Open access peer-reviewed chapter - ONLINE FIRST
Summary of the classification of peripheral nerve injuries. Adapted from Menorca et al. [18].
Abstract
Peripheral nervous system (PNS) injuries pose a significant clinical challenge, often resulting in motor, sensory, or autonomic dysfunction that impacts patients’ quality of life. Despite the PNS’s capacity for regeneration, outcomes are not always satisfactory. In response to these challenges, new research is encouraged to provide more effective therapeutic approaches. In this context, cellular therapy emerges as a promising alternative. Evidence of the therapeutic potential of Schwann cells (SCs) in PNS injuries has been observed, yet their clinical application faces significant limitations. To address these difficulties, several studies have highlighted the ability of mesenchymal stem cells (MSCs) to transdifferentiate into Schwann-like cells (SLCs), holding the potential for treating peripheral nerve injuries. Therefore, this chapter not only reviews the involvement of SCs in peripheral nerve regeneration but also provides an overview of recent advancements in developing SLCs derived from MSCs and their therapeutic potential in peripheral nerve injuries. Additionally, it explores the future perspective of manufacturing nerve guidance conduits (NGCs).
Keywords
- nerve injury
- neuroregeneration
- cell-based therapy
- nerve guidance conduits
- regenerative medicine
1. Introduction
Injuries to the peripheral nervous system (PNS) are prevalent among both humans and animals, presenting a significant clinical challenge [1, 2]. These injuries stem from various causes, frequently associated with traumatic incidents [3, 4]. The resulting motor and sensory impairments are the foremost consequences, often leading to functional deficits and detrimentally impacting the patient’s quality of life [5, 6].
While the PNS demonstrates an innate ability for regeneration, primarily attributed to Schwann cells (SCs), the results frequently fall short of expectations [7, 8]. Given the complexities associated with peripheral nerve injuries, new research is encouraged to develop more efficacious therapeutic strategies.
In this context, cellular therapy emerges as a promising alternative. Evidence of Schwann cells’ therapeutic potential in treating PNS injuries has been observed [9, 10]. Nevertheless, its clinical application faces substantial limitations, including the necessity to sacrifice a functional nerve to obtain the cells and the challenge of cell expansion [11, 12].
To address these challenges, several studies have highlighted the potential of mesenchymal stem cells (MSCs) sourced from diverse sources and species to transdifferentiate into Schwann-like cells (SLCs), offering promising avenues for treating peripheral nerve injuries [13, 14, 15].
Therefore, this chapter reviews the role of SCs in peripheral nerve regeneration and offers insights into recent progress in creating SLCs from MSCs and their therapeutic potential in peripheral nerve injuries. Furthermore, it explores the future perspectives of fabricating nerve guidance conduits (NGCs).
2. Anatomy of the peripheral nerve
The PNS is composed of neurons, glial cells (including SCs), and stromal cells [16, 17]. This system consists of a combination of motor, sensory, and autonomic nerves responsible for connecting tissues and organs to the central nervous system (CNS) [18, 19]. Each peripheral nerve is formed by various bundles of fibers known as nerve fascicles or nerve bundles [20, 21]. The nerve fibers consist of axons surrounded by SCs, with differences in their diameter [22]. Axons with larger diameters are considered myelinated, as they are covered by the myelin sheath [23]. This is discontinuous, and the small areas between two segments of myelin, the unmyelinated space, are called Ranvier’s nodes, whose function is to allow the saltatory conduction of nerve impulses from one node to another, speeding up their transmission [22, 24].
Histologically, three layers of connective tissue support the peripheral nerves (Figure 1). The epineurium is the outermost layer comprising numerous nerve fascicles, blood vessels, lymphocytes, and fibroblasts, and is formed by loose connective tissue, whose function is to provide support to nerve bundles, mechanical protection, and isolation from the external environment [20, 25, 26]. The perineurium is the intermediate region that surrounds each nerve fascicle, providing tensile strength to the nerves and acting as a barrier regulating the entry and exit of substances from the nerve [25, 27]. The endoneurium is the innermost layer composed of loose collagen that surrounds both myelinated and unmyelinated nerve fibers, responsible for providing protection and nourishment to the individual axons [26, 28].
Figure 1.
Schematic representation of peripheral nerve anatomy. Created with Biorender.com
3. Peripheral nervous system injuries
Injuries to the PNS hold considerable clinical significance for medicine. These injuries are prevalent and can result in chronic pain, as well as loss of motor, sensory, or autonomic function in affected body segments, thereby diminishing the quality of life for both animals and humans [24, 29, 30, 31].
This condition affects a global population of at least 2 million individuals [2]. Epidemiological studies in developed countries indicate that peripheral nerve injuries occur at an estimated rate of 13–23 cases per 100,000 individuals annually [32]. The outcome of peripheral nerve repair after an injury is often unsatisfactory. It is estimated that only 3% of patients regain sensitivity, while motor function is regained by less than 25% of patients [33].
