (MR1KO) demonstrated greater level of functional recovery compared with those infused with MWT MSCs (MR1KO). This was noted by higher LVDP, +dp/dt, –dp/dt, and lower EDP during reperfusion (A, C, E, G) and at the end of reperfusion (B, F, H). A statistically significant trend was observed when comparing the groups at the end of reperfusion (p = 0.1, D). (A, B, E–H): data were expressed as % of equilibration. (* = p < 0.05 MWT vs MR1KO as determined using two-way analysis of variance with repeated measures followed by a Bonferroni post hoc analysis [n = 5]; EDP = end diastolic pressure; LVDP = left ventricular developed pressure; MR1KO = male TNFR1KO; MSCs = mesenchymal stem cells; MWT = male wild type; TNFR1 = tumor necrosis factor receptor 1; • = MFWT; = MR1KO.)

View larger version (28K): [in this window] [in a new window]   Fig 3. No significant difference was observed in stem cell mediated cardioprotection between MSCs isolated from female TNFR1 deficient mice and their wild type counterparts. The MSCs isolated from TNFR1 knockout female mice did not demonstrate a greater level of cardioprotection compared with FWT MSCs after ischemia-reperfusion injury. No significant difference was observed in LVDP and EDP during reperfusion and at end reperfusion (A, B, C, D). Although +dp/dt and –dp/dt were significantly faster at 30 minutes after reperfusion (E, G), there is no difference in +dp/dt and –dp/dt at end reperfusion (F, H). (A, B, E–H): data were expressed as % of equilibration. (EDP = end diastolic pressure; FR1KO = female TNFR1KO; FWT = female wild type; LVDP = left ventricular developed pressure; MSCs = mesenchymal stem cells; TNFR1 = tumor necrosis factor receptor 1; * = p < 0.05 FWT vs FR1KO as determined using two-way analysis of variance with repeated measures followed by a Bonferroni post hoc analysis [n = 5]; • = FWT; = FR1KO.)

View larger version (29K): [in this window] [in a new window]   Fig 4. Intracoronary infusion of male MSCs isolated from TNFR1 deficient mice provided greater cardioprotection compared with FWT MSCs. The heart infused with male TNFR1 ablated MSCs (MR1KO) demonstrated higher LVDP, +dp/dt, –dp/dt, and lower EDP during reperfusion (A, C, E, G) and at the end of reperfusion (F). No significant differences were noted when comparing EDP at the end of reperfusion (D). (A, B, E–H): data were expressed as % of equilibration. (EDP = end diastolic pressure; MR1KO = male TNFR1KO; FWT = female wild type; LVDP = left ventricular developed pressure; MSCs = mesenchymal stem cells; TNFR1 = tumor necrosis factor receptor 1; * = p < 0.05 FWT vs MR1KO as determined using two-way analysis of variance with repeated measures followed by a Bonferroni post hoc analysis [n = 5]; • = FWT; = MR1KO.)

	Comment

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More than a decade of research in experimental models indicates that delivery of stem cells into ischemic myocardium positively remodels and regenerates injured tissue, improves cardiac function, and protects tissue from further insult [4]. Stem cells may exert their beneficial effects by several different mechanisms. Some studies suggest that stem cells differentiate into specific end organ cells, which then become incorporated into the tissue to increase postinjury functional recovery [23]. However, other evidence indicates that stem cells may mediate their beneficial effects by the release of cytoprotective paracrine factors that promote tissue repair and improvement in organ function [9, 24]. Evidence to support the paracrine actions of stem cells has been demonstrated from several studies. First, donor stem cell engraftment and survival after transplantation has been shown from previous studies to be only 1% to 5%, which is likely too few cells to be relevant therapeutically and to directly influence organ function [25]. Second, we and others have demonstrated that stem cell-mediated improvement in end organ function occurs within 72 hours of injury, precluding differentiation as a cause due to time required for meaningful differentiation and regeneration of these donor cells [4]. Third, in vitro and in vivo animal studies have revealed that much of the functional improvement and attenuation of injury afforded by stem cells can be replicated by the cell-free, conditioned media that derived from stem cells in culture [7, 26]. In this study, acute application of MSCs into injured cardiac tissue attenuated I/R injury and these protective effects occur less than 1 hour after injury, thus precluding a cardioprotective benefit due to any meaningful rate of donor cell myogenic differentiation and regeneration. Indeed, we have previously shown that myocardium infused with female MSCs exhibited decreased TNF- and increased VEGF compared with hearts infused with male MSCs [17]. Taken together, these observations indicate that stem cells mediate their protection by releasing cytoprotective paracrine factors and decreasing proinflammatory cytokines in myocardium. The beneficial growth factors could improve heart function by the following: (1) binding to their receptors localized on cardiomyocytes (in vitro isolated heart preparation); (2) suppressing proinflammatory cytokines (in vitro and in vivo myocardial infarction models); and (3) facilitating angiogenesis (in vivo models of myocardial infarction).

