Between 10,000 and 14,000 spinal cord injury (SCI) are reported every year in the United States [1], and medical treatments that deal with acute SCI and subsequent complications are extremely expensive. Following the occurrence of SCI, there is a therapeutic window in which the devastating outcomes of secondary injury can be improved [2]. Therapeutic schemes implemented in response to SCI can be divided into two categories: 1) prevention or amelioration of secondary injury and 2) regenerative intervention. At present, there are no therapeutic methods capable of promoting the complete recovery of neurological damage resulting from SCI. Nonetheless, several research teams have reported limited recoveries through the transplantation of pluripotent cells; therefore, stem cells are being widely studied to develop strategies for the regenerative treatment of SCI [3].

Neuronal cell death is the major pathogenetic mechanism of various neurological disorders, including SCI disorder; therefore, stem cell therapy is a promising strategy to replace injured cells through regeneration [4]. The effectiveness of transplanting embryonic stem cells in patients suffering from neurodegenerative disorders, such as Parkinson's [5], Huntington's [6], and SCI has been investigated [7]. However, logistical and ethical considerations have presented challenges to further therapeutic developments in this area, raising the clinical applicability of autologous stem cells [8]. Peripheral stem cells (PSCs) can be isolated from various tissues, such as bone marrow, adipose tissue, umbilical cord blood, muscles, corneal stroma, tooth buds, and nasal mucosa, thereby providing an alternative source for use in transplantation medicine [9,10]. The preparation of autologous stem cells may be an appropriate strategy for clinical applications, as there is no need for in vitro extension and because these cells can be cultured in serum free conditions [11].

Various strategies have been developed for the treatment of animals with SCI, such as adding growth factors [12], providing peripheral nerve or embryonic tissue [13], and transplanting Schwann cells [14]. Recent studies have shown that olfactory ensheathing cells (OECs) have therapeutic potential to enhance axonal restoration and repair in demyelinating-related disorders [15,16]. Previous researchers have further highlighted the therapeutic potential of OECs in neurodegenerative disorders including SCI; however, the mechanisms underlying neural regeneration have yet to be elucidated [16,17]. This review presents information currently available on SCI and OECs, summarizes the potential therapeutic effects of OECs in SCI animal models and human clinical trials, and discusses various potential molecular mechanisms.

OECs are found in the olfactory bulb and olfactory mucosa in the vicinity of the lamina propria. In animal neurodegenerative disorders, they are believed to induce neurotrophic effects similar to those of Schwann cells [18]. The olfactory mucosa are stimulated by a variety of external environmental variables. As a result, they are under perpetual threat of damage and constantly being repaired. Nonetheless, the fact that the sense of smell is rarely lost throughout this process of injury and repair can be attributed to the constant regeneration of olfactory nerve cells [19]. More specifically, the olfactory mucosa is constantly renewed through OECs which are capable of supporting neurogenesis throughout life [20,21]. Nerve cells projected from the nasal mucosa are directed to olfactory nerves associated with the central nervous system [22].

As demonstrated in previous studies, the olfactory mucosa includes unmyelinated olfactory nerves with OECs and sheet-like processes of olfactory nerve fibroblasts [23,24]. The OECs enable the growth of axons from the neurons of the olfactory mucosa to reinnervate the olfactory bulb and in turn form synapses in the brain [17]. The neuroregenerative ability OECs through axonal outgrowth has shown promise in the treatment of SCI in relevant animal models [25]. Furthermore, a number of investigations have shown that OECs can play an important role in the recovery of bladder function and phrenic nerve activity following SCI [3]. This makes OECs a useful type of pluripotent cell for transplantation, capable of facilitating nerve regeneration in SCI patients.

The spinal cord contains neuronal cell bodies and serves as a conduit connecting motor and sensory information, which is necessary for neurotransmission between the brain and the body [26]. In component of spinal cord include neuron cells and the axon of long nerve fibers [27]. Axonal conduction follows either a downward or upward path, carrying signals to and from the brain [28]. Most axonal pathways are insulated by a white sheath called myelin, otherwise known as white matter. Neuronal trees have branches called dendrites, which receive signals from other nerve cells, constitute gray matter, located in the center of the spinal disc as a butterfly shaped region.

SCI refers to spinal cord damage and is more commonly caused by trauma than disease [29]. Traumatic injuries to the vertebrae often result from accidents, such as motor vehicle mishaps, falls, acts of violence, and recreational injuries. SCI may also be caused by infection or inflammation in the region of the spinal tissue, as well as polio, spina bifida, transverse myelitis, and multiple sclerosis [30]. If damage occurs longitudinally across the spinal tract, SCI can lead to the loss of nerve function [31]. Without effective treatment, the neurological deficits of SCI can have long-term effects for the patient, the family, and society as a whole [32].

