Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

Lee, Chang Youn; Kim, Ran; Ham, Onju; Lee, Jihyun; Kim, Pilseog; Lee, Seokyeon; Oh, Sekyung; Lee, Hojin; Lee, Minyoung; Kim, Jongmin; Chang, Woochul

doi:https://doi.org/10.1155/2016/4285938

Stem Cells International

On this page

Abstract Introduction Conclusions Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

Cardiovascular Regeneration: Biology and Therapy

View this Special Issue

Review Article | Open Access

Volume 2016 | Article ID 4285938 | https://doi.org/10.1155/2016/4285938

Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

Chang Youn Lee,¹Ran Kim,²Onju Ham,³Jihyun Lee,²Pilseog Kim,²Seokyeon Lee,²Sekyung Oh,⁴Hojin Lee,⁵Minyoung Lee,⁶Jongmin Kim,⁷and Woochul Chang²

Academic Editor: Wenbin Liang

Received31 May 2016

Revised09 Aug 2016

Accepted20 Sept 2016

Published18 Oct 2016

Abstract

Despite development of medicine, cardiovascular diseases (CVDs) are still the leading cause of mortality and morbidity worldwide. Over the past 10 years, various stem cells have been utilized in therapeutic strategies for the treatment of CVDs. CVDs are characterized by a broad range of pathological reactions including inflammation, necrosis, hyperplasia, and hypertrophy. However, the causes of CVDs are still unclear. While there is a limit to the currently available target-dependent treatments, the therapeutic potential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. Various studies have recently reported increased therapeutic potential of transplantation of microRNA- (miRNA-) overexpressing stem cells or small-molecule-treated cells. In addition to treatment with drugs or overexpressed miRNA in stem cells, stem cell-derived extracellular vesicles also have therapeutic potential because they can deliver the stem cell-specific RNA and protein into the host cell, thereby improving cell viability. Here, we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy.

1. Introduction

Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality that have a significant impact on health care systems and financial and social consequences. It is estimated that CVDs will be responsible for 23.3 million global cardiovascular deaths worldwide in 2030 [1]. CVDs include diseases that have different causes and characteristics [2]. There is a state of acute conditions such as myocardial infarction and chronic diseases induced by genetic mutations [3]. Classic treatments of CVDs, such as physical surgery and medicinal treatment, are not sufficient to recover damaged cardiovascular tissue and instead only delay the progression of CVDs.

Stem cells, including embryonic stem cells (ESCs), adult stem cells, and induced pluripotent stem cells (iPSCs), are useful in the field of regenerative medicine because they have pluripotency and self-renewal. In addition, stem cells have beneficial effects such as paracrine effects [4, 5], anti-inflammatory activity [6, 7], and immunomodulatory capacity [8]. However, transplantation of stem cells for treatment of heart disease is hampered by their potential for differentiation into host cell types, such as cardiac cells or blood vessel cells, to hinder cardiac function by causing arrhythmia [9] and their low therapeutic effects and viability under the harsh conditions of damaged tissue [10]. To overcome these problems, establishment of new strategies is needed for priming of stem cells.

Interestingly, it has recently been reported that miRNA, small molecules, and extracellular vesicles can modulate the biological activity of stem cells, such as their survival [11, 12], migration [13], and differentiation [14–16]. According to reports, they have been attracting attention owing to their potential to overcome the limitations associated with stem cell therapy. Moreover, a previous study of miRNA small molecules and extracellular vesicles demonstrated that they were effective in the treatment of CVDs. Based on these studies, the stem cell therapy can contribute to treatment of CVDs.

In this review, we describe the state of stem cell therapy for the treatment of CVDs and evaluate the potential for the use of miRNA or stem cell-derived extracellular vesicles.

2. Cardiovascular Diseases and Stem Cells

2.1. Cause of CVDs

CVDs include a range of major clinical disease conditions, such as cardiomyopathy, hypertensive heart failure, valvular heart disease, peripheral arterial disease, and coronary artery disease [25, 26]. Senescence and male typically raise hazards of CVDs and are primary criteria used to classify risk evaluation [27, 28]. CVDs are strongly connected to lifestyle, age, and gender, with alcohol and tobacco consumption, physical inactivity, psychosocial factor, diet and obesity, and increased blood pressure being major factors [28]. In addition, psychosocial risk elements including low socioeconomic status, deficiency of social support, stress, depression, anxiety disorder, and hostility contribute to development of CVDs [28–34]. Familial prevalence of CVDs is another major risk factors [28]. Nutrient deficiency including low vitamin D levels also plays a role in CVDs pathogenesis [35]. Several studies have shown that vitamin D affects heart function through regulation of hormonal systems including the parathyroid hormone and renin-angiotensin system [36, 37]. Vitamin D has also been shown to affect the cell cycle of cardiomyocytes, to inhibit cardiac cell proliferation, and to protect the structure and function of cardiomyocytes [35, 38, 39]. Hypertension is the most common CVD, leading to a growing risk of stroke, myocardial infarction, and heart and renal failures [40]. Previous clinical tests have indicated that decreased blood pressure reduces the outbreak of CVDs such as stroke and heart attack [40]. There have been various efforts to overcome CVDs in the past few decades [41]. Despite advanced medical and surgical trials, there are still no effective therapies for treatment of CVDs [42, 43]. Unlike other organs, the recuperative ability of heart is limited for treatment of injured cardiac tissue [43]. Heart transplantation can be utilized as a last resort to treat CVDs, but the approach is expensive and extremely limited for patients because of their comorbidities or poor supply of donor organs [43].

2.2. Embryonic Stem Cell Therapy for CVDs

Recent studies have suggested that stem cell therapies target cardiac regeneration in CVDs [42, 43]. Application of stem cells to therapeutic devices and methods may lead to effective and rapid myocardium regeneration and eventually affect cardiovascular morbidity and mortality [44]. There are different types of stem cells such as embryonic stem cells, adult stem cells, and induced pluripotent stem cells for treatment of CVDs (Table 1). Previous studies have demonstrated therapeutic effects of ESCs differentiated into cardiomyocytes [17] and endothelial cells [18] for myocardial infarction, umbilical-cord-blood-derived MSCs for dilated cardiomyopathy [19], bone-marrow-derived-MSCs for cellular cardiomyoplasty [20], and iPSCs [21] and iPSCs-derived cardiovascular progenitor cells [22], endothelial progenitor cells (EPCs) [23], and cardiac stem cells [24] for myocardial infarction.