In veterinary medicine, studies demonstrate that occurrences of brachial plexus or sciatic nerve injuries are frequent in dogs and cats [34, 35]. Moreover, a study revealed that direct trauma is the most common cause of peripheral neuropathies in the thoracic limbs of horses [36]. Additionally, facial nerve paralysis is one of the most common neuropathies in horses, often attributed to traumatic events [37].
4. Classification of peripheral nerve injuries
The researcher Herbert Seddon first introduced the classification of peripheral nerve injuries in 1943, suggesting three distinct grades of injury [38]. The mildest grade, neuropraxia, involves focal demyelination without damage to the axons or surrounding connective tissues. In second-degree injuries, termed axonotmesis, there is a loss of axon continuity beyond focal demyelination. Finally, neurotmesis, the most severe grade, involves complete nerve sectioning.
In 1951, Sydney Sunderland expanded the classification to five grades (I–V), aiming to differentiate the extent of injuries to the connective tissues [39]. Grades I and V correspond to neuropraxia and neurotmesis, respectively, as classified by Seddon. Grades II and IV represent subdivisions of axonotmesis, differing in the involvement of connective tissue. In grade II, axon injury occurs without connective tissue involvement; in grade III, both axon and endoneurium are injured, while in grade IV, damage extends to axons, endoneurium, and perineurium. A new degree of injury was proposed by Mackinnon and Dellon in 1988, although its usage is not widely adopted, it is characterized by the occurrence of mixed lesions (Table 1) [40].
| Seddon | Sunderland | Injury |
|---|---|---|
| Neuropraxia | I | Focal demyelination |
| Axonotmesis | II | Axon damaged without the involvement of the connective tissue |
| III | Axon and endoneurium damaged | |
| IV | Axon, endoneurium, and perineurium damaged | |
| Neurotmesis | V | Complete section of the nerve |
Table 1.
5. Peripheral nerve degeneration
After PNS injury, Wallerian degeneration ensues, marked by distal degeneration of the injured nerve, clearance of inhibitory cellular debris, and proliferation of SCs, establishing a pro-regenerative microenvironment [41]. The axonal microtubules start to disorganize, initiating the dissolution of the axonal cytoskeleton [22]. During the initial days following injury, an influx of calcium ions triggers the activation of calpain proteases, which proceed to degrade axonal neurofilaments, resulting in the release of granular debris [42, 43, 44].
Additionally, SCs convert into a repair phenotype, characterized by a specific profile that facilitates the regeneration process [45]. These cells assist in the degradation of cellular debris and myelin residues, an essential process, considering that myelin contains molecules that inhibit axonal growth [24, 46].
The expression of cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1α, -1β, leukemia inhibitory factor (LIF), and monocyte chemoattractant protein (MCP)-1 is positively regulated [47]. This process leads to SC proliferation and the recruitment of macrophages and other immune cells to the injury site [48]. The macrophages, attracted to the site of injury along with the SCs, are essential for neuroregeneration, as they control the inflammatory process and degrade myelin debris, thus promoting a favorable microenvironment for regeneration [49]. After phagocytizing myelin debris and other waste, macrophages are either eliminated through local apoptosis or re-enter circulation [22].
In the proximal segment of the injured nerve, to a lesser extent, the process of retrograde degeneration occurs until the next preserved Ranvier node [18, 22, 50]. The alterations in this segment differ depending on the severity and location of the injury. Apoptosis typically occurs in lesions near the neuronal cell body, while reversible chromatolysis may occur in certain cases [18, 51].
6. Involvement of Schwann cells in peripheral nerve regeneration
After injury, the PNS exhibits a remarkable capacity for regeneration [52]. Concurrently with the degeneration process, a series of cellular and molecular events are initiated to facilitate nerve repair. Essential to this process is the integrity of both the neuronal body and SCs [53]. The SCs promote regeneration through proliferation, secretion of neurotrophic factors, cytokines, and phagocytosis of myelin debris [46, 54]. These cells proliferate, undergo elongation, and align within their basal lamina to form Büngner bands, which serve as guidance and support for axonal growth [23, 44].
Furthermore, SCs play a pivotal role in synthesizing neurotrophic factors crucial for axonal guidance and growth. These factors include brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), fibroblast growth factor 2 (FGF-2), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophins -3, -4, and -5 (NT-3/4/5), which selectively interact with tropomyosin receptor kinases (TrkA, -B, and -C) and p75 neurotrophin receptors [50, 55].
SCs play a pivotal role in creating a conducive environment post-injury, employing autophagy/myelinophagy mechanisms and orchestrating macrophage recruitment [23]. Macrophages, in turn, release molecules associated with neovascularization, such as vascular endothelial growth factor A (VEGF-A), which aids in oxygen supply to the injury site and guides repair SCs during the regenerative phase [49]. Additionally, SCs produce proteins such as laminin and fibronectin that are incorporated into the extracellular matrix and promote the extension of regenerating axons [56].
