Apelin and stem cells: the role played in the cardiovascular system and energy metabolism

Introduction

Stem cells are cells capable of differentiating into tissue-specific cells. These cells exist in different tissues and play a pivotal role in repair and regeneration after tissue injuries. On the basis of the differentiation potential, these cells can be classified into five groups: totipotent, pluripotent, multipotent, oligopotent, and unipotent. Moreover, stem cells are categorized according to their origin into three major classes: embryonic, fetal, and adult stem cells (ASCs). Embryonic stem cells (ESCs) are pluripotent cells able to differentiate into all three germ lineages. ASCs reside within different tissues and participate in tissue regeneration. Mesenchymal stem cells (MSCs), an example of ASCs, express specific surface cell markers and are multipotent (Dominici et al., 2006; Smith, 2006; Ilic and Polak, 2011; Kolios and Moodley, 2013). MSCs have various differentiation capacities and statuses related to their microenvironment and origin (Watt et al., 2013; Yang et al., 2018). These cells can be isolated from endodermal, mesodermal or ectodermal tissues (Fortier, 2005). For example, MSCs derived from bone marrow MSCs (BM-MSCs) or adipose tissues MSCs (AD-MSCs) can be obtained from mesodermal tissues (Pittenger et al., 1999; Zuk et al., 2001). These cells can differentiate into different cell lineages under specific growth factors (Schuldiner et al., 2000).

Several investigations have shown the beneficial effects of stem cells on the treatment of different diseases (Hahn et al., 2008; Larijani et al., 2012; Liu et al., 2014). These cells participate in tissue repair and regeneration by different mechanisms, including homing to damaged tissues (Cheng et al., 2008), differentiation into specialized cells (Toma et al., 2002), and their paracrine effects (Li et al., 2013; Watt et al., 2013). In spite of the recent progress made in stem cell research, some limitations affect the practical applications of stem cells in cell therapy. For example, cell therapy is costly, and after transplantation, these cells may be rejected because of the immune response (Fortier, 2005). In addition, several factors, such as ischemic conditions, can affect the efficiency of cell transplantation through the reduction of cell survival (Wang et al., 2008; Huang et al., 2010).

Numerous strategies can be used to increase the regenerative capacity and therapeutic potential of stem cells including tissue engineering and genetic modification of the cells (Huang et al., 2016). The beneficial effects of hypoxic preconditioning on cell viability have been shown by Wang and colleagues (Wang et al., 2008). It is also possible to enhance cell survival by adding growth factors and peptides, which affect stem cell properties (Hahn et al., 2008; Zeng et al., 2012).

Apelin is a regulatory peptide which exerts a protective effect on different cells and tissues. Recently, its regulatory role in various signaling pathways has been reviewed (O’Carroll et al., 2013; Kurowska et al., 2018). It is associated with metabolic disorders via its effects on lipid and glucose metabolism (Castan-Laurell et al., 2011; Hwangbo et al., 2017). It has multiple biological actions, including cardiovascular function regulation, fluid homeostasis, and angiogenesis (O’Carroll et al., 2013). In addition, the beneficial effects of apelin on the efficiency of stem cell therapy have been demonstrated (Zeng et al., 2012). Therefore, the purpose of this paper is to review some current knowledge related to the apelin effects on stem cell properties. It also presents the effects of apelin on stem cell therapy for the cardiovascular system and energy metabolism. To better understand the apelin effects on the therapeutic potential of stem cells, we briefly review the current knowledge about the effects of stem cells or apelin on the treatment of diseases. Then, the effect of apelin on stem cell therapy will be discussed.

Apelin and the APJ (apelin receptor, putative receptor protein related to the angiotensin receptor [AT1]) receptor