2.2.1. Therapeutic Characteristics of ESCs

ESCs are pluripotent cells derived from the inner cell mass and infinitely replicate without senescence, maintaining their undifferentiated state [45]. This cell population is called ESCs and follows irreversible process of differentiation to become specialized [44, 46]. ESCs have pluripotency, with the capacity of differentiation into approximately 210 different cell types, making them an up-and-coming stem cell source for cell-based tissue engineering [44]. ESCs can be differentiated into cardiomyocytes, endothelial cells, and vascular smooth muscle cells [17, 18, 47, 48]. Owing to their potential for use in the treatment of CVDs, efforts for stem cell therapy have been concentrated on the differentiation of human ESCs into the cardiac lineage directly [44, 49].

2.2.2. Using ESCs for Myocardial Regeneration Therapy

In previous studies, undifferentiated ESCs or ESCs differentiated into cardiomyocytes, endothelial cells, or vascular cells were directly injected into animal CVDs models [17, 18, 50]. Treatment with those ESC-derived cells showed beneficial effects such as improvement of cardiac regeneration and remodeling and increased myocardial performance [1, 17, 18, 50]. Therapeutic effects of the differentiated cells are mediated through cell engraftment and proliferation and paracrine effects [1, 51, 52]. Recent studies have suggested that genetic and epigenetic regulations of cardiomyocytes differentiation are new approaches to inducing a cardiac lineage for stem cell therapy [43]. Deletion or knockdown of microRNA (miRNA), a small regulator of gene expression, brings about dysregulation of morphogenesis, electrical conduction and hypertrophy of heart, and the cell cycle of cardiocytes [14, 43, 53]. Ivey et al. demonstrated that miR-1 and miR-133 can control the ability to differentiate into the cardiac lineage in mouse and human ESCs [53]. Moreover, epigenetic modification can regulate ESCs differentiation and genetic control [43]. Weber et al. suggested that histone deacetylation is involved in cardiovascular development through target regulation of hey bHLH as major effector in Notch signaling [54]. Although ESCs have considerable potential for direct differentiation into cardiac lineage in various models, several limitations hinder their clinical applications [41]. The greatest limitation is that research using ESCs is hampered by ethical issues that prevent their actual clinical applications [41, 55]. Moreover, treatment with ESCs poses the risk of immunorejection because of differences in genome information among patients [41, 56].

2.3. Adult Stem Cell Therapy for CVDs

2.3.1. Therapeutic Characteristics of MSCs

In adult bodies, tissues and organs contain a small cell subpopulation with the capacity for self-maintenance through the potential to proliferate indefinitely and the ability to form an extended family of daughter cells [57, 58]. These cells are widely known as adult stem cells [7]. Mesenchymal stem cells (MSCs) are found in most of adult tissues, including bone marrow and adipose tissues [58, 59]. The nonhematopoietic cells can be differentiated and modified in vitro to present phenotypes of cardiomyocytes and vascular endothelial cells [58]. In addition, MSCs are able to produce and secrete a broad variety of cytokines, chemokines, and growth factors for enhancing neovascularization, attenuating fibrosis in heart, and recovering cardiac functions [4, 5, 60]. Accordingly, it is possible that MSCs could be a therapeutic cell source with the capacity to repair injured tissue in CVDs.

2.3.2. Treatments of Myocardial Diseases by Using MSCs

Bone-marrow-derived MSCs (BM-MSCs) have been widely reported as a promising therapeutic strategy for CVDs [61]. These cells can differentiate into cardiomyocytes and endothelial cells [20, 61]. Many studies have indicated that BM-MSCs possess therapeutic effects in heart diseases such as myocardial infarction, diabetic cardiomyopathy, and dilated cardiomyopathy [61–63], and BM-MSCs are now considered one of the most attractive adult stem cell populations for cardiovascular repair [61, 64]. Cai et al. showed that BM-MSCs cocultured with neonatal rat ventricular cardiomyocytes prevented isoproterenol-induced typical hypertrophic characteristics of cardiomyocytes in in vitro and in vivo studies [61]. Moreover, interplay of BM-MSCs with cardiomyocytes produced synergistic effects on VEGF secretion [61]. Today, many studies showed that paracrine factors, such as VEGF, bFGF, and IGF-1, play an essential therapeutic role [4]. Tang et al. demonstrated that autologous BM-MSCs transplantation in rat MI model improved vascular regeneration and cardiac performance through paracrine effect of VEGF, bFGF, and SDF-1 [5]. Ohnishi et al. also found conditioned medium of BM-MSCs affected the antiproliferation of cardiac fibroblasts via expressing paracrine antifibrotic effects of MMPs [60]. Adipose tissue-derived MSCs (AD-MSCs) have become an attractive therapeutic cell source [65] because they are easily expanded in vitro and express the same cell surface markers as BM-MSCs [65, 66]. Moreover, injected AD-MSCs have been shown to differentiate toward a cardiogenic phenotype [67] and reduce the infracted size, exhibiting a powerful and persisting angiogenic potential [65, 68]. Siciliano et al. reported on plasticity of human AD-MSCs and their phenotypical modification in cardiac-specific microenvironments [65]. They also indicated that human AD-MSCs cocultured with cardiospheres-conditioned media changed toward a cardiac/endothelial/muscular-like phenotype in response to regulation of the expression of cardiogenic markers and induction of the activation of intracellular survival signaling pathways [65]. Umbilical-cord-blood-derived MSCs (UCB-MSCs) are a new xenogeneic stem cell therapy source for CVDs [19]. The newly proposed cell source may be optimum for CVDs because they have a low immunogenicity and a large change of cardiomyocyte reprogramming of UCB-MSCs in comparison with xenogeneic stem cells [19, 69–71]. In addition, UCB-MSCs are easily obtained through low-invasive surgery without raising ethical issues, demonstrating their promising clinical application [19]. Gong et al. demonstrated that intramyocardial grafts of human UCB-MSCs promote cardiac function via mechanisms of antiapoptosis, anti-inflammation, and proangiogenesis in cardiomyopathy of transgenic mice [19]. They also found that UCB-MSCs derived conditioned medium protects H9C2 cells from apoptosis in hypoxic condition by paracrine effects in vitro [19].

2.3.3. Treatments of Myocardial Diseases by Using Other Stem Cells (CPCs, EPCs)

The tissue-specific stem cells were found in several tissues, such as skeletal muscle, brain, fat, liver, gastrointestinal tract, and epidermis. These stem cells are differentiated into specific tissue cells and contribute to maintaining tissue homeostasis. Interestingly, the tissue-specific stem cells were found in heart [72]. Heart was not known to be able to self-regenerate before the establishment of cardiac progenitor cells (CPCs). Since then, cardiac progenitor cells have been reported on therapeutic potential in CVDs.

