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    • br Materials and methods br Conflict of

    2018-11-12


    Materials and methods
    Conflict of interest statement
    Acknowledgements This work was supported by the National Natural Science Foundation of China (No. 81070798), Nature Science Foundation of Jiangsu Province (No. BK2009346), Funding Project to Science Facility in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality (No. PXM2011_014226_07_000066) and 355 Project of Stomatological Hospital of Jiangsu Province (No. 52008103).
    Introduction Bone marrow-derived mesenchymal stem cells (BMSCs) are self-renewing progenitor cells that differentiate into osteoblasts, chondrocytes, astrocytes, neurons, skeletal muscle cells, and cardiomyocytes in vitro and in vivo (Pereira et al., 1995; Azizi et al., 1998). Besides their differentiating potentials, autologous BMSCs can be isolated from bone marrow and expanded, which makes BMSCs a conceivable source of stem cells for repairing damaged tissues. So far, BMSCs have been tested in several animal brain and heart ischemia models and have shown beneficial effects by promoting tissue repair and functional recovery (Li et al., 2001; Zubko and Frishman, 2009; Hu et al., 2008; Barry and Murphy, 2004). Previous reports have shown that transplanted stem cells including BMSCs do not survive well within diseased tissues (Geng, 2003). For instance, after injection into the left ventricle of immunodeficient adult CB17 SCID/beige mice that are deficient in B- and T-cells, more than 99% of injected cells die within 4days of injection (Toma et al., 2002). This result provides a piece of compelling evidence that transplanted BMSCs are unlikely eliminated by cells in the immune system, but die due to other mechanisms. Evidence suggests that transplanted cells die from apoptosis (Geng, 2003; Zhang et al., 2001), therefore strategies that enhance tolerance to apoptotic insults should have significant impacts on improving the efficiency of BMSC transplantation therapy. Apelin is a natural ligand for an orphan G protein coupled receptor, APJ (putative receptor protein related to the angiotensin receptor AT1) (O\'Dowd et al., 1993), which had previously been identified by the Human Genome Project in 1993 (O\'Dowd et al., 1993; Falcao-Pires and Leite-Moreira, 2005). Apelin is derived from a 77 amino elastase inhibitor length preproapelin that can be cleaved into active apelin containing 13, 17 or 36 amino acids by angiotensin-converting enzymes. The 13C-terminal amino acids are completely conserved across all species (Lee et al., 2000). Moreover, apelin-13 invariably exhibits greater degrees of biological potency (Simpkin et al., 2007). The apelin/APJ system distributes over many tissues, suggesting that they might play broad roles in physiology and pathophysiology. Current data shows that apelin is involved in the regulation of cardiovascular, gastrointestinal, and immune functions, as well as in bone physiology, fluid homeostasis, and cardiovascular system development (Kleinz and Davenport, 2005; Masri et al., 2005). Apelin has been shown to suppress apoptosis in osteoblastic cell line MC3T3-E1 and human osteoblasts via the APJ/PI3K/Akt signaling pathway (Xie et al., 2000; Tang et al., 2007). However, there has been no report about the effect of apelin on the viability of BMSCs. Serum deprivation (SD) has been widely used as a typical apoptotic insult to a variety of cell types and is regarded as an insult that mimics a major ischemic component in vivo (Behrens et al., 1996; Tsubokawa et al., 2010; Chauvier et al., 2005). SD has been shown to induce apoptosis in BMSCs through the mitochondrial pathway (Tatemoto et al., 1998). The present investigation employed this apoptotic model to test the protective effect of apelin-13 on BMSCs. Reactive oxygen species (ROS) generation, mitochondrial depolarization, cytochrome c release, and caspase activation play important roles in the SD-induced neuronal apoptosis (Chauvier et al., 2005). Inhibited PI3K and increased extracellular signal-regulated MAPK (extracellular regulated kinases, ERK1/2) have been linked to SD-induced neuronal apoptosis (Chang et al., 2004). Our recent work shows that apelin-13 is protective against SD- and ischemia-induced cell death in cortical neurons and cardiomyocytes via the mechanism of regulating the ERK1/2 and Akt phosphorylation (Zeng et al., 2009, 2010). Apelin-13 treatment prevented the loss of mitochondrial membrane potential during SD treatment. Moreover, apelin-13 reduced the ROS generation and the cytochrome c release from mitochondria to cytoplasm as well as activation of caspase-3. These results indicate that apelin protects cells via multiple mechanisms (Zeng et al., 2009, 2010). Whether apelin-13 has similar protective effects on undifferentiated stem cells or progenitor cells has not been explored. The present investigation tested the hypothesis that apelin-13 could protect BMSCs from apoptosis by mitochondrial protection mediated by MAPK/ERK1/2 and PI3K/Akt signaling pathways. Data from this investigation may be useful for promoting survival of transplanted BMSCs in ischemic tissue, which will enhance the efficacy of cell therapy.