Sex differences exist in stem cell paracrine growth factor production. Interestingly, there is an apparent sex difference in cardiovascular diseases. Men appear to have more rapid progression of heart failure, less preservation of myocardial mass as they age, and worse age-matched cardiac contractility compared with women [27]. Conversely, females have a lower incidence of heart failure, a higher rate of survival [28], and a cardioprotective advantage after I/R injury [29]. It is unknown whether differences in cardiovascular diseases between males and females may be due in part to the differences in endogenous stem cell function and repair.

Production of TNF- by cardiomyocytes and resident macrophages is significantly upregulated after I/R injury [10]. We reported previously [30] that TNF- stimulates MSCs to release beneficial growth factors. However, TNF- can also induce apoptosis [13], suppress proliferation of neural progenitor cells [11] and decrease the secretion of VEGF and insulin-like growth factor 1 (IGF-1) by mouse MSCs [12]. This led to the important appreciation that TNF- itself may have both beneficial and detrimental effects on stem cell-mediated protection depending on which of its receptors (TNFR1 or TNFR2) is activated. The TNFR1 correlates with decreased progenitor cell proliferation [31], generation of ROS as well as capable of inducing apoptosis [11]; in contrast, TNFR2 could be essential for cell survival, proliferation, and growth factor production [14–16]. Indeed, TNFR1 deficiency increased VEGF production and decreased IL-6 and TNF production in male MSCs, but not in female MSCs [19]. These observations, together with data presented in this manuscript, demonstrate that TNFR1 signaling attenuates MSC-mediated protection and beneficial growth factor production in males, but not in females. The higher level of beneficial growth factors, lower level of proinflammatory cytokines produced by female MSCs, and their relatively higher resistance to insult may be attributable to differential intracellular TNF signaling [32]. The estrogen-upregulated, suppressor-of-cytokine-signaling-3 and signal transducer and activator of transcription 3, could underlie the relative TNFR1 resistance in female MSCs as demonstrated by previous work in our lab [32, 33]. Further studies to examine this mechanism, however, are warranted.

In conclusion, we demonstrate that sex differences influence the cardioprotective effects of MSCs. The ablation of TNFR1 significantly increases male MSC-mediated cardioprotection, but had no effect on the cardioprotective effects of female stem cells. Understanding how stem cells protect ischemic myocardium is important for optimizing the cytoprotective effects of these cells and may result in pharmacologically or genetically modified cells that provide maximum protection to injured tissue. Additional in vivo studies must be implemented to address the long-term efficacy and potential tumorigenicity of implanted stem cells prior to widespread human application.

	Acknowledgments

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This work was supported in part by National Institutes of Health grants NIH R01GM070628, NIH R01HL085595, NIH K99/R00 HL0876077-01, and NIH F32 HL085982, an American Heart Association (AHA) Grant in aid, and AHA Postdoctoral Fellowship 0526008Z.

	Footnotes

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^_* Drs Zeller and Wang contributed equally to this work.

	References

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