Beltrami et al. reported on Lin^- c- cells in CPCs. They are self-renewing and multipotent and have colony forming ability [72]. Injected CPCs into the ischemic heart can be differentiated into cardiomyocytes, reconstruct heart, and induce new blood vessel. They suggest that CPCs to repair the heart provide a new opportunity. However, CPCs present in very small amounts in the heart and require in vitro expansion of a few weeks [73].

In 1997, Asahara et al. reported that isolated cells are endothelial progenitor cells which are separate from peripheral blood [74]. EPCs also have capacity of differentiation into endothelial cells and angiogenesis. For that reason, EPC was noted in the study for treating various ischemic injury. Kawamoto et al. studied effects of heart regeneration by transplantation of EPCs into rat MI heart in 4 weeks after transplantation [23]. According to this paper, the effect of regeneration is caused by angiogenesis which is promoted by transplanted EPCs into ischemic damage area.

Another strategy is reported based on the stimulation of the EPCs in vivo for treating ischemic disease. Oikonomou et al. reported that 26 patients with heart disease have improved blood vessel function after administration of atorvastatin for 4 weeks by increasing circulated EPCs [75].

Transplantation of EPC has benefit for treatment of disease, but we need to concern about immune rejection in the allograft because therapy using EPCs is based on the autograft method. Therefore, we need to overcome this limitation for transplantation into damaged area.

2.4. iPSCs as a Source of Cell Therapies for CVDs

In 2006, iPSCs were established by Takahashi and Yamanaka by reprogramming mouse fibroblasts through overexpression of four specific transcription factors: Oct3/4, Sox2, c-Myc, and Klf4 [76]. Since this breakthrough, various opportunities for application have been reported in cell therapy, modeling of new diseases, and studies of complex genetic features and allelic variations, as substrates for drug, in toxicity, differentiation, and regenerative medicine therapies, and in therapeutic screening [77, 78]. In addition, using the iPSCs, it is possible to differentiate into patient- and disease-specific cell types. Thus, using iPSC is one of the tools for treatment of the patients [79, 80]. However, many considerations, including the optimal materials for reprogramming, high cost, safety, and efficient derivation, still remained regarding using iPSCs for clinical applications [81]. Thus, it is essential to understand the following events after the activation of reprogramming factors for transplantation of iPSCs for a safe way.

2.4.1. Methods for Differentiation from iPSCs to Cardiomyocytes

Recently various efficient methods for inducing differentiation into cardiac lineage cells using iPSCs or direct reprogramming (Figure 1). iPSCs have been tried to use genetic transduction or integrated-free methods. Using viral vector for reprogramming has higher efficiency than using integrated-free methods, but safety is lower than using integrated-free methods (Figure 2) [82]. Another method for differentiation into cardiac lineage cells is direct differentiation. One of the protocols for direct differentiation is overexpression of combined cardiac-specific transcription factors such as GATA4, Mef2c, and Tbx5 (GMT) [83, 84] or GMT and Hand2 [85]. Another method is using miRNAs or small molecules without lineage-specific transcription factors: overexpression of miRNAs 1, 133, 208, and 499 is effective to increase the capacity of direct differentiation into cardiac lineage cells [86]: chemically defined medium (CDM) containing three components is also reported that can induce differentiation into cardiomyocytes [87]. Recently, Hou et al. also reported that treatment of seven small molecules into cells can generate iPSCs [88]. Direct differentiation into cardiac-specific lineage may provide the therapeutic strategy for cardiac regeneration; however, it needs to improve the low efficiency of differentiation into the cardiac lineage cells [84].

2.4.2. Treatment of CVDs by Transplanted iPSCs

iPSCs have characters like embryonic stem cells (ESCs)—pluripotency and self-renewal—so that iPSCs can be provided to be transplanted into damaged tissue or organ [89]. Masumoto et al. reported cardiac regeneration by transplantation of engineered human iPSC as a cardiac tissue sheet (hiPSC-CTSs) into rat heart [90]. They checked that heart function was improved and survival of transplanted cells was over 40% cells. Rojas et al. performed transplantation of iPSCs with fibrinogen into heart of myocardial injury model [21]. Although heart function was recovered by transplantation of iPSCs into damaged heart, they suggested transplantation of iPSC-derived cardiomyocytes is more relevant for clinical trial. In addition, the problems of transplantation of iPSCs including tumorigenicity, immunogenicity, and genomic instability have been reported [88, 91–94]. Recently, transplantation of differentiated cells into tissue-specific lineage is reported to overcome the aforementioned problems; Funakoshi et al. reported transplantation of iPSC-derived cardiomyocyte and they tried to optimize condition for transplantation [95]; and Ja et al. showed the effects of the transplantation of iPSC-derived human cardiac progenitor cells improved heart function [22]. They suggested that the improvement of heart function is caused by angiogenesis and interstitial networking of damaged heart.

2.5. Cell-Free Therapeutic Strategy for CVDs

Extracellular vesicles have been reported to modulate a variety of biological actions in the cells, such as proliferation, migration, apoptosis, and differentiation. Stem cell-derived extracellular vesicles especially have potent cardiac protection, regeneration, and angiogenic properties. In addition to affordable benefits, it is well known the vesicles can be used to communicate with other cells and control level of protein expression. Thus, transplantation of extracellular vesicles has the potential as a novel cell-free therapy for treatment of CVDs, which has various advantages to overcome the limitations related to the cell-based therapeutics.

2.5.1. Treatment of CVDs by Extracellular Vesicles-Derived Stem Cells

Various reports have emphasized the effectiveness of secretion factors during treatment of heart disease using stem cells. Paracrine effect is one of the benefits by transplantation of stem cells into the damaged area causing secretion of various cytokines and growth factors [4, 5]. Recently, many studies have investigated cell-derived extracellular vesicles, and they have been shown to exert positive effects on a variety of cellular activities such as antiapoptosis, migration, differentiation, and cell recruitment [96]. In fact, extracellular vesicles have a biologic function of communication between the cells and recipient cells. Several studies have reported that the extracellular vesicles contained various factors including nucleic acids, cytokines, growth factor, and miRNAs [97–99]. Lai et al. reported that extracellular vesicles can promote repair of damaged heart by myocardial ischemia/reperfusion injury [100]. They have demonstrated that the exosome was contained in the stem cell conditioned media so that it contributed to the cardiac protection. Lee et al. demonstrated that mesenchymal stromal cell-derived exosomes (MEX) inhibited vascular remodeling and hypoxic pulmonary hypertension [101]. They also demonstrated that MEX inhibit the inflammatory response and cell proliferation of vascular pulmonary hypertension in animal models. They suggested that the reason of the advantages was based on the downregulation of miR-17 cluster and stat3 signaling in MEX-treated vessel cells. Khan et al. reported that ESC-derived exosome promoted the repair of ischemic myocardium [102]. Therapeutic potential of ESC-derived exosome stimulates CPCs activity including survival, cell cycle progression, and proliferation, by overexpression of ESC-specific miR-294. Furthermore, therapeutic effects of CPCs-derived exosomes have been reported [103]. Vrijsen et al. reported that CPCs-derived exosomes promote cell migration in vitro wound assay [104]. According to their report, CPCs-derived exosomes include EMMPRIN and MMP, to induce endothelial cell migration. Chen et al. reported a myocardial infarction protective effect of the CPCs-derived exosome [105]. CPCs-derived exosome contains higher level of miR-451 so it can protect H9C2 cells from oxidative stress by inhibiting caspase-3 and caspase-7 activation.

