Cardiac stem cell therapy to modulate inflammation upon myocardial infarction

BBAGEN-27305; No. of pages: 10; 4C: 3, 5, 6, 8 Biochimica et Biophysica Acta xxx (2012) xxx–xxx

Contents lists available at SciVerse ScienceDirect

Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen

Review

Cardiac stem cell therapy to modulate inflammation upon myocardial infarction☆ F. van den Akker a, J.C. Deddens a, P.A. Doevendans a, b, J.P.G. Sluijter a, b,⁎ a b

Department of Cardiology, University Medical Center Utrecht, The Netherlands ICIN - Netherlands Heart Institute, Utrecht, The Netherlands

a r t i c l e

i n f o

Article history: Received 3 May 2012 Received in revised form 20 July 2012 Accepted 28 August 2012 Available online xxxx Keywords: Mesenchymal stem cell Myocardial infarction Inflammation Mononuclear cell Neutrophil T-cell

a b s t r a c t Background: After myocardial infarction (MI) a local inflammatory reaction clears the damaged myocardium from dead cells and matrix debris at the onset of scar formation. The intensity and duration of this inflammatory reaction are intimately linked to post-infarct remodeling and cardiac dysfunction. Strikingly, treatment with standard anti-inflammatory drugs worsens clinical outcome, suggesting a dual role of inflammation in the cardiac response to injury. Cardiac stem cell therapy with different stem or progenitor cells, e.g. mesenchymal stem cells (MSC), was recently found to have beneficial effects, mostly related to paracrine actions. One of the suggested paracrine effects of cell therapy is modulation of the immune system. Scope of review: MSC are reported to interact with several cells of the immune system and could therefore be an excellent means to reduce detrimental inflammatory reactions and promote the switch to the healing phase upon cardiac injury. This review focuses on the potential use of MSC therapy for post-MI inflammation. To understand the effects MSC might have on the post-MI heart the cellular and molecular changes in the myocardium after MI need to be understood. Major conclusions: By studying the general pathways involved in immunomodulation, and examining the interactions with cell types important for post-MI inflammation, it becomes clear that MSC treatment might provide a new therapeutic opportunity to improve cardiac outcome after acute injury. General significance: Using stem cells to target the post-MI inflammation is a novel therapy which could have considerable clinical implications. This article is part of a Special Issue entitled Biochemistry of Stem Cells. © 2012 Elsevier B.V. All rights reserved.

1. Introduction Ischemic heart disease is the number one killer worldwide [1]. During ischemia there is a shortage of oxygen and nutrients in the heart leading to cellular apoptosis and necrosis. One of the key steps to prevent further cardiac deterioration is to restore blood flow into the affected myocardium. Upon reperfusion the restored blood flow reintroduces oxygen, leading to the generation of damaging reactive oxygen species [2]. In addition to the ischemia induced cell death, this reperfusion progresses cell death even further. As in all tissue damages an inflammatory response is stimulated to remove cell remnant and debris. The cardiac ischemic response also triggers a strong immune reaction in the heart [3–5]. This reaction includes the activation of local macrophages and the attraction of other immune cells from the blood, such as neutrophils, monocytes and lymphocytes [3,4,6]. This inflammatory reaction clears the wound of dead cells and debris, thereby simultaneously providing key signals to activate reparative pathways. The different immune cells produce a large number of pro-inflammatory cytokines. This leads to a cascade in which ☆ This article is part of a Special Issue entitled Biochemistry of Stem Cells. ⁎ Corresponding author at: Department of Cardiology, University Medical Center Utrecht, The Netherlands. Tel.: +31 88 755 7155; fax: +31 30 252 2693. E-mail address: [email protected] (J.P.G. Sluijter).

more immune cells are attracted, causing further damage and stress on the surviving cardiomyocytes and leading to even more cell death. Due to this strong response the inflammatory reaction has great influence on ventricular remodeling and cardiac function [7]. Resolution of the inflammatory response is currently thought to be an active process. It is mediated by factors produced by the cardiac cells, released from the matrix, and secreted by the infiltrated immune cells themselves [7]. These chemotactic and pro-inflammatory cytokines, which accumulate in high concentrations, attract and activate various components of the immune system. For over thirty years different ways of suppressing this immune reaction have been investigated to evaluate the effect on cardiac function. One of the most investigated approaches involves the administration of immunosuppressive drugs, usually corticosteroids [8]. Although the observed outcomes on cardiac performance differed strongly between studies, there was an overall decrease in leukocyte influx into the infarcted tissue. A recent meta-analysis on all clinical trials with corticosteroids shows that there is a non-significant trend towards decreased mortality with corticosteroid treatment [8]. At the same time, corticosteroids were also found to disrupt the healing process by delaying collagen deposition and scar formation. Smaller and weaker scars were formed, both in animal models and in humans, leading to an increased chance of LV rupture [8–10]. Non-steroidal anti-inflammatory treatments, such as ibuprofen, were also investigated. Although a reduction in neutrophils

0304-4165/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbagen.2012.08.026

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

2

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

en leukocyte infiltrate was observed the broad suppression of the entire inflammation response resulted again in a thinner scar [11,12]. In addition, several NSAIDs were found to significantly increase the risk of recurrent myocardial infarction and death [13]. As a result, treatment with broad immunosuppressive drugs in the post-MI setting has largely been abandoned and no adequate therapy for the inflammatory response has yet emerged. An effective therapy that influences the immune response should reduce the length and damage of the inflammatory response and not interfere with or even augment the activation of reparatory pathways. This shift in balance between inflammation and repair might be achieved by using stem cell therapy in the heart. 2. Clinical stem cell therapy During the last decades the use of stem cell transplantation therapy, to repair or regenerate damaged tissue, has become increasingly popular in clinical research. In the mid-fifties, researchers could cure mice with leukemia by near-lethal whole body irradiation, after which bone marrow from a healthy donor was transplanted [14]. Within a few years this treatment was also given to humans and despite initial disappointments, it quickly developed into a successful therapy [15]. Since then more research has focused on stem cell therapy. Over the years many more adult stem cells and progenitor cells have been investigated for potential regenerative therapies. One of the most investigated cells in recent years is the mesenchymal stem cells (MSC). MSC are present in the bone marrow, where they regulate the microenvironment. MSC secrete many paracrine factors, which can reduce cell death, fibrosis and even inflammation [6,16,17]. MSC are reputedly immuno-privileged, meaning that the host immune system will not attack them and allogeneic transplantation should be feasible [18,19]. The strength of the paracrine factors produced by MSC is demonstrated by experiments in which MSC-derived conditioned medium (CM) or components thereof are used. Such experiments demonstrated cytoprotective effects [20,21], reduced infarct size, improved cardiac function [10,22], stimulated human renal proximal tubule regeneration [23], and reduced autoimmune encephalitis [24]. Aside from numerous growth factors and cytokines produced by stem cells, exosomes have gained interest as one of the factors in the conditioned medium that serve an important role in these paracrine effects. Exosomes are small vesicles secreted by a large variety of cells containing a specific subset of proteins, mRNAs, and miRNAs, which can influence various biological processes [25]. For example, MSC-derived exosomes were found to reduce ischemia/reperfusion injury [26], while tumor-derived exosomes stimulated angiogenesis [27] and cardiac progenitor-derived exosomes stimulated endothelial cell migration [28]. Within the immune system exosomes offer an important means of cross-talk between the various subsets of immune cells, thereby regulating the immune response [29]. It is therefore not unlikely that exosomes produced by MSC can modulate the immune system as well. The notion that MSC are active immune-suppressors appeared about ten years ago [30], when a suppressive effect of MSC on T-cell proliferation was observed. This immunomodulatory capacity was further investigated and quickly applied in therapy, as patients with therapy-resistant severe acute graft-versus-host-disease (GVHD) could be cured with repetitive MSC injections [31,32]. In fact, concomitant administration of MSC with the HSC transplantation enhanced engraftment of HSC and reduced the chances of acute GVHD [33]. These stunning results sparked an enormous interest to investigate their potential in other diseases. In the field of graft rejection, MSC were found to be able to prolong graft retention of skin grafts [34] as well as semi-allogeneic heart transplants [35]. MSC were also considered in auto-immune diseases. MSC applied in arthritis showed contrasting results, possibly related to the timing of administration [36–38], while research on inflammatory bowel disease (IBD) shows a positive response [37,39]. Interestingly, recently neural stem

