Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy

3.1 Neural regeneration

The application of MSCs derived from human WJ has been yielded promising results in the treatment of neurological diseases. It has been established that the WJ-MSCs are capable of differentiating into neural cells (Ma et al., 2005; Peng et al., 2011). WJ-MSCs are also associated with more nerve regeneration, neuroprotection, and less inflammation following spinal cord injury (SCI) in dogs compared to adult MSCs from BM or adipose tissue (Ryu et al., 2012). In 2008, a study provided evidence that transplantation of human WJ-MSCs is an effective approach to promote the regeneration of corticospinal fibers and locomotor recovery after SCI in rats (Yang et al., 2008). Intrathecal transplantation of WJ-MSCs has demonstrated anti-inflammatory effects in SCI rat models through targeting the inflammasome complex (Mohamadi et al., 2018; Mohamadi et al., 2019). Additionally, Li et al. (2016), indicated that the recovery of motor function and integrity of the spinal cord was better in WJ-MSC transplanted rats than the control group because of reducing interleukin-1b and increasing nerve growth factor expression. It has also been concluded that the therapeutic effect of WJ-MSCs in SCI is dose-dependent and could be accelerated by repeated application (Krupa et al., 2018). Nevertheless, it has been proven by Chudickova et al. (2019) that conditioned media derived from WJ-MSCs has a superior effect than direct MSC transplantation for the treatment of SCI in rats.

In a study conducted by Fu et al (2006), human WJ-MSCs were successfully differentiated into dopaminergic neurons in vitro. Then, the administration of these differentiated MSCs into the striatum of rats with Parkinson's disease (PD) could alleviate amphetamine-induced rotation, showing their promising therapeutic effects. Transplantation of undifferentiated human WJ-MSCs was also significantly reduced amphetamine-evoked rotation in the rat model of PD (Weiss et al., 2006).

Ding et al. (2007) reported that intracerebral injection of WJ-MSCs into the stroke rat model could enhance neuroplasticity via regulating the expression of β1-integrin. Furthermore, neural differentiation of human WJ-MSCs could improve the recovery of neurological function after implantation in ischemic stroke rats (Zhang et al., 2017). Intracerebral transplantation of human WJ-MSCs has also neuroprotective effects on a rodent model of stroke through reducing inflammation and increasing the expression of trophic factors (Wu et al., 2018b).

Moreover, Wang et al. (2019) have recently investigated the therapeutic effect of human WJ-MSCs in a mouse model of transected sciatic nerves. The data showed that the human WJ-MSCs group had a significantly better functional recovery, quality of regenerated nerve, and higher neurotrophic factors in comparison with the nontreated and human adipose stem cell treated control groups.

In another study, Zhang et al. (2014a) focused on the potential of human WJ-MSCs in the treatment of neonatal rats with hypoxic-ischemic encephalopathy (HIE). The results indicated that intravenous transplantation of these MSCs at an early stage of HIE significantly improved the behavior of rats and suppressed gliosis. It has also been shown that thrombin preconditioning of human WJ-MSCs could remarkably attenuate severe HIE-induced brain infarction and improve behavioral function in neonatal rats through enhancing their anti-inflammatory, antiapoptotic and antiastroglial activities (Kim et al., 2019). Another study suggested that extracellular vesicles derived from human WJ-MSCs might protect against HI-induced apoptosis in neuronal cells by delivering let-7-5p miR (Joerger-Messerli et al., 2018).

3.2 Myocardial regeneration

The beneficial effects of WJ-MSCs in the regeneration of myocardial tissue have been shown in several studies. For instance, Lopez et al. (2013) suggested that intravenous administration of WJ-MSCs might be more beneficial than BM-MSCs as an off-the-shelf therapy for myocardial ischemia. Liu et al. (2016) found that intracoronary transplantation combined with multiple intravenous deliveries of WJ-MSCs may enhance left ventricular function, perfusion, and remodeling in the porcine model of chronic myocardial infarction. The impact of WJ-MSCs has also been evaluated in acute myocardial infarction (AMI) porcine models and followed-up to 6 weeks (Zhang et al., 2013). The transplanted MSCs were able to differentiate into cardiomyocytes, induce angiogenesis, reduce apoptosis and fibrosis, decrease infarct size, and consequently enhanced ventricular remodeling and function. Moreover, WJ-MSC therapy was shown to attenuate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by decreasing tumor necrosis factor-alpha and transforming growth factor-beta 1 (TGF-β1) expression and ERK1/2 signaling activation (Zhang et al., 2018b). Bhuvanalakshmi, Arfuso, Kumar, Dharmarajan, and Warrier (2017) reported that epigenetic modification could enhance the differentiation of WJ-MSCs into the cardiomyocyte lineage through regulation of Wnt mediators in cardiac injury mice model. It has also been proposed that combinatory therapy with human WJ-MSCs and insulin-like growth factor-1 significantly enhanced myocardial regeneration, angiogenesis, reduced fibrosis, and improved cardiac function in a rabbit model of MI (Rabbani et al., 2018). Furthermore, WJ-MSCs modified to overexpress antifibrotic factors provided a novel strategy for protecting cardiac fibrosis in vitro (Nimsanor, Phetfong, Kitiyanant, Kamprom, & Supokawej, 2019). It has also been shown that WJ-MSCs could be a more suitable substitute of endothelial and interstitial cells in cardiovascular regenerative medicine as compared to amniotic membrane because of their higher viability, proliferation, and superior collagen deposition properties (Pu et al., 2017).