Although there are a lot of experiments that have studied transplantation of extracellular vesicles which have beneficial effect in treating CVD in vitro and in vivo, we still need to consider side effects on other organs, appropriate amount for transplantation, and compatibility for clinical practices in human. Therefore, more researches which targeted safety to use for therapeutic approaches using extracellular vesicles are required in future clinical trials.

2.6. Limitations of Stem Cell and Cell-Free Therapy Strategies for CVDs

Stem cell therapy should be more considered for efficient clinical application in CVDs. Despite the many positive efforts for stem cell therapy, it has still some problems, such as low efficiency, immune rejection, and difficulty in control of stem cell behavior in vivo. In addition, administered stem cells often do not show effective integration or persistence in the heart tissues and trigger tumor formation [106].

On the other hand, the cell-free therapy was proposed as a means to avoid such a problem which can occur in stem cell therapy. However, the short half-life is a problem of the cell-free therapy because the proteins and nucleic acids are rapidly biodegradable in vivo as a main component [107–109]. For this reason, cell-free therapy must be administered more frequently. Moreover, disease specificity, biodistribution, and persistency of the cell-free factors must be validated before clinical application [110].

3. Conclusions

In this review, we focus on the strategy for treatment of CVDs by transplantation of stem cells. Transplantation of stem cells including ESCs, adult stem cells, and iPSCs can promote tissue regeneration of damaged area. Stem cells have specific characters such as self-renewal and pluripotency. In addition, stem cells secrete paracrine factors, so transplantation of which shows beneficial effects. Stem cell-derived vesicles can stimulate the cell activity by transferring beneficial materials, including the stem cell-specific transcription factor and miRNA to the damaged tissue. Thus, transplantation of vesicle can contribute to recovery in damaged area. In addition, treatment of additional materials such as miRNA or small molecules for promoting differentiation of stem cells into specific cell types can improve therapeutic effects for treatment of CVDs.

Although stem cell therapy has problems such as low survival rate after transplantation into harsh condition and still needs to overcome these problem, stem cell therapy and cell-free based therapy have potential to improve heart function after CVDs.

Competing Interests

The authors report no conflict of interests in this work.

Authors’ Contributions

Chang Youn Lee, Ran Kim, and Onju Ham contributed equally to this work.

Acknowledgments

This research was supported by a 2-Year Research Grant of Pusan National University.