cells were also found to be immunosuppressive, raising the question whether immunomodulation is a general stem cell characteristic [40–43]. 3. Current attempts in cardiac stem cell therapy As cardiovascular disease is the most prevalent cause of death, still looking for new therapeutic modalities, it was quickly selected as a target population for stem cell therapy. In the past years, the focus of cardiac stem cell therapy has mainly been on the regeneration of damaged myocardium and angiogenesis, via paracrine signals or cellular differentiation. Results of these stem cell therapies include an increase in ejection fraction, a measure of cardiac function, and positive effects on cardiac remodeling [44,45]. After a week, however, only less than 5% of the injected stem cells are still present in the heart [45,46], none of which show true differentiation towards the cardiac phenotype. This clearly indicated that possible differentiation and direct functional contribution is only a minor factor in the observed effects, whereas supportive or paracrine factors are likely more important. These paracrine effects include a reduction in apoptosis and an increase in angiogenesis. However, a possible explanation, which has seen limited study, is the possible effect of MSC on post-MI inflammation. Since the immune response shortly after MI has a strong correlation with cardiac function and outcome [7], it is likely that these processes are affected by these paracrine factors of the transplanted MSC soon after injection as well. To gain more understanding of the transplanted stem cell effects on different cells in the immune system, and to investigate the possibilities of using cell therapy as a treatment for post-MI inflammation, it is important to know the temporal profile and location of inflammatory cells after MI. In this review, we provide an overview of post-MI inflammation, the protagonists from the immune system and known interactions between them and the MSC, one of the most abundantly studied cell types, in an effort to elucidate/ predict the effects of immunomodulatory cardiac stem cell therapy. 4. Post-MI inflammation During cardiac ischemia there is a shortage in supply of oxygen and nutrients to the cardiomyocytes. As the heart is extremely sensitive for ischemia, the first ultrastructural changes, such as myofibrillar relaxation, glycogen depletion and mitochondrial swelling, are visible within minutes of onset [47]. In humans, the effects of the oxygenshortage are still largely reversible within the first twenty minutes. After that time permanent damage occurs [47]. During the following hours, oxygen-deprived cells can undergo necrosis, apoptosis or remain in a so-called hibernating state [47,48]. In response to, or during either of these processes, the stressed myocardial cells release cytokines, such as IL-1, express damage-associated proteins or loose proteins and lipids, thereby displaying their hydrophobic portions. After MI, these signals are all recognized as damage-associated molecular patterns (DAMPs) and are important for attraction and activation of various components of the immune system [49–51] (Fig. 1). Additionally, the complement system plays an important role in post-MI inflammation. The complement system becomes activated via natural IgM classes, targeting non-muscle myosin heavy chain type II A and C [52]. This IgM leads to the activation of the complement system, leading to a strong attraction of neutrophils and macrophages. Initially, the immune response is aimed at cleaning up the debris of dead cells and matrix. Later on, the actual repairs start with myofibroblast activation, collagen deposition and angiogenesis stimulation [2,7]. Toll like receptors (TLR) are of essential importance in the activation of the immune response after MI [7,53]. TLR are ubiquitously present receptors involved in perceiving danger signals. These danger signals were initially thought to be only pathogen-associated, yet recently it was found that DAMPs, released by stressed or damaged cells, can also activate TLR [49]. Although TLR were primarily found on

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx ROS & NO

TLR activation

3

Phagocytosis

ECM destruction

IL-1β IL-8 TNFα

tMφ

Angiogenesis

DAMPs

PMN Mφ2

DAMPs IL-1

Damaged myocardium

Mφ1 TGF-β

C5b67 C3a

Natural IgM

C5a

Complement activation

DAMPs

Myofibroblast activation

Collagen deposition

Fig. 1. Attraction and activation of the immune system after MI. The first cells activated after myocardial infarction are the local macrophages. Soon after, DAMPs, complement system and IL-1 attract neutrophils, which enter the damaged tissue to clear the debris. Within days large numbers of macrophages infiltrate the tissue, clearing both the debris and activating the reparative pathways. The M1 macrophages are the first to arrive and have a pro-inflammatory character. They are followed by the anti-inflammatory M2 macrophage. Lymphocytes arrive relatively late on the scene, due to the lengthy process of activation. PMN: polymorphonucleosides, Mϕ: macrophage.

immune cells, a number of TLR are also present on cardiomyocytes, endothelial cells, SMCs and fibroblasts [3,54]. Activation of several of these cardiac TLR has been described after MI and especially upon reperfusion. Activation of the TLR signaling pathways converges mainly on nuclear translocation of NF-κB and transcription of various genes involved in acute inflammation [3,19,50,54,55]. In the next section, the course of post-MI inflammation as well as its protagonists will be described in more detail. 5. Neutrophils and macrophages Two cell types of the immune system play a major role in cardiac inflammation: the neutrophils and the macrophages. A schematic overview showing the presence and occurrence of various inflammatory cell types in the human post-MI heart is given in Fig. 2. As is the case in many organs in the body some local macrophages are present in the heart [4]. After MI, the cardiac macrophages are the first to be activated. Upon activation they secrete high levels of various proinflammatory cytokines and chemokines, such as IL-1, IL-6, IL-8, NO

D1

D2

D3

D4

D5

and TNFα [2,4]. Together with DAMPs, released by damaged cells, these cytokines create a pro-inflammatory environment and attract neutrophils to the damaged area. Neutrophils are circulating phagocytic granulocytes involved in the early inflammatory response. In the case of human cardiac inflammation, neutrophils enter the tissue in large numbers around six hours after infarction and remain the most prevalent immune cell for approximately three days. Migration of neutrophils into the injured tissue depends on chemotactic factors, of which IL-1 and IL-8 are among the most important. When activated by these chemotactic signals, neutrophils produce reactive oxygen species (ROS) and reactive nitrogen intermediates. This respiratory burst is normally aimed at micro-organisms, however, in the postinfarct heart it progressively damages the cardiomyocytes. This is facilitated by ICAM-1 expression by cardiomyocytes, allowing the neutrophil to be in close proximity during the burst [56–58]. This neutrophilic discharge increases cardiac cell death, leading to the release of more inflammatory signals and thus further strengthening the immune response. In addition to the respiratory burst, neutrophils release a number of proteases to dissolve the extracellular matrix

D6

D7

D8

D9

D10

Local Mφ

PMN infiltrate

PMN debris

Mφ1 Fibroblast activation Mφ2 Lymphocytes Pro-inflammatory environment Anti-inflammatory environment Fig. 2. Timeline showing the presence of various components of the immune system present in the human post-MI heart. The presence of neutrophils and M1 macrophages in the first days after myocardial infarction and the cytokines they secrete, create a strong pro-inflammatory environment resulting in chemo-attraction of more immune cells and additional damage to the myocardium. When the switch to the M2 macrophage phenotype is made, the cytokine palate is changed to anti-inflammatory and healing and angiogenesis is promoted. PMN: polymorphonucleosides, Mϕ: macrophage.

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

4

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

(ECM) and phagocytose cell debris, thereby starting to clean up of the infarcted area. After approximately three days after MI, macrophages appear in large numbers at the infarct border and slowly make their way through the whole infarcted area [47]. Arriving monocytes can either become the classically activated M1 macrophage, or, by other means convert into the alternatively activated M2 macrophage. In the postMI heart, first an infiltration of M1 macrophages occurs, which stimulate local inflammation by secretion of pro-inflammatory cytokines, such as IL-1β, IL-6, TNFα and IFNγ [59,60]. These macrophages produce many matrix metalloproteinases (MMPs), which lead to further degradation of the extracellular matrix (ECM) [59,60], making it easier to phagocytose both the cellular debris and neutrophil remains in the infarcted area. Five days after MI, M2 macrophages become more prevalent [61]. The M2 macrophages secrete an anti-inflammatory mixture of cytokines, characterized by high levels of IL-10 and TGF-β1 and low levels of IL-1, IL-6, TNFα and IFNγ [59,60]. Compared to the M1, M2 macrophages also secrete high levels of basic fibroblast growth factor (bFGF), thereby creating the right environment for wound healing and scar formation. In addition, vascular endothelial growth factor (VEGF) is produced, which stimulates angiogenesis [60]. 6. In vivo: depletion and knock-out models To investigate the importance of various components of the immune system, for cardiac inflammation upon infarction, several different in vivo models have been created. The first models created aimed at reduction of different cell types of the immune system. Depletion of neutrophils from the body prevented most inflammation-induced cardiac damage accompanied by a significantly smaller infarct size [50,62–64]. However, in a cutaneous model of wound healing the absence of cytokines and growth factors from neutrophils did not affect granulation tissue formation [65]. Nowadays, neutrophil-depletion is actually applied in cardiothoracic surgery to prevent I/R-damage, with promising results, such as a reduction in reperfusion injury after coronary revascularization with cardiopulmonary bypass [66]. In contrast, depletion of macrophages impaired wound healing and scar formation in rats, and resulted in increased mortality [50,67]. This demonstrates that macrophages, or at least one of its subtypes, are necessary for cardiac repair. However, in the attempts complete depletion of macrophages was performed, and at this moment specific subgroup depletion is not possible. Prevention of activation of the complement system can be achieved by a selective depletion of natural IgM, which was found to protect the heart from I/R injury, and reduced the inflammatory response [52,68]. Monoclonal antibodies against C5a, which play a central role in complement activation, decreased infarct size [69]. Unfortunately, both neutrophil depletion and complement inhibition are quite invasive and therefore inconvenient for large scale clinical use. Other animal models were created to investigate the role of different cytokines. Conventional knock-out mice were created for TNF receptors 1 and 2, a cytokine known for its potent pro-inflammatory effects. Surprisingly, these knock-outs resulted in a larger infarct size and increased apoptosis of cardiomyocytes [70]. This indicated that TNFα also has cardio-protective functions after MI. It is likely that the exact effect of TNFα depends on the concentration as well as on the TNF receptor it binds [70,71]. One of the cytokines that attracts neutrophils to the site of injury is IL-8. Inhibition of this chemokine with neutralizing antibodies gave a significantly smaller infarct size, yet it did not affect the invasion of neutrophils in the cardiac tissue [72]. A knock-out model for IL-1R strongly diminished neutrophilic inflammation after cell death [50,73,74], while lacking the active form of IL-1B leads to improved survival with reduced cardiac (LV) remodeling [75]. Knock-out models were created for several TLR to determine their role in post-infarct inflammation. Most of these showed no effect on cardiac inflammation, except in the case of TLR2−/− and TLR4−/−