Apelin is a member of the adipose-secreted adipokine family (Boucher et al., 2005). Its gene is located on the X chromosome encoding a 77 amino acid preproapelin (Lee et al., 2000). Apelin-36 (apelin42-77), apelin-17 (apelin61-77), apelin-13 (apelin65-77), and pyroglutaminated apelin-13 (Pyr-apelin-13) are different isoforms of the apelin peptide (Tatemoto et al., 1998). These isoforms are different based on their binding affinity, biological potency, and tissue distribution (Kawamata et al., 2001). Apelin activates its receptor named APJ, which is a member of the G protein-coupled receptor family (Tatemoto et al., 1998). This peptide is expressed in different tissues and cells such as the heart, blood vessels, and adipocytes, implying the role of apelin in multiple physiological and pathophysiological functions (Kleinz and Davenport, 2004; Boucher et al., 2005; Kleinz and Davenport, 2005; Maguire et al., 2009). Moreover, its expression can be affected by several factors such as hormones, cytokines, fasting status, and hypoxic conditions (Boucher et al., 2005; Daviaud et al., 2006; Ronkainen et al., 2007). Apelin affects several signaling cascades such as extracellular signal-regulated kinases (ERKs) and protein kinase B (PKB), thereby contributing to different cellular processes such as migration and proliferation (Masri et al., 2004; Liu et al., 2010; Li et al., 2017). It is also involved in the regulation of the cardiovascular system and hormones (Taheri et al., 2002; Kidoya et al., 2010; Azizi et al., 2013; O’Carroll et al., 2013). Moreover, it has been demonstrated that not only has apelin signaling effects on the aging process but also its expression is affected by aging. Expression of apelin and its receptor in different tissues reduces due to the aging process. Apelin signaling down-regulation is correlated with age-related diseases and accelerates them. Administration of apelin can ameliorate these disorders (Rai et al., 2017). Oxidative stress can lead to aging-associated diseases (Liguori et al., 2018). Apelin raises the activity of antioxidant enzymes (Than et al., 2014), indicating this peptide acts as an anti-aging factor (Rai et al., 2017). Apelin also decreases the reactive oxygen species (ROS) generation and pro-oxidant enzyme expression in adipocytes, regulates glucose metabolism, and improves insulin resistance. These findings suggest that apelin may be used as a promising therapeutic strategy in the treatment of oxidative stress associated metabolic diseases (Zhu et al., 2011; Than et al., 2014). Additionally, apelin has effects on angiogenesis in hypoxic conditions through increasing the proliferation of endothelial progenitor cells (Zhang et al., 2015, 2016).

Apelin and stem cells: effect on stem cell properties

Apelin and stem cells: effects on cardiovascular system

Cardiovascular diseases (CVDs) are one of main causes of death in the world (Benjamin et al., 2018). There are a number of interventions to treat these diseases, and most of them are not efficient. Cell-based therapy is a potentially valuable therapeutic option to treat CVDs (Wang et al., 2012; Watt et al., 2013). Although plenty of preclinical and clinical studies have demonstrated the potential of stem cells in the treatment of heart and vascular diseases (Chen et al., 2004; Hu et al., 2008; Nesselmann et al., 2008; Watt et al., 2013), the current cell therapy is not efficient due to the low survival and differentiation potential of stem cells after transplantation. Further investigations are needed to optimize cell therapy efficacy (Murry et al., 2004; Huang et al., 2010; van der Bogt et al., 2012; Der Sarkissian et al., 2017; Muller et al., 2018). Different strategies can be used to improve stem cell-based therapies, including pre-treatment of stem cells with cytokines and growth factors, tissue engineering, and genetic manipulation of the cells (Muller et al., 2018).

Apelin and its receptor express in different parts of the cardiovascular system, including the adult cardiac endothelium, atria, and endothelial cells (Szokodi et al., 2002; Kleinz and Davenport, 2004; Kleinz et al., 2005). The role of this peptide in heart development has been demonstrated (Zeng et al., 2007; Kang et al., 2013). Disturbance in apelin signaling leads to a defective vascular patterning (Cox et al., 2006) and an abnormal heart and vessel formation (Kang et al., 2013). In addition to the apelin role in cardiovascular development, it can affect cardiac function through different mechanisms. For instance, it exerts positive inotropic effects, improves cardiac function, and has antioxidant activity. Apelin protects cardiomyocytes against oxidative stress in ischemia/reperfusion injury and reduces cellular apoptosis (Szokodi et al., 2002; Berry et al., 2004; Atluri et al., 2007; Zeng et al., 2009; Azizi et al., 2013). It is involved in different signal transduction pathways regulating angiogenesis in hypoxic conditions (Novakova et al., 2016). Apelin also exerts protective effects against CVDs associated with obesity and diabetes. It regulates glucose and lipid metabolism in mice fed a high-fat diet (Ceylan-Isik et al., 2013). It protects cardiomyocytes against hyperglycemia-induced injury via its effect on cardiac gap junctions (Li et al., 2018), upregulates anti-aging proteins such as Sirtuins (Zeng et al., 2014; Grabowska et al., 2017), and eliminates oxidative stress (Foussal et al., 2010). Moreover, apelin treatment enhances the protective effects of stem cells on heart function (Li et al., 2013).