References

T. H. Chao, I. C. Chen, S. Y. Tseng, and Y. H. Li, “Pluripotent stem cell therapy in ischemic cardiovascular disease,” Zhonghua Minguo Xin Zang Xue Hui Za Zhi, vol. 30, no. 5, pp. 365–374, 2014.
View at: Google Scholar
P. Elliott, B. Andersson, E. Arbustini et al., “Classification of the cardiomyopathies: a position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases,” European Heart Journal, vol. 29, no. 2, pp. 270–276, 2008.
View at: Publisher Site | Google Scholar
I. Y. Chen, E. Matsa, and J. C. Wu, “Induced pluripotent stem cells: at the heart of cardiovascular precision medicine,” Nature Reviews Cardiology, vol. 13, no. 6, pp. 333–349, 2016.
View at: Publisher Site | Google Scholar
M. Gnecchi, Z. Zhang, A. Ni, and V. J. Dzau, “Paracrine mechanisms in adult stem cell signaling and therapy,” Circulation Research, vol. 103, no. 11, pp. 1204–1219, 2008.
View at: Publisher Site | Google Scholar
Y. L. Tang, Q. Zhao, X. Qin et al., “Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction,” The Annals of Thoracic Surgery, vol. 80, no. 1, pp. 229–237, 2005.
View at: Publisher Site | Google Scholar
R. H. Lee, A. A. Pulin, M. J. Seo et al., “Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6,” Cell Stem Cell, vol. 5, no. 1, pp. 54–63, 2009.
View at: Publisher Site | Google Scholar
J. Y. Oh, M. K. Kim, M. S. Shin et al., “The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury,” STEM CELLS, vol. 26, no. 4, pp. 1047–1055, 2008.
View at: Publisher Site | Google Scholar
A. Uccelli, L. Moretta, and V. Pistoia, “Mesenchymal stem cells in health and disease,” Nature Reviews Immunology, vol. 8, no. 9, pp. 726–736, 2008.
View at: Publisher Site | Google Scholar
H. J. Hwang, W. Chang, B.-W. Song et al., “Antiarrhythmic potential of mesenchymal stem cell is modulated by hypoxic environment,” Journal of the American College of Cardiology, vol. 60, no. 17, pp. 1698–1706, 2012.
View at: Publisher Site | Google Scholar
Y.-J. Geng, “Molecular mechanisms for cardiovascular stem cell apoptosis and growth in the hearts with atherosclerotic coronary disease and ischemic heart failure,” Annals of the New York Academy of Sciences, vol. 1010, pp. 687–697, 2003.
View at: Publisher Site | Google Scholar
W. Chang, C. Y. Lee, J.-H. Park et al., “Survival of hypoxic human mesenchymal stem cells is enhanced by a positive feedback loop involving mir-210 and hypoxia-inducible factor 1,” Journal of Veterinary Science, vol. 14, no. 1, pp. 69–76, 2013.
View at: Publisher Site | Google Scholar
R. Damoiseaux, S. P. Sherman, J. A. Alva, C. Peterson, and A. D. Pyle, “Integrated chemical genomics reveals modifiers of survival in human embryonic stem cells,” STEM CELLS, vol. 27, no. 3, pp. 533–542, 2009.
View at: Publisher Site | Google Scholar
W. Chang, R. Kim, S. I. Park et al., “Enhanced healing of rat calvarial bone defects with hypoxic conditioned medium from mesenchymal stem cells through increased endogenous stem cell migration via regulation of ICAM-1 targeted-microRNA-221,” Molecules and Cells, vol. 38, no. 7, pp. 643–650, 2015.
View at: Publisher Site | Google Scholar
Y. Zhao, E. Samal, and D. Srivastava, “Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis,” Nature, vol. 436, no. 7048, pp. 214–220, 2005.
View at: Publisher Site | Google Scholar
J.-F. Chen, E. M. Mandel, J. M. Thomson et al., “The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation,” Nature Genetics, vol. 38, no. 2, pp. 228–233, 2006.
View at: Publisher Site | Google Scholar
H. Sadek, B. Hannack, E. Choe et al., “Cardiogenic small molecules that enhance myocardial repair by stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 16, pp. 6063–6068, 2008.
View at: Publisher Site | Google Scholar
O. Caspi, I. Huber, I. Kehat et al., “Transplantation of human embryonic stem cell-derived cardiomyocytes improves myocardial performance in infarcted rat hearts,” Journal of the American College of Cardiology, vol. 50, no. 19, pp. 1884–1893, 2007.
View at: Publisher Site | Google Scholar
Z. Li, K. D. Wilson, B. Smith et al., “Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction,” PLoS ONE, vol. 4, no. 12, Article ID e8443, 2009.
View at: Publisher Site | Google Scholar
X. Gong, P. Wang, Q. Wu, S. Wang, L. Yu, and G. Wang, “Human umbilical cord blood derived mesenchymal stem cells improve cardiac function in $cTn T^{R141W}$ transgenic mouse of dilated cardiomyopathy,” European Journal of Cell Biology, vol. 95, no. 1, pp. 57–67, 2016.
View at: Publisher Site | Google Scholar
C. Toma, M. F. Pittenger, K. S. Cahill, B. J. Byrne, and P. D. Kessler, “Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart,” Circulation, vol. 105, no. 1, pp. 93–98, 2002.
View at: Publisher Site | Google Scholar
S. V. Rojas, A. Martens, R. Zweigerdt et al., “Transplantation effectiveness of induced pluripotent stem cells is improved by a fibrinogen biomatrix in an experimental model of ischemic heart failure,” Tissue Engineering Part A, vol. 21, no. 13-14, pp. 1991–2000, 2015.
View at: Publisher Site | Google Scholar
P. M. M. Ja, Q. Miao, N. G. Zhen Tee et al., “iPSC-derived human cardiac progenitor cells improve ventricular remodelling via angiogenesis and interstitial networking of infarcted myocardium,” Journal of Cellular and Molecular Medicine, vol. 20, no. 2, pp. 323–332, 2016.
View at: Publisher Site | Google Scholar
A. Kawamoto, H.-C. Gwon, H. Iwaguro et al., “Therapeutic potential of ex vivo expanded endothelial progenitor cells for myocardial ischemia,” Circulation, vol. 103, no. 5, pp. 634–637, 2001.
View at: Publisher Site | Google Scholar
F. Song, F. Hua, H. Li et al., “Cardiac stem cell transplantation with 2,3,5,4′-tetrahydroxystilbehe-2-O-β-D-glucoside improves cardiac function in rat myocardial infarction model,” Life Sciences, vol. 158, pp. 37–45, 2016.
View at: Publisher Site | Google Scholar
M. J. Sarnak, A. S. Levey, A. C. Schoolwerth et al., “Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention,” Hypertension, vol. 42, no. 5, pp. 1050–1065, 2003.
View at: Publisher Site | Google Scholar
M. Lafeber, W. Spiering, F. L. Visseren, and D. E. Grobbee, “Multifactorial prevention of cardiovascular disease in patients with hypertension: the cardiovascular polypill,” Current Hypertension Reports, vol. 18, no. 5, article 40, 2016.
View at: Publisher Site | Google Scholar
R. M. Conroy, K. Pyörälä, A. P. Fitzgerald et al., “Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project,” European Heart Journal, vol. 24, no. 11, pp. 987–1003, 2003.