mice, where a reduced mortality was observed as well as decreased LV remodeling [50,76,77]. It appears that especially TLR2 on the circulating cells, rather than the cardiomyocytes, was the mediator of TLR2-induced reperfusion injury [53]. Since all of the signaling via TLR depends on NF-κB activation and subsequent signaling, NF-κB subunit p50−/− mice were used to follow-up these studies. These mice displayed less I/R damage and there was a strong reduction in the influx of neutrophils. This resulted in decreased LV remodeling with a preserved LV function [78]. This effect was completely based on the NF-κB −/− status of bone marrow cells [78]. NF-κB signaling by TLR2 and TLR4 leads to the activation of various downstream signaling pathways, one of which is MyD66. Knock-out models of MyD66 have almost no neutrophilic response to cell death, while macrophage response remains normal [76].

7. Interactions between MSC and the immune system The immune response after myocardial infarction is complex and still not entirely understood. It has however become clear that a general suppression of the immune system is not beneficial in the setting of post-MI inflammation, as many necessary and beneficial actions of the immune cells will also be suppressed. The goal for treatment of post-MI inflammation should be to prevent collateral damage from the inflammatory response, while boosting the healing component. MSC are known to modulate the immune system and are currently being tried in various diseases to shift the balance of the immune response to a more tolerant type. Based on previously discovered interactions between MSC and the immune system, we can speculate what the beneficial effect of MSC treatment on post-MI inflammation can be. Although over the years many molecules and pathways have been implied in MSC-dependent immunomodulation, several pathways are reported, including IDO, PGE2, IL-10, NO and TGF-β1, not limited to specific immune cell types. For a better understanding of the mechanism, through which MSC can modulate different immune cells, the major pathways will be shortly summarized. Currently, one of the most popular enzymes in immunomodulation by MSC is indoleamine-pyrrole 2,3-dioxygenase (IDO). IDO is an intracellular enzyme, which is up-regulated in pro-inflammatory environments and partly controlled by NF-kB [79–81]. IDO is involved in tryptophan metabolism expression and leads to local tryptophan depletion and accumulation of metabolites, such as kynurenic acid (KYNA) and kynurenine. Whether IDO only interacts with immune cells via the tryptophan–kynurenine pathway, is still unknown. Another powerful modulator of the immune system is prostaglandin E2 (PGE2). PGE2 is a lipid compound produced by cyclooxygenases (COX-1 and COX-2) and secreted by MSC [80,82,83]. In response to pro-inflammatory stimulation, PGE2 production by COX-2 is sharply increased [80]. PGE2 can have many effects on different cells types and processes, such as cytokine secretion and T-cell differentiation, however the mechanism remains poorly understood. Another MSC mediator in immunomodulation is nitric oxide (NO) produced by the intrinsic nitric oxide synthase (iNOS). As NO is an unstable compound, signaling with NO only reaches those cells located near the MSC. Although initial reports on murine MSC attributed many effects to NO signaling, it was later found that in humans this pathway is of lower significance [81]. Transforming growth factor B1 (TGF-β1) is a protein known to play important roles in tissue regeneration, cell differentiation and immune regulation. TGF-β1 is produced by MSC but also by macrophages, which might explain why it can both stimulate and suppress the immune system, likely depending on the local environment, concentration and the receptor it binds [79,84]. The last cytokine discussed here is IL-10, an anti-inflammatory cytokine produced by various cells of the immune system and MSC [7,80,85]. IL-10 can alter cytokine secretion from target cells and can also trigger immune cells to differentiate towards a specific subtype [7,85].

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

7.1. MSC vs neutrophils Neutrophils play a major role in the early immune response, yet surprisingly little research has focused on the interaction between MSC and neutrophils. Neutrophils are short-living cells, developed in and released from the bone marrow upon perception of inflammatory chemotactic signals, such as IL-1 and IL-8. In the bone marrow, large numbers of mature neutrophils are retained near the MSC [86,87]. It is thought that MSC protect these neutrophil pools from apoptosis, while preventing inappropriate activation and release of granules to prevent accidental damage to the bone marrow [87]. However, when these cells are released into the blood stream, upon inflammatory signaling, the effector functions should immediately be fully functional [87,88]. This indicates that the effect of MSC is probably local and temporal, pointing to a paracrine process. The mechanisms via which MSC could be used and thereby interact with neutrophils in the post-MI inflammation are schematically depicted in Fig. 3. Most research on MSC-neutrophil interactions has focused on modulation of neutrophil survival and granule release. Both are essential for retaining a neutrophil pool in the bone marrow. In vitro, it was indeed found that co-culture of MSC and neutrophils significantly prolonged neutrophil life-span [87,89]. This anti-apoptotic effect lasted for about 40 h in culture and was strongest in high ratio of numbers of neutrophils to MSC [89]. A key factor in this process is MSC-derived IL-6, which activates STAT3 transcription factors, thereby prolonging the neutrophilic lifespan [87,89]. The implications

of an increased life span are still unclear: prolonging the life of a damaging cell in an already damaged heart seems counterintuitive. Fortunately, some researchers looked into the effect of MSC on the destructive degranulation of neutrophils. They found that in the presence of MSC, neutrophil granule release is reduced or inhibited [87,89,90]. One of the factors found to influence neutrophilic degranulation is IDO, which was found to inhibit the release of human neutrophil peptide 1–3 (HNP1-3), better known as defensin-α [90]. Defensin-α is a group of proteins stored in the neutrophilic granules with various pro-inflammatory functions. They induce adhesion and expression of co-stimulatory molecules and promote oxidative stress. Defensin-α also inhibits fibrinolysis and block angiogenesis. At high concentrations defensin-α even has a cytotoxic effect [91]. Blocking the secretion of these proteins by inhibition of degranulation could be very beneficial in the post-MI setting. It is interesting to note that synthesis of defensin-α is not altered in the presence of KYNA, a tryptophan metabolite, confirming that immune modulation by MSC is a local and temporary process [90]. MSC inhibit basal and N-formyl-L-methionin-L‐leucyl-L-phenylalanine (f-MLP)-induced respiratory burst, thereby reducing the tissue-damaging potential of neutrophils on the myocardium [87]. Whether this also depends on IDO or another pathway is not yet known. When the MSC were pre-conditioned by activating TLR3 and TLR4, mimicking a bacterial infection, both survival and bactericidal capacity of neutrophils was increased in co-culture [89]. As TLR activation by DAMPs is reported after MI [49], it will be interesting to see whether MSC will suppress or stimulate the infiltrating neutrophils in the post-MI setting (Fig. 4).

lifespan

Neutrophils

ROS release

5

tissue migration

STAT3 activation

IL-6

KYNA accumulation

TGF-β

IDO

MSC

Fig. 3. Schematic overview of the interactions between MSC and neutrophils. MSC trigger an IL-6 dependent increase in neutrophil lifespan. In addition, they can reduce the amount of reactive oxygen species (ROS) production and release. One of the pathways involved in this process is IDO-related KYNA accumulation. Different reports exist on the effect on tissue migration and adhesion, although TGF-β1 appears to increase chemotaxis yet reduce adhesion to ICAM-1.