Martin-Rendon et al. (2008) compared the differentiation potential of MSCs derived from BM, umbilical cord, and cord blood into cardiomyocytes in vitro. In spite of other studies, their result indicated that WJ and cord blood MSCs did not express cardiac-specific markers either spontaneously or after treatment with 5-azacytidine and may not able to generate an acceptable amount of cardiomyocytes in MI cell therapy without pharmacological or genetic modification.

3.3 Cutaneous regeneration

WJ-MSCs have also been broadly studied as a promising source for skin wound healing. For example, as described by Azari et al. (2011) in their article, caprine WJ-MSCs showed complete re-epithelialization of the wounds with minimum inflammation and scar formation on Day 7. However, no complete epithelialization was observed in the untreated control group after 12 days. Administration of human WJ-MSCs has also improved wound healing in an excisional full-thickness skin murine model through enhancing re-epithelialization, vascularization, proliferation, survival, and migration of skin fibroblasts (Arno et al., 2014). An animal model of burn has also been employed to confirm the potential of WJ-MSC therapy in this pathology. Subcutaneous injection of the WJ-MSCs suppressed secondary inflammation via reducing inflammatory cytokines and, therefore, promoted burn healing process and skin repair in rat burn models (Zhang et al., 2015). Sun, Zhang, Song, Zhu, and Zhu (2019) assessed the healing effects of these MSCs in radiation-induced skin injury in rats. They found that WJ-MSCs improved wound healing quality by promoting cell proliferation, sebaceous glands regeneration, and angiogenesis. Another animal study showed that WJ-MSCs primed with poly I:C or Interferon-gamma have enhanced anti-inflammatory potential in atopic dermatitis (Park et al., 2019). The impact of heterologous WJ-MSCs has also been investigated on a nonhealing large chronic wound in a filly. In this study, the application of WJ-MSCs contributed to complete wound healing with no side events or scar tissue formation (Lanci, Merlo, Mariella, Castagnetti, & Iacono, 2019). Recently, Martin-Piedra et al. (2019) also reported that because of their epidermal differentiation capability and lack of HLA antigens, WJ-MSCs are more suitable sources for the generation of bioengineered human skin substitute than MSCs derived from adipose tissue, dental pulp, and BM. Additionally, two studies have been demonstrated that a mixture of WJ-MSCs and skin microparticles could remarkably elevate the quality of cutaneous wound regeneration in mice models (Shi, Jia, Liu, & Chen, 2015; Zhang, Hao, Liu, Fu, & Han, 2012b). WJ-MSCs administrated on a decellularized amniotic membrane scaffold into the wound bed, showed reduced scar formation with hair growth (Sabapathy, Sundaram, Mankuzhy, & Kumar, 2014). Similarly, the combination of WJ-MSCs and silk fibroin scaffold exhibited significant enhancement in wound re-epithelization and reduced fibrotic scar formation (Millan-Rivero et al., 2019). Besides, the association of human WJ-MSCs and poly (vinyl alcohol) hydrogel membrane resulted in the promotion of wound healing in two dogs with chronic skin wounds where the standard treatments failed (Ribeiro et al., 2014).