View at: Publisher Site | Google Scholar
J. Perk, G. De Backer, H. Gohlke et al., “European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts),” European Heart Journal, vol. 33, no. 13, pp. 1635–1701, 2012.
View at: Google Scholar
A. R. Rahimi, J. A. Spertus, K. J. Reid, S. M. Bernheim, and H. M. Krumholz, “Financial barriers to health care and outcomes after acute myocardial infarction,” The Journal of the American Medical Association, vol. 297, no. 10, pp. 1063–1072, 2007.
View at: Publisher Site | Google Scholar
F. Mookadam and H. M. Arthur, “Social support and its relationship to morbidity and mortality after acute myocardial infarction: systematic overview,” Archives of Internal Medicine, vol. 164, no. 14, pp. 1514–1518, 2004.
View at: Publisher Site | Google Scholar
E. D. Eaker, L. M. Sullivan, M. Kelly-Hayes, R. B. D'Agostino Sr., and E. J. Benjamin, “Marital status, marital strain, and risk of coronary heart disease or total mortality: the Framingham Offspring Study,” Psychosomatic Medicine, vol. 69, no. 6, pp. 509–513, 2007.
View at: Publisher Site | Google Scholar
R. Rugulies, “Depression as a predictor for coronary heart disease. A review and meta-analysis,” American Journal of Preventive Medicine, vol. 23, no. 1, pp. 51–61, 2002.
View at: Publisher Site | Google Scholar
J. W. Smoller, M. H. Pollack, S. Wassertheil-Smoller et al., “Panic attacks and risk of incident cardiovascular events among postmenopausal women in the Women's Health Initiative Observational Study,” Archives of General Psychiatry, vol. 64, no. 10, pp. 1153–1160, 2007.
View at: Publisher Site | Google Scholar
Y. Chida and A. Steptoe, “The association of anger and hostility with future coronary heart disease. a meta-analytic review of prospective evidence,” Journal of the American College of Cardiology, vol. 53, no. 11, pp. 936–946, 2009.
View at: Publisher Site | Google Scholar
M. Liu, X. Li, R. Sun, Y. Zeng, S. Chen, and P. Zhang, “Vitamin D nutritional status and the risk for cardiovascular disease (review),” Experimental and Therapeutic Medicine, vol. 11, no. 4, pp. 1189–1193, 2016.
View at: Publisher Site | Google Scholar
P. Andersson, E. Rydberg, and R. Willenheimer, “Primary hyperparathyroidism and heart disease—a review,” European Heart Journal, vol. 25, no. 20, pp. 1776–1787, 2004.
View at: Publisher Site | Google Scholar
W. Xiang, J. Kong, S. Chen et al., “Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems,” American Journal of Physiology—Endocrinology and Metabolism, vol. 288, no. 1, pp. E125–E132, 2005.
View at: Publisher Site | Google Scholar
T. D. O'Connell, J. E. Berry, A. K. Jarvis, M. J. Somerman, and R. U. Simpson, “1, 25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy,” American Journal of Physiology, vol. 272, no. 4, part 2, pp. H1759–H1769, 1997.
View at: Google Scholar
S. Bae, S. S. Singh, H. Yu, J. Y. Lee, B. R. Cho, and P. M. Kang, “Vitamin D signaling pathway plays an important role in the development of heart failure after myocardial infarction,” Journal of Applied Physiology, vol. 114, no. 8, pp. 979–987, 2013.
View at: Publisher Site | Google Scholar
E. G. Nabel, “Cardiovascular disease,” The New England Journal of Medicine, vol. 349, no. 1, pp. 60–72, 2003.
View at: Publisher Site | Google Scholar
Q. Sun, Z. Zhang, and Z. Sun, “The potential and challenges of using stem cells for cardiovascular repair and regeneration,” Genes and Diseases, vol. 1, no. 1, pp. 113–119, 2014.
View at: Publisher Site | Google Scholar
M. L. Moreira, P. da Costa Medeiros, S. A. de Souza, B. Gutfilen, and P. H. Rosado-de-Castro, “In vivo tracking of cell therapies for cardiac diseases with nuclear medicine,” Stem Cells International, vol. 2016, Article ID 3140120, 15 pages, 2016.
View at: Publisher Site | Google Scholar
H. S. Bernstein and D. Srivastava, “Stem cell therapy for cardiac disease,” Pediatric Research, vol. 71, no. 4, part 2, pp. 491–499, 2012.
View at: Publisher Site | Google Scholar
R. K. Sharma, D. J. Voelker, R. Sharma, and H. K. Reddy, “Understanding the application of stem cell therapy in cardiovascular diseases,” Stem Cells and Cloning: Advances and Applications, vol. 5, no. 1, pp. 29–37, 2012.
View at: Google Scholar
M. Yousefi, V. Hajihoseini, W. Jung et al., “Embryonic stem cell interactomics: the beginning of a long road to biological function,” Stem Cell Reviews and Reports, vol. 8, no. 4, pp. 1138–1154, 2012.
View at: Publisher Site | Google Scholar
D. C. Kraushaar and K. Zhao, “The epigenomics of embryonic stem cell differentiation,” International Journal of Biological Sciences, vol. 9, no. 10, pp. 1134–1144, 2013.
View at: Publisher Site | Google Scholar
S. G. Nir, R. David, M. Zaruba, W.-M. Franz, and J. Itskovitz-Eldor, “Human embryonic stem cells for cardiovascular repair,” Cardiovascular Research, vol. 58, no. 2, pp. 313–323, 2003.
View at: Publisher Site | Google Scholar
A. M. Wobus, G. Wallukat, and J. Hescheler, “Pluripotent mouse embryonic stem cells are able to differentiate into cardiomyocytes expressing chronotropic responses to adrenergic and cholinergic agents and Ca²⁺ channel blockers,” Differentiation, vol. 48, no. 3, pp. 173–182, 1991.
View at: Publisher Site | Google Scholar
S. S. Wong and H. S. Bernstein, “Cardiac regeneration using human embryonic stem cells: producing cells for future therapy,” Regenerative Medicine, vol. 5, no. 5, pp. 763–775, 2010.
View at: Publisher Site | Google Scholar
Q. Xiong, L. Ye, P. Zhang et al., “Bioenergetic and functional consequences of cellular therapy: activation of endogenous cardiovascular progenitor cells,” Circulation Research, vol. 111, no. 4, pp. 455–468, 2012.
View at: Publisher Site | Google Scholar
C. Freund and C. L. Mummery, “Prospects for pluripotent stem cell-derived cardiomyocytes in cardiac cell therapy and as disease models,” Journal of Cellular Biochemistry, vol. 107, no. 4, pp. 592–599, 2009.
View at: Publisher Site | Google Scholar
H. Ebelt, M. Jungblut, Y. Zhang et al., “Cellular cardiomyoplasty: improvement of left ventricular function correlates with the release of cardioactive cytokines,” Stem Cells, vol. 25, no. 1, pp. 236–244, 2007.
View at: Publisher Site | Google Scholar
K. N. Ivey, A. Muth, J. Arnold et al., “MicroRNA regulation of cell lineages in mouse and human embryonic stem cells,” Cell Stem Cell, vol. 2, no. 3, pp. 219–229, 2008.
View at: Publisher Site | Google Scholar