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

6

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

IL-10

Mφ1

IL-4 IL-13 IL-10

IFNγ

Mφ2

Mφ

IL-8

PGE2

TNFα IL-1 IL-6 IL-10 TGF-β

NO

COX-2

MSC

IDO

Fig. 4. Schematic overview of the interactions between MSC and macrophages. MSC trigger macrophages to differentiate towards the anti-inflammatory M2 macrophage. Different mechanisms appear to be involved in this process, amongst which IDO, TGF-β, IL-10 and PGE2 are the most important ones. In addition, the production and release of proinflammatory cytokines by macrophages is reduced.

The effects of MSC on neutrophil tissue migration and adhesion molecules expression remain unclear. Sometimes MSC are considered not to have any effects on these processes [87], while other groups do find substantial changes [84,92]. For example, KYNA is an endogenous ligand to GPR35, a receptor expressed on neutrophils and monocytes [93]. Interaction between KYNA and GPR35 resulted in strong adhesion of neutrophils to ICAM-1 expressing cells [92]. Among these ICAM-1 expressing cells are not only endothelial cells, but also cardiomyocytes [56–58]. The in vivo effect of this binding remains unclear, as strong adherence of neutrophils to ICAM-1 on endothelial cells might reduce extravasation, while binding to cardiomyocytes could increase damage due to the respiratory burst. Furthermore, TGF-β1 produced by MSC has a strong chemotactic effect on neutrophils and monocytes. Yet when endothelial cells are exposed to TGF-β1 or IL-10 they reduce E-selectin expression, thereby preventing immune cell extravasation [7,94]. Moreover, TGF-β1 can inhibit neutrophil cytotoxicity [95]. Whether the pro- or anti-inflammatory effect will have the overhand, likely depends on the local environment and the concentration of TGF-β1 [84]. In summary, although it has not yet been investigated in the post-MI setting, we hypothesize that MSC therapy after MI could reduce extravasation and degranulation of neutrophils, thereby preventing substantial collateral damage. As no effect on the phagocytotic capacity has been found [87], neutrophils can still scavenge the dead material and thus play their part in the healing process. The prolonged lifespan should not be problematic as long as the respiratory burst is strongly down-regulated.

7.2. MSC vs macrophages Considering the dual role macrophages have in inflammation and tissue repair, most in vitro research on MSC-macrophage interaction has focused on the switch towards the M1 or M2 phenotype. In fact, it was found that when MSC are co-cultured with macrophages they trigger the macrophage to go towards the anti-inflammatory M2 phenotype [80,96–98]. Different pathways were found to be involved in this process, such as the PGE2 pathway [96,98], the IDO-pathway [80] and MSC-derived IL-10 [97]. The use of specific inhibitors for both IDO and PGE2 reduced the beneficial effects [79,80,98]. Others found IL-10, which is constantly produced by MSC [99], could direct the switch to the M2 phenotypes, while anti-IL-10 significantly reduced the number of M2 macrophages [97]. By inducing a cellular switch towards a more immuno-tolerant and reparative phenotype, MSC also reduce the amount of pro-inflammatory cytokines produced by macrophages, such as IL-1b, IL-6, TNFα and IFNγ [97,98], while anti-inflammatory cytokine secretion, especially IL-10, is markedly increased [96,97]. These changes in cytokine production are thought to be attributable to PGE2 and TGF-β1 [7,84,96]. This cytokine profile reduces the lymphocyte activation in the inflammatory response and is even thought to help generate regulatory T-cells, as will be explained in the next section. This aids the generation of a reparative environment in the damaged tissue, in which fibroblast activation, collagen deposition and angiogenesis more readily occur [7]. Furthermore, phagocytosis, the most important function of macrophages, is boosted in the presence of MSC [7,98].

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

Two in vivo models confirm the in vitro findings [96,97]. A mouse model of inflammation was created by inducing sepsis in mice [96]. MSC therapy significantly reduced mortality during sepsis and it was found that these beneficial effects were related solely to the alternative activation of macrophages. In fact, macrophage depletion abrogated this effect [96]. In addition, in a mouse model of myocardial infarction, where MSC were infused 48 h after MI [97], an overall reduction of monocyte levels was observed within 24 h, while the proportion of M2 macrophages was strongly increased. After 16 weeks LV remodeling was significantly reduced, while no difference in angiogenesis in the infarct area was observed. A short-term beneficial effect was found on fractional shortening, yet no long term cardiac functional difference to control was found. These results were suggested to be related to the positive inotropic effect of IL-10 and a reduction in negative inotropes, such as IL-1 and IL-6 [97]. In short, MSC can trigger macrophages to create an antiinflammatory environment, where the emphasis is on regeneration rather than destruction. The removal of necrotic tissue is boosted, while cardiac remodeling was reduced. Although more research on the effect of MSC on macrophages in the post-MI will be necessary, the switch to M2 macrophages appears promising. 7.3. MSC vs T-cells Most research on the immuno-modulative capacities of MSC has focused on the interaction with T-cells, due to their role in Graftversus-Host-Disease (GVHD). In acute post-MI inflammation their role is unclear [100]. A number of articles were published investigating the possibility of an immune response against cardiac self-antigens. Maisel and colleagues isolated splenocytes after MI in rats and injected these splenocytes after activation with ConA into healthy syngeneic rats [101]. After six weeks, they found lymphocyte mediated myocardial injury in the recipient rats, while no infiltrates were observed in other organs. Additionally, lymphocytes were isolated from rat spleen after MI and added to syngeneic rat myocytes in vitro [100]. The isolated lymphocytes, mainly cytotoxic T-cells (TC-cells), had a strong capacity to damage cardiac myocytes. Interestingly, it took some time for these auto-reactive lymphocytes to be formed. The harmful effect of the lymphocytes was not visible after one week, but increased over time and showed the strongest effect when the lymphocytes were isolated three weeks after MI. This indicates that auto-reactive lymphocytes are formed after MI, which can also respond to auto-antigens expressed on healthy cardiomyocytes [100–102]. This delayed immune attack on the heart could affect cardiac remodeling [103–105]. Recent research identified a systemic shift towards the TH1 subclass of T-helper-lymphocytes after MI [106]. The TH1 lymphocytes play an important role in the cellular component of the adaptive immune response, where they activate cytotoxic T-cells and maximize bactericidal activity of phagocytes, such as neutrophils and macrophages. Even though they do not attack the myocardium themselves, these TH1-lymphocytes could trigger TC-cells to become auto-reactive. These TH1-lymphocytes also produce high levels of pro-inflammatory cytokines, thereby suppressing the formation of so-called regulatory T-cells (Treg) and TH2 [79]. Treg are a specialized sub-population of T cells, CD4+ CD25+ FoxP3+, known to suppress activation of the immune system and maintaining tolerance to self-antigens. The presence of Treg reduces the inflammatory reaction and protects against adverse ventricular remodeling [105]. Inhibition of Treg formation allows a stronger auto-reactive cardiac response, thereby creating more cardiac damage. TH2 cells are involved in humoral immunity, where they induce B-cell maturation [79]. Contrary to TH1, they do not enhance cytotoxic or phagocytic activity. Accordingly, their cytokine production is more immunosuppressive, including IL-10 and IL-4. However, due to the relatively long activation and proliferation time needed by T-lymphocytes, this immune response does not take place immediately following MI, but builds up over the weeks after injury [100].