3.4 Hepatic regeneration

The potential of WJ-MSCs to differentiate into the endodermal lineage, such as hepatocyte-like cells, makes them an attractive alternative for the treatment of liver diseases (Buyl et al., 2014; Mortezaee et al., 2015; Vojdani et al., 2015; Zhang, Lie, & Wei, 2009). The impact of WJ-MSCs has been investigated in a liver fibrosis rat model by Tsai et al. (2009). They reported that the administration of human WJ-MSCs could significantly reduce liver fibrosis by decreasing the collagen deposition, levels of serum glutamic oxaloacetic transaminasea, glutamic pyruvate transaminase, as well as TGF-β1 and increasing mesenchymal-epithelial transition factor–phosphorylated type and hepatocyte growth factor (HGF). Lin et al. (2010) also determined that intravenous injection of human WJ stem cells downregulate liver collagen and thus could alleviate liver fibrosis in rat models. In addition, WJ-MSCs have been proven to have the capacity in the enhancement of sepsis-associated liver damage in rats (Condor et al., 2016). Li et al. (2015) also loaded WJ-MSCs into poly scaffolds and administrated into liver-injured mice. One month after WJ-MSC transplantation, the liver morphology significantly promoted and looked similar to a normal one. Furthermore, one report has indicated that WJ-MSC therapy is able to improve liver function and rescue the hepatotoxicity induced by D-Galactosamine in acute liver injury mice model (Ramanathan et al., 2017). Zhang et al. (2012a) found that human WJ-MSCs could be a potential source for cell therapy of acute liver failure when compared to human hepatocytes, because of their ability in stimulating endogenous liver regeneration through paracrine effects. It has been also shown that intrauterine xenotransplantation of WJ-MSCs successfully relived liver injury in rabbit fetuses through inducing the expressions of albumin, α-fetoprotein, hepatic nuclear Factor 4, and CYP2B6 messenger RNA (Rezaeian et al., 2018). Another study suggested that the application of praziquantel in combination with WJ-MSCs has more beneficial effects in the treatment of the Schistosoma mansoni-induced liver fibrosis, presumably via enhancing differentiation capacity of the transplanted WJ-MSCs to functioning liver-like cells (Hammam et al., 2016).

Nevertheless, Rengasamy et al. (2017) suggested that human BM-MSCs alleviate CCl4-induced liver fibrosis more effectively than WJ-MSCs in rat models which could be associated with their expression of certain matrix metalloprotease and angiogenic factors.

3.5 Renal regeneration

With a rat model of unilateral ischemia-reperfusion injury (IRI), a single intravenous administration of WJ-MSCs exerted beneficial effects on IRI-induced acute and chronic kidney injury via an endocrine mechanism (Du et al., 2012). According to the results of this study, activated Akt signal in tubular epithelial cells (TECs) resulted in a decrease of apoptosis, the elevation of proliferation, and the induction of endogenous HGF. Similarly, another animal study demonstrated that these MSCs contributed to the induction of native and foreign HGF in damaged TECs at the initial stage of acute kidney injury (AKI), which subsequently resulted in the EMT delay and mitigation of renal fibrosis (Du et al., 2013). It has also been shown that human WJ-MSCs seeded in a decellularized kidney scaffold could ameliorate renal fibrosis through decreasing EMT by the TGF-β/Smad signaling pathway after subtotal nephrectomy in rats (Hu et al., 2020). Moreover, the human WJ-MSC potential has been proven in the promotion of renal injury in streptozotocin-induced diabetic mice (Maldonado, Huang, Yang, Xu, & Ma, 2017).

Several studies also indicated that microvesicles derived from WJ-MSCs ameliorate renal IRI through various mechanisms including regulating Erk1/2 signaling, enhancing renal cell proliferation, mitigating apoptosis and inflammation, and suppressing CX3CL1 (Chen, Yan, Song, Ding, & Du, 2017; Wu et al., 2018a; Zou et al., 2014). Zhang et al. (2014b) reported that a single infusion of human WJ-MSC-microvesicles could prevent renal injury by alleviating oxidative stress in the early stage of IRI through downregulating NOX2 expression. Moreover, extracellular vesicles released from human WJ-MSCs protected against AKI via antioxidation by improving Nrf2/ARE activation in rats (Zhang et al., 2016).