D. Weber, J. Heisig, S. Kneitz, E. Wolf, M. Eilers, and M. Gessler, “Mechanisms of epigenetic and cell-type specific regulation of Hey target genes in ES cells and cardiomyocytes,” Journal of Molecular and Cellular Cardiology, vol. 79, pp. 79–88, 2015.
View at: Publisher Site | Google Scholar
E. C. Perin, Y.-J. Geng, and J. T. Willerson, “Adult stem cell therapy in perspective,” Circulation, vol. 107, no. 7, pp. 935–938, 2003.
View at: Publisher Site | Google Scholar
M. Murata, S. Tohyama, and K. Fukuda, “Impacts of recent advances in cardiovascular regenerative medicine on clinical therapies and drug discovery,” Pharmacology and Therapeutics, vol. 126, no. 2, pp. 109–118, 2010.
View at: Publisher Site | Google Scholar
E. Fuchs and J. A. Segre, “Stem cells: a new lease on life,” Cell, vol. 100, no. 1, pp. 143–155, 2000.
View at: Publisher Site | Google Scholar
R. Poulsom, M. R. Alison, S. J. Forbes, and N. A. Wright, “Adult stem cell plasticity,” The Journal of Pathology, vol. 197, no. 4, pp. 441–456, 2002.
View at: Publisher Site | Google Scholar
P. Bianco, M. Riminucci, S. Gronthos, and P. G. Robey, “Bone marrow stromal stem cells: nature, biology, and potential applications,” STEM CELLS, vol. 19, no. 3, pp. 180–192, 2001.
View at: Publisher Site | Google Scholar
S. Ohnishi, H. Sumiyoshi, S. Kitamura, and N. Nagaya, “Mesenchymal stem cells attenuate cardiac fibroblast proliferation and collagen synthesis through paracrine actions,” FEBS Letters, vol. 581, no. 21, pp. 3961–3966, 2007.
View at: Publisher Site | Google Scholar
B. Cai, X. Tan, Y. Zhang et al., “Mesenchymal stem cells and cardiomyocytes interplay to prevent myocardial hypertrophy,” Stem Cells Translational Medicine, vol. 4, no. 12, pp. 1425–1435, 2015.
View at: Publisher Site | Google Scholar
R. S. Ripa, M. Haack-Sørensen, Y. Wang et al., “Bone marrow derived mesenchymal cell mobilization by granulocyte-colony stimulating factor after acute myocardial infarction: results from the Stem Cells in Myocardial Infarction (STEMMI) trial,” Circulation, vol. 116, no. 11, supplement, pp. I24–I30, 2007.
View at: Publisher Site | Google Scholar
V. Volarevic, N. Arsenijevic, M. L. Lukic, and M. Stojkovic, “Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus,” Stem Cells, vol. 29, no. 1, pp. 5–10, 2011.
View at: Publisher Site | Google Scholar
J.-Y. Hahn, H.-J. Cho, H.-J. Kang et al., “Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction,” Journal of the American College of Cardiology, vol. 51, no. 9, pp. 933–943, 2008.
View at: Publisher Site | Google Scholar
C. Siciliano, I. Chimenti, M. Ibrahim et al., “Cardiosphere conditioned media influence the plasticity of human mediastinal adipose tissue-derived mesenchymal stem cells,” Cell Transplantation, vol. 24, no. 11, pp. 2307–2322, 2015.
View at: Publisher Site | Google Scholar
D. A. De Ugarte, Z. Alfonso, P. A. Zuk et al., “Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow,” Immunology Letters, vol. 89, no. 2-3, pp. 267–270, 2003.
View at: Publisher Site | Google Scholar
A. Schäffler and C. Büchler, “Concise review: adipose tissue-derived stromal cells—basic and clinical implications for novel cell-based therapies,” Stem Cells, vol. 25, no. 4, pp. 818–827, 2007.
View at: Publisher Site | Google Scholar
L. Casteilla, V. Planat-Bénard, B. Cousin, P. Laharrague, and P. Bourin, “Vascular and endothelial regeneration,” Current Stem Cell Research and Therapy, vol. 5, no. 2, pp. 141–144, 2010.
View at: Publisher Site | Google Scholar
I. Perea-Gil, M. Monguió-Tortajada, C. Gálvez-Montón, A. Bayes-Genis, F. E. Borràs, and S. Roura, “Preclinical evaluation of the immunomodulatory properties of cardiac adipose tissue progenitor cells using umbilical cord blood mesenchymal stem cells: a direct comparative study,” BioMed Research International, vol. 2015, Article ID 439808, 9 pages, 2015.
View at: Publisher Site | Google Scholar
M. Lee, S. Y. Jeong, J. Ha et al., “Low immunogenicity of allogeneic human umbilical cord blood-derived mesenchymal stem cells in vitro and in vivo,” Biochemical and Biophysical Research Communications, vol. 446, no. 4, pp. 983–989, 2014.
View at: Publisher Site | Google Scholar
G. Yannarelli, V. Dayan, N. Pacienza, C.-J. Lee, J. Medin, and A. Keating, “Human umbilical cord perivascular cells exhibit enhanced cardiomyocyte reprogramming and cardiac function after experimental acute myocardial infarction,” Cell Transplantation, vol. 22, no. 9, pp. 1651–1666, 2013.
View at: Publisher Site | Google Scholar
A. P. Beltrami, L. Barlucchi, D. Torella et al., “Adult cardiac stem cells are multipotent and support myocardial regeneration,” Cell, vol. 114, no. 6, pp. 763–776, 2003.
View at: Publisher Site | Google Scholar
P. Oettgen, A. J. Boyle, S. P. Schulman, and J. M. Hare, “Cardiac stem cell therapy. Need for optimization of efficacy and safety monitoring,” Circulation, vol. 114, no. 4, pp. 353–358, 2006.
View at: Publisher Site | Google Scholar
T. Asahara, T. Murohara, A. Sullivan et al., “Isolation of putative progenitor endothelial cells for angiogenesis,” Science, vol. 275, no. 5302, pp. 964–967, 1997.
View at: Publisher Site | Google Scholar
E. Oikonomou, G. Siasos, M. Zaromitidou et al., “Atorvastatin treatment improves endothelial function through endothelial progenitor cells mobilization in ischemic heart failure patients,” Atherosclerosis, vol. 238, no. 2, pp. 159–164, 2015.
View at: Publisher Site | Google Scholar
K. Takahashi and S. Yamanaka, “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors,” Cell, vol. 126, no. 4, pp. 663–676, 2006.
View at: Publisher Site | Google Scholar
F. González, S. Boué, and J. C. Izpisua Belmonte, “Methods for making induced pluripotent stem cells: Reprogramming à la carte,” Nature Reviews Genetics, vol. 12, no. 4, pp. 231–242, 2011.
View at: Publisher Site | Google Scholar
M. Csobonyeiova, S. Polak, and L. Danisovic, “Perspectives of induced pluripotent stem cells for cardiovascular system regeneration,” Experimental Biology and Medicine, vol. 240, no. 5, pp. 549–556, 2015.
View at: Publisher Site | Google Scholar
K. Narsinh, K. H. Narsinh, and J. C. Wu, “Derivation of human induced pluripotent stem cells for cardiovascular disease modeling,” Circulation Research, vol. 108, no. 9, pp. 1146–1156, 2011.
View at: Publisher Site | Google Scholar
K. Schenke-Layland, K. E. Rhodes, E. Angelis et al., “Reprogrammed mouse fibroblasts differentiate into cells of the cardiovascular and hematopoietic lineages,” Stem Cells, vol. 26, no. 6, pp. 1537–1546, 2008.
View at: Publisher Site | Google Scholar