7

In the past ten years, many different mechanisms for T-cell suppression by MSC have been proposed (see Fig. 5). Again IDO and PGE2 are the most popularly studied. It is thought that IDO-induced tryptophan depletion and accumulation of metabolites, such as KYNA and kynurenine, are responsible for inhibiting the proliferation of T-cells. In addition to a reduction in proliferation, IDO was also found to promote a switch towards Treg, as implied by the expression of FoxP3. Similar actions in human MSC have been described for prostaglandin-E2 (PGE2). PGE2 was also shown to inhibit T-cell proliferation and promote Treg formation directly [107]. Other factors with potential roles in MSC–T-cell interaction are TGF-β1 and IL-10. Both IL-10 and TGF-β are produced by MSC [99] and affect the ratio of T-cell subtypes. Whereas TGF-β1 is involved in the induction of Treg formation [79,108,109], IL-10 shifts cells towards the TH2 phenotype by blocking TH1 differentiation [79]. Both these subtypes of T-lymphocytes reduce the amount of pro-inflammatory cytokines produced. The additional advantage of an increased percentage of TH2 cells is that IL-4, produced in large quantities by TH2 cells, promotes the formation of M2 macrophages [110]. In conclusion, despite the uncertainties which still exist on the exact mechanism(s) involved, we know that MSC affect T-cell response by strongly inhibiting proliferation and simultaneously altering the TH1/TH2 ratio. This leads to a larger percentage of Treg cells, which create an immuno-tolerant environment and more TH2 cells, suppressing the formation of TH1 lymphocytes. Meanwhile, cell-mediated immune response via TH1 cells, recruiting more TC-cells and neutrophils, is strongly suppressed. 8. Targeting post-MI inflammation with MSC The post-infarct inflammatory response is a necessary reaction, which clears cellular debris and initiates the healing pathways. However, this early infiltration causes cytotoxic injury to the surviving cardiomyocytes as well. Therefore clinicians and researchers have tried over thirty years to find a way to promote the beneficial effects of this immune response, while suppressing the detrimental results. Where past pharmaceutical options have failed, cardiac stem cell therapy with MSC might provide a solution. In the last decade the immunomodulatory potential of MSC has generated hope for treatment of many immune-related diseases. MSC have been found to interact with all cells of the immune system, where they gently steer the immune reaction towards an anti-inflammatory response. Although the exact mechanisms by which this is achieved remain unclear, it is quite likely that various dependent and independent pathways modulate different aspects of immunomodulation. This could also explain why different groups find different molecules or pathways to be the protagonist in immunomodulation. Additionally, the exact set up of the experiment, the types of immune cell(s) present and the mode of activation could augment these observed differences. However, to use MSC as a treatment for post-MI inflammation it is essential to know the course of this process. Knowledge on the cell types present and processes at play can help pick the optimal time-frame for MSC-administration and achieve the best results. Interestingly, a recent meta-analysis on cardiac stem cell therapy [44] showed that the optimal effect of the therapy is reached with stem cell injection at least a week after MI [44]. This could imply that stem cell therapy is best given when the pro-inflammatory reaction in the heart has switched towards a reparative environment. Using stem cell therapy at an earlier time point could, besides reducing inflammation-related damage, create this healing environment sooner. A second stem cell injection within a few days could create a synergism, when both the endogenous repair mechanisms and the boost of the stem cells together improves cardiac repair. Lastly, in vitro research elucidating potential pathways is interesting for scientific insight; however, it is impossible to recreate the immune system with its complex interactions between the different components in vitro. More focus should be on in vivo elucidation of immunosuppressive potential of

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

8

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

Fig. 5. Schematic overview of the interactions between MSC and T-cells. Co-culture of MSC and T-cells results in reduced T-cell proliferation and a decreased pro-inflammatory cytokine production. In addition, differentiation to TH2 and regulatory T-cells is triggered, resulting in an anti-inflammatory environment.

MSC by measuring long- and short-term effects on tissue repair and function. Animal models can be created in which pathways thought to be involved are knocked-out, to estimate the true involvement of that mediator. Only hereby direct effects of stem cells can be studied on inflammation. Acknowledgements This work was supported by a grant from the Alexandre Suerman program for MD/PhD students of the University Medical Center Utrecht, the Netherlands. References [1] V.L. Roger, A.S. Go, D.M. Lloyd-Jones, E.J. Benjamin, J.D. Berry, W.B. Borden, D.M. Bravata, S. Dai, E.S. Ford, C.S. Fox, H.J. Fullerton, C. Gillespie, S.M. Hailpern, J.A. Heit, V.J. Howard, B.M. Kissela, S.J. Kittner, D.T. Lackland, J.H. Lichtman, L.D. Lisabeth, D.M. Makuc, G.M. Marcus, A. Marelli, D.B. Matchar, C.S. Moy, D. Mozaffarian, M.E. Mussolino, G. Nichol, N.P. Paynter, E.Z. Soliman, P.D. Sorlie, N. Sotoodehnia, T.N. Turan, S.S. Virani, N.D. Wong, D. Woo, M.B. Turner, Executive summary: heart disease and stroke statistics—2012 update: a report from the American Heart Association, Circulation 125 (1) (2012) 188–197. [2] N.G. Frangogiannis, C.W. Smith, M.L. Entman, The inflammatory response in myocardial infarction, Cardiovasc. Res. 53 (1) (2002) 31–47. [3] G. Vilahur, O. Juan-Babot, E. Pena, B. Onate, L. Casani, L. Badimon, Molecular and cellular mechanisms involved in cardiac remodeling after acute myocardial infarction, J. Mol. Cell. Cardiol. 50 (3) (2011) 522–533. [4] T. Harel-Adar, T. Ben Mordechai, Y. Amsalem, M.S. Feinberg, J. Leor, S. Cohen, Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair, Proc. Natl. Acad. Sci. U. S. A. 108 (5) (2010) 1827–1832. [5] F. Eefting, B. Rensing, J. Wigman, W.J. Pannekoek, W.M. Liu, M.J. Cramer, D.J. Lips, P.A. Doevendans, Role of apoptosis in reperfusion injury, Cardiovasc. Res. 61 (3) (2004) 414–426.

[6] W.A. Noort, D. Feye, F. Van Den Akker, D. Stecher, S.A. Chamuleau, J.P. Sluijter, P.A. Doevendans, Mesenchymal stromal cells to treat cardiovascular disease: strategies to improve survival and therapeutic results, Panminerva Med. 52 (1) (2010) 27–40. [7] N.G. Frangogiannis, Regulation of the inflammatory response in cardiac repair, Circ. Res. 110 (1) (2012) 159–173. [8] G.R. Giugliano, R.P. Giugliano, C.M. Gibson, R.E. Kuntz, Meta-analysis of corticosteroid treatment in acute myocardial infarction, Am. J. Cardiol. 91 (9) (2003) 1055–1059. [9] D.E. Sholter, P.W. Armstrong, Adverse effects of corticosteroids on the cardiovascular system, Can. J. Cardiol. 16 (4) (2000) 505–511. [10] L. Timmers, J.P. Sluijter, C.W. Verlaan, P. Steendijk, M.J. Cramer, M. Emons, C. Strijder, P.F. Grundeman, S.K. Sze, L. Hua, J.J. Piek, C. Borst, G. Pasterkamp, D.P. de Kleijn, Cyclooxygenase-2 inhibition increases mortality, enhances left ventricular remodeling, and impairs systolic function after myocardial infarction in the pig, Circulation 115 (3) (2007) 326–332. [11] H. Hammerman, R.A. Kloner, F.J. Schoen, E.J. Brown Jr., S. Hale, E. Braunwald, Indomethacin-induced scar thinning after experimental myocardial infarction, Circulation 67 (6) (1983) 1290–1295. [12] E.J. Brown Jr., R.A. Kloner, F.J. Schoen, H. Hammerman, S. Hale, E. Braunwald, Scar thinning due to ibuprofen administration after experimental myocardial infarction, Am. J. Cardiol. 51 (5) (1983) 877–883. [13] G.H. Gislason, S. Jacobsen, J.N. Rasmussen, S. Rasmussen, P. Buch, J. Friberg, T.K. Schramm, S.Z. Abildstrom, L. Kober, M. Madsen, C. Torp-Pedersen, Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction, Circulation 113 (25) (2006) 2906–2913. [14] E.D. Thomas, H.L. Lochte Jr., W.C. Lu, J.W. Ferrebee, Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy, N. Engl. J. Med. 257 (11) (1957) 491–496. [15] E.D. Thomas, R.B. Epstein, Bone marrow transplantation in acute leukemia, Cancer Res. 25 (9) (1965) 1521–1524. [16] A.J. Nauta, W.E. Fibbe, Immunomodulatory properties of mesenchymal stromal cells, Blood 110 (10) (2007) 3499–3506. [17] W.A. Noort, M.I. Oerlemans, H. Rozemuller, D. Feyen, S. Jaksani, D. Stecher, B. Naaijkens, A.C. Martens, H.J. Buhring, P.A. Doevendans, J.P. Sluijter, Human versus porcine mesenchymal stromal cells: phenotype, differentiation potential, immunomodulation and cardiac improvement after transplantation, J. Cell. Mol. Med. 16 (8) (2012) 1827–1839.