3.6 Cartilage regeneration

It has been established that human WJ-MSCs could be better sources for fibrocartilage tissue engineering compared to BM-MSCs (Wang, Tran, Seshareddy, Weiss, & Detamore, 2009). It has been shown that WJ-MSCs could be an appealing source, when combined with appropriate scaffolds, for cell therapy in cartilage disorders. Recently, Zhang et al (2019) revealed that coculture of human WJ-MSCs and primary articular cartilage cells in acellular cartilage extracellular matrix-oriented scaffold could successfully construct engineered hyaline articular acrtilage in vitro. Moreover, a study conducted by Paduszyński et al. (2016), assessed changes in transcriptional activity of cartilaginous genes through in vitro chondrogenic differentiation of WJ-MSCs on 3D poly (l-lactide-co-glycolide, PLGA) scaffolds. Their findings suggested that the chondrogenic capacity of WJ-MSCs cultured on the PLGA scaffolds could be used as a promising cell-based cartilage repair therapy. Similarly, combining WJ-MSCs with 3D HyStem hydrogel and hybrid scaffolds promoted cartilage regeneration (Aleksander-Konert, Paduszynski, Zajdel, Dzierzewicz, & Wilczok, 2016; Shie et al., 2017). Besides, WJ-MSCs embedded into collagen hydrogel underwent enhanced chondrogenic differentiation by elevating the expression of cartilage-specific matrix proteins (Chen et al., 2013). A combination of WJ-MSCs and acellular cartilage extracellular matrix scaffold also provided better quality in repair and regeneration of cartilage in comparison with microfracture in a caprine model (Zhang et al., 2018a).

It has also been indicated that WJ-MSCs have great potential for fabricating tissue-engineered cartilage without scaffold (Liu et al., 2014). Modulation of metalloproteinase gene expression in synovium and prevention of cartilage degradation reported in 30 rabbits with osteoarthritis (OA), following intra-articular administration of WJ-MSCs into the knee joint (Saulnier et al., 2015). Cheng et al. (2019) have found that combined extracorporeal shockwave therapy and WJ-MSCs are more effective for the treatment of early OA in rat knee.

3.7 Bone regeneration

Growing evidences have demonstrated that WJ-MSCs are potentially valuable candidates for bone regeneration as an alternative to BM-MSCs (Ansari et al., 2018; Cabrera-Perez et al., 2019; Kang et al., 2012; Lim et al., 2018). In a recent report, Bustos et al.(2017) have found that modulation of RUNX2/p57 expression via inhibition of JARID1B histone demethylase is associated with the upregulation of WJ-MSC osteoblastic potential. Likewise, RUNX2/p57, but not SP7 gene expression, has demonstrated to be strongly activated upon induction of WJ-MSC osteoblast differentiation (Sepulveda et al., 2017). Another study conducted by Shi, Zhou, Huang, Zhang, and Wang (2018) provided additional insight about the interactions of hydroxyapatite nanoparticles with WJ-MSCs and suggested their promising therapeutic potential in bone repair.

Todeschi et al. (2015) proposed that subcutaneous implantation of WJ-MSCs loaded onto scaffolds in mice with bone defects could result in bone regeneration by the enhancement of angiogenesis. Human WJ-MSCs seeded into hierarchical fibrous scaffolds were also shown as an appropriate strategy for bone tissue engineering (Canha-Gouveia et al., 2015). Moreover, human WJ-MSCs-loaded nano-hydroxyapatite/chitosan/gelatin scaffolds were shown as an ideal bone substitute (Jamalpoor, Taromi, Soleimani, Koudehi, & Asgari, 2019).

A recent systematic review conducted by Ansari et al. (2018) systematically analyzed the osteogenic induction capacity of WJ-MSCs. They concluded that WJ-MSCs are potential stem cell sources which could be used as an alternative to BM-MSCs for bone fracture healing.

3.8 Muscular regeneration

Recently, Su et al. (2019) reported that WJ-MSCs could restore functional impairment postmuscle injury in mice via downregulating neutrophil-mediated acute inflammation and antifibrotic effects. Kwon et al. (2016) elucidated that human WJ-MSCs and human WJ-MSC-derived XCL1 protein could be used as novel therapeutic approaches for the treatment of myopathies by their antiapoptotic effects. In addition, human WJ-MSCs successfully attenuated sarcopenia in aged mice model associated with skeletal muscle cell activation, and downregulation of apoptosis and inflammation (Wang et al., 2018a). It has also been demonstrated that TGF-β1 and ascorbic acid are effective in differentiating WJ-MSCs towards smooth muscle cells (Mesure, Huber-Villaume, Menu, & Velot, 2017). The pretreatment of WJ-MSCs with Sdf-1 was proven to play a key role in increasing their migration ability during skeletal muscle regeneration in vitro (Kowalski et al., 2017). Moreover, WJ-MSCs are associated with an increased neuro-muscular regeneration when combined with biodegradable and biocompatible biomaterials, enhancing the recovery of sensory and motor function in neurotmesis injuries (Caseiro et al., 2017).