Z. Tong, A. Solanki, A. Hamilos et al., “Application of biomaterials to advance induced pluripotent stem cell research and therapy,” The EMBO Journal, vol. 34, no. 8, pp. 987–1008, 2015.
View at: Publisher Site | Google Scholar
F. Jia, K. D. Wilson, N. Sun et al., “A nonviral minicircle vector for deriving human iPS cells,” Nature Methods, vol. 7, no. 3, pp. 197–199, 2010.
View at: Publisher Site | Google Scholar
M. Ieda, J.-D. Fu, P. Delgado-Olguin et al., “Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors,” Cell, vol. 142, no. 3, pp. 375–386, 2010.
View at: Publisher Site | Google Scholar
J. X. Chen, M. Krane, M.-A. Deutsch et al., “Inefficient reprogramming of fibroblasts into cardiomyocytes using Gata4, Mef2c, and Tbx5,” Circulation Research, vol. 111, no. 1, pp. 50–55, 2012.
View at: Publisher Site | Google Scholar
K. Song, Y.-J. Nam, X. Luo et al., “Heart repair by reprogramming non-myocytes with cardiac transcription factors,” Nature, vol. 485, no. 7400, pp. 599–604, 2012.
View at: Publisher Site | Google Scholar
T. M. Jayawardena, B. Egemnazarov, E. A. Finch et al., “MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes,” Circulation Research, vol. 110, no. 11, pp. 1465–1473, 2012.
View at: Publisher Site | Google Scholar
P. W. Burridge, E. Matsa, P. Shukla et al., “Chemically defined generation of human cardiomyocytes,” Nature Methods, vol. 11, no. 8, pp. 855–860, 2014.
View at: Publisher Site | Google Scholar
P. Hou, Y. Li, X. Zhang et al., “Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds,” Science, vol. 341, no. 6146, pp. 651–654, 2013.
View at: Publisher Site | Google Scholar
X. Lu and T. Zhao, “Clinical therapy using iPSCs: hopes and challenges,” Genomics, Proteomics & Bioinformatics, vol. 11, no. 5, pp. 294–298, 2013.
View at: Publisher Site | Google Scholar
H. Masumoto, T. Ikuno, M. Takeda et al., “Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration,” Scientific Reports, vol. 4, article 6716, 2014.
View at: Publisher Site | Google Scholar
M. Tong, Z. Lv, L. Liu et al., “Mice generated from tetraploid complementation competent iPS cells show similar developmental features as those from ES cells but are prone to tumorigenesis,” Cell Research, vol. 21, no. 11, pp. 1634–1637, 2011.
View at: Publisher Site | Google Scholar
K. Okita, T. Ichisaka, and S. Yamanaka, “Generation of germline-competent induced pluripotent stem cells,” Nature, vol. 448, no. 7151, pp. 313–317, 2007.
View at: Publisher Site | Google Scholar
T. Zhao, Z.-N. Zhang, Z. Rong, and Y. Xu, “Immunogenicity of induced pluripotent stem cells,” Nature, vol. 474, no. 7350, pp. 212–216, 2011.
View at: Publisher Site | Google Scholar
C. E. Pasi, A. Dereli-Öz, S. Negrini et al., “Genomic instability in induced stem cells,” Cell Death and Differentiation, vol. 18, no. 5, pp. 745–753, 2011.
View at: Publisher Site | Google Scholar
S. Funakoshi, K. Miki, T. Takaki et al., “Enhanced engraftment, proliferation, and therapeutic potential in heart using optimized human iPSC-derived cardiomyocytes,” Scientific Reports, vol. 6, Article ID 19111, 2016.
View at: Publisher Site | Google Scholar
S. El Andaloussi, I. Mäger, X. O. Breakefield, and M. J. A. Wood, “Extracellular vesicles: biology and emerging therapeutic opportunities,” Nature Reviews Drug Discovery, vol. 12, no. 5, pp. 347–357, 2013.
View at: Publisher Site | Google Scholar
M. Simons and G. Raposo, “Exosomes—vesicular carriers for intercellular communication,” Current Opinion in Cell Biology, vol. 21, no. 4, pp. 575–581, 2009.
View at: Publisher Site | Google Scholar
S. Mathivanan and R. J. Simpson, “ExoCarta: a compendium of exosomal proteins and RNA,” Proteomics, vol. 9, no. 21, pp. 4997–5000, 2009.
View at: Publisher Site | Google Scholar
M. Mittelbrunn, C. Gutiérrez-Vázquez, C. Villarroya-Beltri et al., “Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells,” Nature Communications, vol. 2, no. 1, article 282, 2011.
View at: Publisher Site | Google Scholar
R. C. Lai, F. Arslan, M. M. Lee et al., “Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury,” Stem Cell Research, vol. 4, no. 3, pp. 214–222, 2010.
View at: Publisher Site | Google Scholar
C. Lee, S. A. Mitsialis, M. Aslam et al., “Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension,” Circulation, vol. 126, no. 22, pp. 2601–2611, 2012.
View at: Publisher Site | Google Scholar
M. Khan, E. Nickoloff, T. Abramova et al., “Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction,” Circulation Research, vol. 117, no. 1, pp. 52–64, 2015.
View at: Publisher Site | Google Scholar
L. Barile, V. Lionetti, E. Cervio et al., “Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction,” Cardiovascular Research, vol. 103, no. 4, pp. 530–541, 2014.
View at: Publisher Site | Google Scholar
K. R. Vrijsen, J. P. G. Sluijter, M. W. L. Schuchardt et al., “Cardiomyocyte progenitor cell-derived exosomes stimulate migration of endothelial cells,” Journal of Cellular and Molecular Medicine, vol. 14, no. 5, pp. 1064–1070, 2010.
View at: Publisher Site | Google Scholar
L. Chen, Y. Wang, Y. Pan et al., “Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury,” Biochemical and Biophysical Research Communications, vol. 431, no. 3, pp. 566–571, 2013.
View at: Publisher Site | Google Scholar
R. C. Lai, T. S. Chen, and S. K. Lim, “Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease,” Regenerative Medicine, vol. 6, no. 4, pp. 481–492, 2011.
View at: Publisher Site | Google Scholar
P. Yde, B. Mengel, M. H. Jensen, S. Krishna, and A. Trusina, “Modeling the NF-κB mediated inflammatory response predicts cytokine waves in tissue,” BMC Systems Biology, vol. 5, article 115, 2011.
View at: Publisher Site | Google Scholar
A. Khosravi, C. M. Cutler, M. H. Kelly et al., “Determination of the elimination half-life of fibroblast growth factor-23,” The Journal of Clinical Endocrinology & Metabolism, vol. 92, no. 6, pp. 2374–2377, 2007.
View at: Publisher Site | Google Scholar
Y. Takahashi, M. Nishikawa, H. Shinotsuka et al., “Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection,” Journal of Biotechnology, vol. 165, no. 2, pp. 77–84, 2013.
View at: Publisher Site | Google Scholar
L. Biancone, S. Bruno, M. C. Deregibus, C. Tetta, and G. Camussi, “Therapeutic potential of mesenchymal stem cell-derived microvesicles,” Nephrology Dialysis Transplantation, vol. 27, no. 8, pp. 3037–3042, 2012.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2016 Chang Youn Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

3889

Downloads

1132

Citations