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx [18] K. Le Blanc, C. Tammik, K. Rosendahl, E. Zetterberg, O. Ringden, HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells, Exp. Hematol. 31 (10) (2003) 890–896. [19] O. DelaRosa, E. Lombardo, Modulation of adult mesenchymal stem cells activity by toll-like receptors: implications on therapeutic potential, Mediat. Inflamm. 2010 (2010) 865601. [20] M. Gnecchi, H. He, O.D. Liang, L.G. Melo, F. Morello, H. Mu, N. Noiseux, L. Zhang, R.E. Pratt, J.S. Ingwall, V.J. Dzau, Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells, Nat. Med. 11 (4) (2005) 367–368. [21] M. Gnecchi, H. He, N. Noiseux, O.D. Liang, L. Zhang, F. Morello, H. Mu, L.G. Melo, R.E. Pratt, J.S. Ingwall, V.J. Dzau, Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement, FASEB J. 20 (6) (2006) 661–669. [22] R. Schafer, H. Northoff, Cardioprotection and cardiac regeneration by mesenchymal stem cells, Panminerva Med. 50 (1) (2008) 31–39. [23] R. Moghadasali, H.A. Mutsaers, M. Azarnia, N. Aghdami, H. Baharvand, R. Torensma, M.J. Wilmer, R. Masereeuw, Mesenchymal stem cell-conditioned medium accelerates regeneration of human renal proximal tubule epithelial cells after gentamicin toxicity, Exp. Toxicol. Pathol. (in press), http://dx.doi.org/10. 1016/j.etp.2012.06.002. [24] L. Bai, D.P. Lennon, A.I. Caplan, A. Dechant, J. Hecker, J. Kranso, A. Zaremba, R.H. Miller, Hepatocyte growth factor mediates mesenchymal stem cell-induced recovery in multiple sclerosis models, Nat. Neurosci. 15 (6) (2012) 862–870. [25] H. Valadi, K. Ekstrom, A. Bossios, M. Sjostrand, J.J. Lee, J.O. Lotvall, Exosomemediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells, Nat. Cell Biol. 9 (6) (2007) 654–659. [26] R.C. Lai, F. Arslan, M.M. Lee, N.S. Sze, A. Choo, T.S. Chen, M. Salto-Tellez, L. Timmers, C.N. Lee, R.M. El Oakley, G. Pasterkamp, D.P. de Kleijn, S.K. Lim, Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury, Stem Cell Res. 4 (3) (2010) 214–222. [27] M. Mineo, S.H. Garfield, S. Taverna, A. Flugy, G. De Leo, R. Alessandro, E.C. Kohn, Exosomes released by K562 chronic myeloid leukemia cells promote angiogenesis in a Src-dependent fashion, Angiogenesis 15 (1) (2012) 33–45. [28] K.R. Vrijsen, J.P. Sluijter, M.W. Schuchardt, B.W. van Balkom, W.A. Noort, S.A. Chamuleau, P.A. Doevendans, Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells, J. Cell. Mol. Med. 14 (5) (2010) 1064–1070. [29] C. Thery, L. Zitvogel, S. Amigorena, Exosomes: composition, biogenesis and function, Nat. Rev. Immunol. 2 (8) (2002) 569–579. [30] M. Di Nicola, C. Carlo-Stella, M. Magni, M. Milanesi, P.D. Longoni, P. Matteucci, S. Grisanti, A.M. Gianni, Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli, Blood 99 (10) (2002) 3838–3843. [31] K. Le Blanc, I. Rasmusson, B. Sundberg, C. Gotherstrom, M. Hassan, M. Uzunel, O. Ringden, Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells, Lancet 363 (9419) (2004) 1439–1441. [32] O. Ringden, M. Uzunel, I. Rasmusson, M. Remberger, B. Sundberg, H. Lonnies, H.U. Marschall, A. Dlugosz, A. Szakos, Z. Hassan, B. Omazic, J. Aschan, L. Barkholt, K. Le Blanc, Mesenchymal stem cells for treatment of therapyresistant graft-versus-host disease, Transplantation 81 (10) (2006) 1390–1397. [33] K. Le Blanc, H. Samuelsson, B. Gustafsson, M. Remberger, B. Sundberg, J. Arvidson, P. Ljungman, H. Lonnies, S. Nava, O. Ringden, Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells, Leukemia 21 (8) (2007) 1733–1738. [34] A. Bartholomew, C. Sturgeon, M. Siatskas, K. Ferrer, K. McIntosh, S. Patil, W. Hardy, S. Devine, D. Ucker, R. Deans, A. Moseley, R. Hoffman, Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo, Exp. Hematol. 30 (1) (2002) 42–48. [35] F. Casiraghi, N. Azzollini, P. Cassis, B. Imberti, M. Morigi, D. Cugini, R.A. Cavinato, M. Todeschini, S. Solini, A. Sonzogni, N. Perico, G. Remuzzi, M. Noris, Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells, J. Immunol. 181 (6) (2008) 3933–3946. [36] F. Djouad, V. Fritz, F. Apparailly, P. Louis-Plence, C. Bony, J. Sany, C. Jorgensen, D. Noel, Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis, Arthritis Rheum. 52 (5) (2005) 1595–1603. [37] F. Dazzi, M. Krampera, Mesenchymal stem cells and autoimmune diseases, Best Pract. Res. Clin. Haematol. 24 (1) (2011) 49–57. [38] A. Tyndall, J.M. van Laar, Stem cells in the treatment of inflammatory arthritis, Best Pract. Res. Clin. Rheumatol. 24 (4) (2010) 565–574. [39] U.P. Singh, N.P. Singh, B. Singh, M.K. Mishra, M. Nagarkatti, P.S. Nagarkatti, S.R. Singh, Stem cells as potential therapeutic targets for inflammatory bowel disease, Front Biosci. (Schol. Ed.) 2 (2010) 993–1008. [40] T. Ben-Hur, Immunomodulation by neural stem cells, J. Neurol. Sci. 265 (1–2) (2008) 102–104. [41] S.Y. Kim, H.S. Cho, S.H. Yang, J.Y. Shin, J.S. Kim, S.T. Lee, K. Chu, J.K. Roh, S.U. Kim, C.G. Park, Soluble mediators from human neural stem cells play a critical role in suppression of T-cell activation and proliferation, J. Neurosci. Res. 87 (10) (2009) 2264–2272. [42] R. Melzi, B. Antonioli, A. Mercalli, M. Battaglia, A. Valle, S. Pluchino, R. Galli, V. Sordi, E. Bosi, G. Martino, E. Bonifacio, C. Doglioni, L. Piemonti, Co-graft of allogeneic immune regulatory neural stem cells (NPC) and pancreatic islets mediates tolerance, while inducing NPC-derived tumors in mice, PLoS One 5 (4) (2010) e10357. [43] S. Pluchino, L. Zanotti, B. Rossi, E. Brambilla, L. Ottoboni, G. Salani, M. Martinello, A. Cattalini, A. Bergami, R. Furlan, G. Comi, G. Constantin, G. Martino,

[44]

[45] [46]

[47] [48]

[49] [50] [51] [52]

[53]

[54]

[55]

[56]

[57]

[58]

[59] [60]

[61]

[62]

[63]

[64] [65] [66]

[67]

[68]