Apelin-13 enhances the efficacy of cell therapy by increasing the BM-MSCs survival and inhibiting cell apoptosis (Zeng et al., 2012). Moreover, it can improve the therapeutic potential of BMCs for cardiac diseases. Li et al. (2013) showed that delivery of apelin-overexpressing BMCs into the myocardium reduced myocardial apoptosis.

PAD is one of the leading causes of cardiovascular morbidity (Criqui and Aboyans, 2015). Stem cell therapy can be effective in the treatment of PAD through the activation of angiogenesis and cytoprotective pathways related to paracrine effects of stem cells (Frangogiannis, 2018). Apelin exerts a synergetic effect with cell therapy and promotes the therapeutic potential of stem cells by increasing angiogenesis and regulating autophagy. Although apelin administration or stem cell therapy can increase the perfusion ratio in the PAD model, their combination improves the treatment of PAD more efficiently. In the myocardial ischemia phase, activation of cardiac autophagy can improve cardiomyocyte survival by providing the energy needed for myocardial functions. However, in the reperfusion period, excessive activation of autophagy can lead to autophagic cardiomyocyte death. During the hypoxia phase, induction of protective autophagy can enhance the viability of stem cells against hypoxia and apelin boosts this process via activation of AMPK signaling and thereby promotes stem cell survival. In contrast, sustained autophagy during H/R may enhance cell death. Apelin, by increasing the AKT/Bcl2 signaling pathway, reduces authophagic cell death and protects the cells against H/R injury (Ma et al., 2015; Liang et al., 2016).

Apelin and stem cells: effects on energy metabolism

The effect of apelin on adipogenic differentiation of stem cells has been demonstrated. Than et al. showed that pyr-apelin-13 suppressed adipogenesis of MSCs derived from adipose tissue. Apelin downregulates the expression of late makers of adipogenesis (such as aP2) in the differentiated cells. Also, apelin via MAPK/ERK-dependent pathways prevents adipogenesis of preadipocytes. This shows an inhibitory effect of apelin on adipogenesis (Than et al., 2012). Apelin is expressed in both white and brown adipose tissues (WAT, BAT) (Butruille et al., 2013), however, its role in brown adipogenesis is different than that in white adipogenesis. Indeed, apelin not only reduces the weight of white adipose tissue and hampers terminal differentiation of white adipocytes (Higuchi et al., 2007; Than et al., 2015) but also induces brown adipogenesis. Apelin administration increases differentiation of preadipocytes into brown adipocytes. It upregulates the markers related to thermogenesis and brown adipocyte in preadipocytes and enhances the numbers of differentiated brown adipocytes. It exerts these effects through the PI3K/Akt and AMPK signaling pathways (Than et al., 2015). Apelin also has a pivotal effect on the adipogenic differentiation of MSCs. Human BM-MSCs differentiate into white adipocytes with a low UCP1 expression. However, the administration of pyr-apelin13 leads to an increase in UCP1 expression in adipocytes derived from BM-MSCs (Than et al., 2015). These findings show that apelin could be considered as an activator to increase adipose browning and apelin-treated MSCs may play a crucial role in the treatment of metabolic-associated diseases.

Conclusion

This review summarizes the effects of the apelin/APJ system on the therapeutic potential of stem cells and their properties (Table 1). The mentioned studies show the beneficial effects of apelin on stem cell properties (Figure 1). Apelin administration affects stem cell survival and their differentiation potential through various signaling pathways (Figure 2). It improves the efficacy of stem cell therapy for CVDs. In addition, apelin exerts regulatory effects on energy metabolism via its effect on glucose and lipid metabolism. Although most of the reports have revealed the beneficial effects of the apelin signaling pathway on stem cells, further studies are needed to use apelin-treated stem cells in the treatment of different diseases. Among the different types of stem cells, most investigations have been performed on MSCs. The role of apelin signaling in other stem cell types has not been explored. The levels of the apelin isoforms in various stem cells remain to be understood. Apelin isoforms can activate different signaling pathways in stem cells. The effects of this activation on the fate of the cells and therapeutic potential of stem cells after transplantation have not been completely defined. More studies are needed to determine the advantages and disadvantages of apelin administration on stem cell therapy.

Conflict of interest

The authors declare that there are no conflict of interests.