ReviewBioactive molecules derived from umbilical cord mesenchymal stem cells
Introduction
Mesenchymal stem cells (MSCs) are multipotent adult stem cells capable of self-renewal that have been isolated from many different tissues, such as bone marrow, adipose tissue, umbilical cord blood, peripheral blood, dermis, liver, skin, and skeletal muscle (Rhee et al., 2015). They are promising tools in cell therapy (Malgieri et al., 2010) and have shown therapeutic efficacy against autoimmune, inflammatory, and degenerative diseases (Maxson et al., 2012, Pati et al., 2010, Shohara et al., 2012, Ullah et al., 2015, van den Akker et al., 2013, Zimmerlin et al., 2013). MSCs have been extensively applied to treat various conditions in animal models (Rastegar et al., 2010), such as rheumatic diseases (Maumus et al., 2013), spinal cord injuries (Dasari, 2014, Ryu et al., 2012), musculoskeletal regeneration (Steinert et al., 2012, Wang et al., 2015), and wound healing (Kim et al., 2013b). Preclinical trials using MSCs have shown encouraging signs for curing a range of otherwise difficult-to-treat diseases. Understanding the molecular and biochemical mechanisms defining MSCs is the key to their therapeutic application. Several studies have demonstrated that multilineage differentiation capacity, immunomodulatory role, homing ability, and strong paracrine capacity of MSCs contribute to tissue repair (Liang et al., 2014). Trans-differentiation into multiple cell lineages, including osteocytes, chondrocytes, adipocytes, cardiomyocytes, islet-like cells, neurocytes, and fibroblasts, enables the replacement of local damaged cells and tissues. MSCs also play an immunomodulatory role when they interact with immune cells and inflammatory factors. Moreover, MSCs display a dramatic homing ability towards tumors and pathological sites. Cultured MSCs secrete valuable factors whose therapeutic effects can be classified into six main categories: immunomodulation, anti-apoptosis, angiogenesis, support for growth and differentiation of local stem and progenitor cells, anti-scarring, and chemoattraction (Meirelles Lda et al., 2009). Primary trophic secretion components include growth factors, chemokines, and anti-inflammatory proteins (Murphy et al., 2013). Regulation of MSC secretions depends on different stimuli, such as hypoxia, pro-inflammatory stimuli, and three-dimensional growth. The most physiologically relevant factors present in MSC conditioned medium (CM) are hepatocyte growth factor (HGF), transforming growth factor (TGF)-β, vascular endothelial growth factor (VEGF), secreted product of tumor necrosis factor (TNF)-stimulated gene-6, prostaglandin E2 (PGE2), and galectins 1 and 9 (Bigildeev et al., 2015, Madrigal et al., 2014). Depending on their source, MSCs possess different proliferation capacity, as well as transcriptome, proteome, and secretome profiles, which define their regenerative, homing, and immunomodulatory activities (El Omar et al., 2014). Therefore, the purpose of many current studies is to find an optimal cell source for clinical therapy (Barberini et al., 2014, El Omar et al., 2014, Kim et al., 2013a, Troyer and Weiss, 2008). Bone marrow-derived MSCs (BMSCs) are still the most frequently researched cell type and are often considered as the gold standard (Hass et al., 2011). However, they require invasive harvesting procedures (Martins et al., 2014) and their use is limited by the likelihood of viral exposure, possibility of donor morbidity, and significant decrease in cell number and proliferation/differentiation capacity with age (Yoo et al., 2009). Umbilical cord blood-derived MSCs are hampered by very low yields, but present clear advantages associated with their origin from umbilical cord blood such as haematopoietic reconstitution (Secco et al., 2008). Although human adipose tissue-derived mesenchymal stem cells (ASCs) and UCMSCs share considerable similarities in their immunological phenotype and pluripotency, UCMSCs exhibit a more prominent cytokine secretion profile (Hu et al., 2013). This has led to a switch in attention towards UCMSCs (Bongso and Fong, 2012, Fan et al., 2010, Moretti et al., 2009, Taghizadeh et al., 2011), which also benefit from superior proliferation rates, powerful differentiation capacity, and low immunogenicity (Jo et al., 2008).
Here, we will provide an overview of the biological characteristics and secretion properties of UCMSCs as well as discuss their potential applications.
Section snippets
Biological properties of UCMSCs
The International Society for Cellular Therapy has proposed a set of minimum criteria that define MSCs: (a) plastic adherence; (b) a specific set of cell surface markers (CD73, CD90, CD105) and concomitant absence of CD14, CD34, CD45, and human leucocyte antigen-DR; and (c) ability to differentiate into adipocytes, chondrocytes, and osteoblasts in vitro (Dominici et al., 2006). UCMSCs, like other MSCs, meet these criteria. Wharton’s jelly is the section of the umbilical cord most commonly used
Secretion by UCMSCs
Cell secretions constitute an extremely complicated pool of molecules and CM contains all the trophic factors secreted by UCMSCs. Tandem mass spectrometry (MS/MS), stable isotype labeling by amino acids combined with liquid chromatography-MS/MS analysis, sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunoblotting, and enzyme-linked immunosorbent assay (ELISA) are used for detecting secretome components (Lavoie and Rosu-Myles, 2013). Wang (2014) analyzed the protein content of
Paracrine mechanisms of UCMSC-based therapy
The effect of MSCs on tissue repair is usually attributed to MSC differentiation and replacement of local dead or dysfunctional cells. However, equally important are soluble secreted trophic factors, such as growth factors, chemokines, and cytokines, which are thought to be essential for migration to damaged tissues via cytomembrane, vesicles, and adhesion molecules. Next, we will discuss in detail whether the above mechanisms are interdependent and which one plays a greater role, with an eye
Conclusion and future perspectives
Stem cell-based therapy represents a new opportunity for the treatment of various difficult-to-treat diseases. The attention has shifted from hematopoietic stem cells to MSCs, among which UCMSCs possess superior beneficial properties. These include homing to injured tissue, low immunogenicity, multidirectional differentiation, and extensive secretion profiles. However, current evidence is insufficient and thorough preclinical studies in different animal models should be performed. Additional
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and materials
There are no experimental datas and materials included in this review.
Competing interests
The authors declare no conflict of interest.
Funding
This work was supported by the Natural Science Foundation of China [grant number: 31172379], the Fostering Fund for Academic-Technology Leaders of Sichuan Province, and the Curriculum of National Innovation Experiment Program for University Students of Sichuan Agricultural University [grant number: 201410626014].
Author contributions
Lipeng Bai, Danting Li, Jie Li, Zhengzhong Luo, Shumin Yu, Suizhong Cao, Liuhong Shen, Zhicai Zuo, and Xiaoping Ma wrote the paper. Shumin Yu edited the paper.
Acknowledgments
Special thanks to the group of Curriculum of Innovation Experiment Program for University Students in Sichuan Agricultural University.
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