9

Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism, Nature 436 (7048) (2005) 266–271. T.I. van der Spoel, S.J. Jansen of Lorkeers, P. Agostoni, E. van Belle, M. Gyongyosi, J.P. Sluijter, M.J. Cramer, P.A. Doevendans, S.A. Chamuleau, Human relevance of preclinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease, Cardiovasc. Res. 91 (4) (2011) 649–658. V.F. Segers, R.T. Lee, Stem-cell therapy for cardiac disease, Nature 451 (7181) (2008) 937–942. A.M. Smits, L.W. van Laake, K. den Ouden, C. Schreurs, K. Szuhai, C.J. van Echteld, C.L. Mummery, P.A. Doevendans, M.J. Goumans, Human cardiomyocyte progenitor cell transplantation preserves long-term function of the infarcted mouse myocardium, Cardiovasc. Res. 83 (3) (2009) 527–535. In: V. Kumar, N. Fausto, A. Abbas (Eds.), Robbins & Cotran Pathologic Basis of Disease, 7th ed., Elsevier Saunders, Philadelphia, 2007. M. Oerlemans, S. Koudstaal, S. Chamuleau, D. de Kleijn, P. Doevendans, J. Sluijter, Targeting cell death in the reperfused heart: pharmacological approaches for cardioprotection, Int. J. Cardiol. (in press), http://dx.doi.org/10.1016/j.ijcard. 2012.03.055. F. Arslan, D.P. de Kleijn, G. Pasterkamp, Innate immune signaling in cardiac ischemia, Nat. Rev. Cardiol. 8 (5) (2011) 292–300. S. Frantz, J. Bauersachs, G. Ertl, Post-infarct remodelling: contribution of wound healing and inflammation, Cardiovasc. Res. 81 (3) (2009) 474–481. S. Gallucci, P. Matzinger, Danger signals: SOS to the immune system, Curr. Opin. Immunol. 13 (1) (2001) 114–119. M. Zhang, L.H. Michael, S.A. Grosjean, R.A. Kelly, M.C. Carroll, M.L. Entman, The role of natural IgM in myocardial ischemia-reperfusion injury, J. Mol. Cell. Cardiol. 41 (1) (2006) 62–67. F. Arslan, M.B. Smeets, L.A. O'Neill, B. Keogh, P. McGuirk, L. Timmers, C. Tersteeg, I.E. Hoefer, P.A. Doevendans, G. Pasterkamp, D.P. de Kleijn, Myocardial ischemia/ reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody, Circulation 121 (1) (2010) 80–90. J. Tillmanns, H. Carlsen, R. Blomhoff, G. Valen, L. Calvillo, G. Ertl, J. Bauersachs, S. Frantz, Caught in the act: in vivo molecular imaging of the transcription factor NF-kappaB after myocardial infarction, Biochem. Biophys. Res. Commun. 342 (3) (2006) 773–774. F. Liotta, R. Angeli, L. Cosmi, L. Fili, C. Manuelli, F. Frosali, B. Mazzinghi, L. Maggi, A. Pasini, V. Lisi, V. Santarlasci, L. Consoloni, M.L. Angelotti, P. Romagnani, P. Parronchi, M. Krampera, E. Maggi, S. Romagnani, F. Annunziato, Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling, Stem Cells 26 (1) (2008) 279–289. K. Youker, C.W. Smith, D.C. Anderson, D. Miller, L.H. Michael, R.D. Rossen, M.L. Entman, Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusion, J. Clin. Invest. 89 (2) (1992) 602–609. C.W. Smith, M.L. Entman, C.L. Lane, A.L. Beaudet, T.I. Ty, K. Youker, H.K. Hawkins, D.C. Anderson, Adherence of neutrophils to canine cardiac myocytes in vitro is dependent on intercellular adhesion molecule-1, J. Clin. Invest. 88 (4) (1991) 1216–1223. G.L. Kukielka, H.K. Hawkins, L. Michael, A.M. Manning, K. Youker, C. Lane, M.L. Entman, C.W. Smith, D.C. Anderson, Regulation of intercellular adhesion molecule-1 (ICAM-1) in ischemic and reperfused canine myocardium, J. Clin. Invest. 92 (3) (1993) 1504–1516. J.M. Lambert, E.F. Lopez, M.L. Lindsey, Macrophage roles following myocardial infarction, Int. J. Cardiol. 130 (2) (2008) 147–158. M. Nahrendorf, F.K. Swirski, E. Aikawa, L. Stangenberg, T. Wurdinger, J.L. Figueiredo, P. Libby, R. Weissleder, M.J. Pittet, The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions, J. Exp. Med. 204 (12) (2007) 3037–3047. C. Troidl, H. Mollmann, H. Nef, F. Masseli, S. Voss, S. Szardien, M. Willmer, A. Rolf, J. Rixe, K. Troidl, S. Kostin, C. Hamm, A. Elsasser, Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction, J. Cell. Mol. Med. 13 (9B) (2009) 3485–3496. M.R. Litt, R.W. Jeremy, H.F. Weisman, J.A. Winkelstein, L.C. Becker, Neutrophil depletion limited to reperfusion reduces myocardial infarct size after 90 minutes of ischemia. Evidence for neutrophil-mediated reperfusion injury, Circulation 80 (6) (1989) 1816–1827. J.L. Romson, B.G. Hook, S.L. Kunkel, G.D. Abrams, M.A. Schork, B.R. Lucchesi, Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog, Circulation 67 (5) (1983) 1016–1023. K.L. Rock, H. Kono, The inflammatory response to cell death, Annu. Rev. Pathol. 3 (2008) 99–126. D.M. Simpson, R. Ross, The neutrophilic leukocyte in wound repair a study with antineutrophil serum, J. Clin. Invest. 51 (8) (1972) 2009–2023. G.M. Palatianos, G. Balentine, E.G. Papadakis, C.D. Triantafillou, M.I. Vassili, A. Lidoriki, A. Dinopoulos, G.M. Astras, Neutrophil depletion reduces myocardial reperfusion morbidity, Ann. Thorac. Surg. 77 (3) (2004) 956–961. D. Fraccarollo, P. Galuppo, S. Schraut, S. Kneitz, N. van Rooijen, G. Ertl, J. Bauersachs, Immediate mineralocorticoid receptor blockade improves myocardial infarct healing by modulation of the inflammatory response, Hypertension 51 (4) (2008) 905–914. M.R. Weiser, J.P. Williams, F.D. Moore Jr., L. Kobzik, M. Ma, H.B. Hechtman, M.C. Carroll, Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement, J. Exp. Med. 183 (5) (1996) 2343–2348.

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026

10

F. van den Akker et al. / Biochimica et Biophysica Acta xxx (2012) xxx–xxx

[69] E.A. Amsterdam, G.L. Stahl, H.L. Pan, S.V. Rendig, M.P. Fletcher, J.C. Longhurst, Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs, Am. J. Physiol. 268 (1 Pt 2) (1995) H448–H457. [70] K.M. Kurrelmeyer, L.H. Michael, G. Baumgarten, G.E. Taffet, J.J. Peschon, N. Sivasubramanian, M.L. Entman, D.L. Mann, Endogenous tumor necrosis factor protects the adult cardiac myocyte against ischemic-induced apoptosis in a murine model of acute myocardial infarction, Proc. Natl. Acad. Sci. U. S. A. 97 (10) (2000) 5456–5461. [71] P. Kleinbongard, R. Schulz, G. Heusch, TNFalpha in myocardial ischemia/ reperfusion, remodeling and heart failure, Heart Fail. Rev. 16 (1) (2011) 49–69. [72] E.M. Boyle Jr., J.C. Kovacich, C.A. Hebert, T.G. Canty Jr., E. Chi, E.N. Morgan, T.H. Pohlman, E.D. Verrier, Inhibition of interleukin-8 blocks myocardial ischemiareperfusion injury, J. Thorac. Cardiovasc. Surg. 116 (1) (1998) 114–121. [73] S. Frantz, A. Ducharme, D. Sawyer, L.E. Rohde, L. Kobzik, R. Fukazawa, D. Tracey, H. Allen, R.T. Lee, R.A. Kelly, Targeted deletion of caspase-1 reduces early mortality and left ventricular dilatation following myocardial infarction, J. Mol. Cell. Cardiol. 35 (6) (2003) 685–694. [74] S. Merkle, S. Frantz, M.P. Schon, J. Bauersachs, M. Buitrago, R.J. Frost, E.M. Schmitteckert, M.J. Lohse, S. Engelhardt, A role for caspase-1 in heart failure, Circ. Res. 100 (5) (2007) 645–653. [75] M. Bujak, M. Dobaczewski, K. Chatila, L.H. Mendoza, N. Li, A. Reddy, N.G. Frangogiannis, Interleukin-1 receptor type I signaling critically regulates infarct healing and cardiac remodeling, Am. J. Pathol. 173 (1) (2008) 57–67. [76] C.J. Chen, H. Kono, D. Golenbock, G. Reed, S. Akira, K.L. Rock, Identification of a key pathway required for the sterile inflammatory response triggered by dying cells, Nat. Med. 13 (7) (2007) 851–856. [77] F. Arslan, B. Keogh, P. McGuirk, A.E. Parker, TLR2 and TLR4 in ischemia reperfusion injury, Mediat. Inflamm. 2010 (2010) 704202. [78] S. Frantz, J. Tillmanns, P.J. Kuhlencordt, I. Schmidt, A. Adamek, C. Dienesch, T. Thum, S. Gerondakis, G. Ertl, J. Bauersachs, Tissue-specific effects of the nuclear factor kappaB subunit p50 on myocardial ischemia-reperfusion injury, Am. J. Pathol. 171 (2) (2007) 507–512. [79] Y. Mandi, L. Vecsei, The kynurenine system and immunoregulation, J. Neural Transm. 119 (2) (2012) 197–209. [80] M. Francois, R. Romieu-Mourez, M. Li, J. Galipeau, Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation, Mol. Ther. 20 (1) (2012) 187–195. [81] G. Ren, J. Su, L. Zhang, X. Zhao, W. Ling, A. L'Huillie, J. Zhang, Y. Lu, A.I. Roberts, W. Ji, H. Zhang, A.B. Rabson, Y. Shi, Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression, Stem Cells 27 (8) (2009) 1954–1962. [82] M. Najar, G. Raicevic, H.I. Boufker, H. Fayyad Kazan, C. De Bruyn, N. Meuleman, D. Bron, M. Toungouz, L. Lagneaux, Mesenchymal stromal cells use PGE2 to modulate activation and proliferation of lymphocyte subsets: combined comparison of adipose tissue, Wharton's Jelly and bone marrow sources, Cell. Immunol. 264 (2) (2010) 171–179. [83] C. Bouffi, C. Bony, G. Courties, C. Jorgensen, D. Noel, IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis, PLoS One 5 (12) (2010) e14247. [84] M. Bujak, N.G. Frangogiannis, The role of TGF-beta signaling in myocardial infarction and cardiac remodeling, Cardiovasc. Res. 74 (2) (2007) 184–195. [85] W. Ouyang, S. Rutz, N.K. Crellin, P.A. Valdez, S.G. Hymowitz, Regulation and functions of the IL-10 family of cytokines in inflammation and disease, Annu. Rev. Immunol. 29 (2011) 71–109. [86] P. Bianco, P. Gehron, Robey, Marrow stromal stem cells, J. Clin. Invest. 105 (12) (2000) 1663–1668. [87] L. Raffaghello, G. Bianchi, M. Bertolotto, F. Montecucco, A. Busca, F. Dallegri, L. Ottonello, V. Pistoia, Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche, Stem Cells 26 (1) (2008) 151–162. [88] C.G. Craddock Jr., S. Perry, L.E. Ventzke, J.S. Lawrence, Evaluation of marrow granulocytic reserves in normal and disease states, Blood 15 (1960) 840–855. [89] M.A. Cassatella, F. Mosna, A. Micheletti, V. Lisi, N. Tamassia, C. Cont, F. Calzetti, M. Pelletier, G. Pizzolo, M. Krampera, Toll-like receptor-3-activated human mesenchymal stromal cells significantly prolong the survival and function of neutrophils, Stem Cells 29 (6) (2011) 1001–1011. [90] Z. Tiszlavicz, B. Nemeth, F. Fulop, L. Vecsei, K. Tapai, I. Ocsovszky, Y. Mandi, Different inhibitory effects of kynurenic acid and a novel kynurenic acid analogue on tumour necrosis factor-alpha (TNF-alpha) production by mononuclear cells, HMGB1 production by monocytes and HNP1-3 secretion by neutrophils, Naunyn Schmiedebergs Arch. Pharmacol. 383 (5) (2011) 447–455.