OEC application in SCI treatment

The traditional view that the central nervous system injury due to poor intrinsic and extrinsic environmental regeneration inhibition, resulting in damage axons cannot regenerate [33]. Recent discoveries have moved the transplantation of OECs to the forefront of SCI treatments [34]. OCEs have attracted considerable attention because the unique nature of these cells can promote nerve regeneration and the recovery of nerve function in the spinal cord. Besides, transplantation of OECs into the injured spinal cord display an excellent regenerative effects mediated through reorganize the glial scar, remyelinate axons and stimulate blood vessel formation [35]. According to the results of behavioral examinations, OEC transplantation can provide considerable improvement in functional recovery following SCI (Table 1) [36-48]. Use of OECs transplantation obtained axonal regeneration, although it looks mildly progressive, might provide an adequate foundation for the functional benefits [38].

Table 1: OECs applications upon SCI in the past few years.

Previous results from clinical trials have also confirmed that OECs can be helpful in neurological recovery and relieving the symptoms of SCI [46]. When OECs are transplanted into the demyelinated spinal cord, these cells help to repair defective myelin and improve the conductance of the remyelinated axons. Other researchers have demonstrated the ability of OECs to promote the regeneration of axons in the vicinity of spinal cord lesions. Additionally, the safety and feasibility of autologous mucosal OECs transplantation have been widely addressed in SCI patients (Table 1). No adverse effects related to the transplantation of OECs have been observed, and no indication of neurological exacerbation, neuropathic pain, neuroinfection or tumorigenesis has been reported [45].

The molecular mechanisms involved in the treatment of OECs have been investigated with regard to neurotrophins, extracellular matrices, ligands, transcriptional coactivators, and other factors [18]. Neurotrophins have demonstrated benefits in prolonging the survival of neurons and axonal expansion. Many neurotrophins secreted from hOECs/ONFs, such as BDNF [47], VEGF [49] and GDNF [50], have been studied extensively to determine whether they play a role in facilitating cerebral plasticity and improving functional rehabilitation in SCI animal models. In recent reports, stromal cells have been used to derive factor-1. Its receptor, CXCR4 (SDF-1/CXCR4), has been shown to provide generalized trophic support to neuronal cells and assist in the repair of the spinal cord [17]. SDF-1 is a CXC chemokine generated by mesenchymal stem cells. This chemokine is a potent chemo-attractant for hematopoietic stem cells that are constitutively expressed by peripheral tissue [17].

For more effective therapeutic potentials of the extracellular matrix (ECM) approach has been deemed a suitable method to control the fate of stem cells, prolong cell survival, and promote differentiation into neuronal precursors [51,52]. Research has indicated that ECM, such as functional three-dimensional scaffolds and microenvironment factors assembled into a matrix, are correlated with neuron-like cells differentiation [53]. In addition, cells cultured in vitro in ECM have demonstrated the ability to perform the standard functions of neuron cells and also have therapeutic potential in relevant animal models. These findings support the applicability of the ECM cultured cells in the treatment of SCI.

The ECM can be remodeled to create a niche that controls the differentiation outcomes and inhibits undifferentiated transplanted cells. Thus, directly programming endogenous stem cells into tissue-specific lineages may be an achievable goal [54]. The alteration of ECM in situ has demonstrated considerable potential to increase the survival and differentiation rate of transplanted cells, thereby enhancing the effectiveness of cell-based therapies [55,56]. A finely defined microenvironment is likely able to provide endogenous undifferentiated stem cells (including transplanted undifferentiated stem cells) with a suitable niche for differentiation [57]. Autologous hematopoietic stem cells (HSCs) are known to exist in bone marrow and have the capacity to differentiate into most cell lines. However, they rarely end up in peripheral tissue, where endogenous PSCs are already scarce [58]. Additionally, granulocyte colony-stimulating factors (GCSFs) are widely applied to mobilize HSCs in many types of treatments. Thus, therapies combining the use of GCSFs could be adopted to transport HSCs to tissues requiring treatment [59,60]. Other studies have demonstrated that the combination of defined transcription factors has the ability to convert somatic cells directly into functional nerve cells and does not require iPS cells fate, to reduce tumorigenic potential [61]. In summary, in situ alteration of the extracellular matrix to direct the programming/reprogramming of endogenous cells is a promising method for the treatment of SCI.