[91] K. Quinn, M. Henriques, T. Parker, A.S. Slutsky, H. Zhang, Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases, Am. J. Physiol. Heart Circ. Physiol. 295 (5) (2008) H1817–H1824. [92] M.C. Barth, N. Ahluwalia, T.J. Anderson, G.J. Hardy, S. Sinha, J.A. Alvarez-Cardona, I.E. Pruitt, E.P. Rhee, R.A. Colvin, R.E. Gerszten, Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions, J. Biol. Chem. 284 (29) (2009) 19189–19195. [93] J. Wang, N. Simonavicius, X. Wu, G. Swaminath, J. Reagan, H. Tian, L. Ling, Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35, J. Biol. Chem. 281 (31) (2006) 22021–22028. [94] W.B. Smith, L. Noack, Y. Khew-Goodall, S. Isenmann, M.A. Vadas, J.R. Gamble, Transforming growth factor-beta 1 inhibits the production of IL-8 and the transmigration of neutrophils through activated endothelium, J. Immunol. 157 (1) (1996) 360–368. [95] L. Shen, J.M. Smith, Z. Shen, M. Eriksson, C. Sentman, C.R. Wira, Inhibition of human neutrophil degranulation by transforming growth factor-beta1, Clin. Exp. Immunol. 149 (1) (2007) 155–161. [96] K. Nemeth, A. Leelahavanichkul, P.S. Yuen, B. Mayer, A. Parmelee, K. Doi, P.G. Robey, K. Leelahavanichkul, B.H. Koller, J.M. Brown, X. Hu, I. Jelinek, R.A. Star, E. Mezey, Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)dependent reprogramming of host macrophages to increase their interleukin-10 production, Nat. Med. 15 (1) (2009) 42–49. [97] V. Dayan, G. Yannarelli, F. Billia, P. Filomeno, X.H. Wang, J.E. Davies, A. Keating, Mesenchymal stromal cells mediate a switch to alternatively activated monocytes/macrophages after acute myocardial infarction, Basic Res. Cardiol. 106 (6) (2011) 1299–1310. [98] J. Maggini, G. Mirkin, I. Bognanni, J. Holmberg, I.M. Piazzon, I. Nepomnaschy, H. Costa, C. Canones, S. Raiden, M. Vermeulen, J.R. Geffner, Mouse bone marrowderived mesenchymal stromal cells turn activated macrophages into a regulatorylike profile, PLoS One 5 (2) (2010) e9252. [99] S.K. Sze, D.P. de Kleijn, R.C. Lai, E. Khia Way Tan, H. Zhao, K.S. Yeo, T.Y. Low, Q. Lian, C.N. Lee, W. Mitchell, R.M. El Oakley, S.K. Lim, Elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells, Mol. Cell. Proteomics 6 (10) (2007) 1680–1689. [100] N. Varda-Bloom, J. Leor, D.G. Ohad, Y. Hasin, M. Amar, R. Fixler, A. Battler, M. Eldar, D. Hasin, Cytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro, J. Mol. Cell. Cardiol. 32 (12) (2000) 2141–2149. [101] A. Maisel, D. Cesario, S. Baird, J. Rehman, P. Haghighi, S. Carter, Experimental autoimmune myocarditis produced by adoptive transfer of splenocytes after myocardial infarction, Circ. Res. 82 (4) (1998) 458–463. [102] S.L. Woodley, M. McMillan, J. Shelby, D.H. Lynch, L.K. Roberts, R.D. Ensley, W.H. Barry, Myocyte injury and contraction abnormalities produced by cytotoxic T lymphocytes, Circulation 83 (4) (1991) 1410–1418. [103] L. Wei, Immunological aspect of cardiac remodeling: T lymphocyte subsets in inflammation-mediated cardiac fibrosis, Exp. Mol. Pathol. 90 (1) (2011) 74–78. [104] Y. Matsui, N. Jia, H. Okamoto, S. Kon, H. Onozuka, M. Akino, L. Liu, J. Morimoto, S.R. Rittling, D. Denhardt, A. Kitabatake, T. Uede, Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy, Hypertension 43 (6) (2004) 1195–1201. [105] T.T. Tang, J. Yuan, Z.F. Zhu, W.C. Zhang, H. Xiao, N. Xia, X.X. Yan, S.F. Nie, J. Liu, S.F. Zhou, J.J. Li, R. Yao, M.Y. Liao, X. Tu, Y.H. Liao, X. Cheng, Regulatory T cells ameliorate cardiac remodeling after myocardial infarction, Basic Res. Cardiol 107 (1) (2012) 1–17. [106] Z. Zhao, Y. Wu, M. Cheng, Y. Ji, X. Yang, P. Liu, S. Jia, Z. Yuan, Activation of Th17/Th1 and Th1, but not Th17, is associated with the acute cardiac event in patients with acute coronary syndrome, Atherosclerosis 217 (2) (2011) 518–524. [107] K. English, J.M. Ryan, L. Tobin, M.J. Murphy, F.P. Barry, B.P. Mahon, Cell contact, prostaglandin E(2) and transforming growth factor beta 1 play non-redundant roles in human mesenchymal stem cell induction of CD4+CD25(High) forkhead box P3+ regulatory T cells, Clin. Exp. Immunol. 156 (1) (2009) 149–160. [108] M.C. Fantini, C. Becker, G. Monteleone, F. Pallone, P.R. Galle, M.F. Neurath, Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7, J. Immunol. 172 (9) (2004) 5149–5153. [109] E. Bettelli, Y. Carrier, W. Gao, T. Korn, T.B. Strom, M. Oukka, H.L. Weiner, V.K. Kuchroo, Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells, Nature 441 (7090) (2006) 235–238. [110] M. Stein, S. Keshav, N. Harris, S. Gordon, Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation, J. Exp. Med. 176 (1) (1992) 287–292.

Please cite this article as: F. van den Akker, et al., Cardiac stem cell therapy to modulate inflammation upon myocardial infarction, Biochim. Biophys. Acta (2012), http://dx.doi.org/10.1016/j.bbagen.2012.08.026