Although the PNS exhibits intrinsic repair capabilities, several factors may hinder this process, such as the disorganized growth of regenerating axons, which may fail to reach their target organs, difficulty in obtaining a large number of axons from the proximal to the distal stump, loss of nerve-muscle connections leading to muscle fiber atrophy. Furthermore, when there is chronic loss of contact between Schwann cells and axons, the basal laminae and Büngner bands are not maintained, creating an environment that does not support regeneration (Figure 2) [23, 48, 53].
Figure 2.
Schematic representation of participation of SCs in peripheral nerve regeneration after injury. The SCs promote regeneration through proliferation, recruitment of macrophages, phagocytosis of myelin debris, secretion of neurotrophic factors, incorporation of proteins into the extracellular membrane, and the formation of Büngner bands. Created with Biorender.com
7. Mesenchymal stem cells
MSCs are multipotent progenitor cells of non-hematopoietic origin isolated from various adult tissues. They are characterized by their ability to proliferate and differentiate
Although it is a widely debated topic, studies suggest that MSCs, under specific conditions, possess the ability to differentiate into cells derived from all three germ layers, including neurons, glial cells, and hepatocytes [15, 59, 60, 61].
The International Society for Cellular Therapy has defined minimum criteria for characterizing MSCs in humans. These criteria include adherence to plastic, expression or absence of specific surface markers (Cluster of Differentiation), and the capacity to differentiate into the three mesodermal lineages, osteogenic, adipogenic, and chondrogenic, when subjected to appropriate stimuli [62].
Cellular therapy based on MSCs holds promise in regenerative medicine, especially for treating nerve injuries in both humans and veterinary medicine. MSCs have the potential to differentiate into various cell types and demonstrate immunomodulatory, neuroprotective, anti-inflammatory, antiapoptotic, and angiogenic properties [61, 63].
The initial source of MSCs was discovered in bone marrow, and despite requiring invasive harvesting procedures, it continues to be extensively investigated [64]. The most commonly utilized MSCs in clinical trials are derived from adipose tissue, bone marrow, and umbilical cord [65]. Adipose tissue-derived MSCs offer several advantages, including easy isolation, high availability, and a high rate of
MSCs can also be isolated from a variety of tissues, including Wharton’s jelly, amniotic fluid, endometrium, placenta, hair follicles, skin, peripheral blood, synovium, and synovial fluid [63].
8. Schwann-like cells derived from mesenchymal stem cells
SCs play a crucial role in peripheral nerve regeneration, as previously discussed. However, their clinical application involves sacrificing a healthy nerve from the donor, and their proliferation in culture is time-consuming [69]. Due to these limitations, transdifferentiating MSCs into SLC cells has been proposed as an alternative approach for cell-based therapy in peripheral nerve injuries.
The first protocol developed to induce the transdifferentiation of MSCs into SLCs
The first documented success in transdifferentiating adipose tissue-derived MSCs into SLCs
Other alternative strategies for transdifferentiation include the addition of neurotrophic factors such as BDNF [72] and NGF [73], as well as glucocorticoids, insulin and progesterone to the differentiation medium [74]. Additionally, methods such as electrostimulation [75], intermittent induction [76], cell imprinting [77], and the use of conditioned culture medium containing factors secreted from peripheral nerves of rats [78, 79, 80] and equine [15] have been reported.
Most studies assess the success of
| Schwann cell markers | References |
|---|---|
| GFAP | [83] |
| S100 | [84, 85, 86] |
| S100, GFAP | [14, 30, 78, 79, 80, 87, 88, 89, 90, 91, 92] |
| S100, p75 NGFR | [75, 93, 94, 95, 96] |
| S100, GFAP, p75 NGFR | [13, 71, 73, 81, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109] |
| S100, GFAP, Nestin | [110, 111] |
| S100, GFAP, MBP | [112, 113, 114] |
| S100, p75 NGFR, Oct-6 | [115] |
| S100, p75 NGFR, Integrin β4 | [116] |
| S100, GFAP, p75 NGFR, O4 | [70] |
| S100, GFAP, p75 NGFR, erbB3 | [117] |
| S100, GFAP, p75 NGFR, Nestin | [118] |
| S100, p75 NGFR, PMP-22 | [119] |
| S100, GFAP, MBP, Nestin | [120] |
| S100, p75 NGFR, P0, MAG | [121] |
| S100, GFAP, P0, PMP-22 | [122] |
| S100, GFAP, p75 NGFR, MBP | [15] |
| S100, GFAP, p75 NGFR, P0, L1 | [123] |
| S100, GFAP, p75 NGFR, MBP, P0 | [124] |
| S100, GFAP, p75 NGFR, P0, O4, Sox10, Krox20 | [125] |
Table 2.
Different markers used to characterize transdifferentiation in SLCs. Adapted from Ramli et al. [82].
Abbreviation: glial fibrillary acidic protein (GFAP); S100 calcium-binding protein (S100); nerve growth factor receptor (NGFR); myelin basic protein (MBP); oligodendrocyte 4 (O4); epidermal growth factor receptor 3 (erbB3); peripheral myelin protein 22 (PMP-22); protein zero (P0); myelin-associated glycoprotein (MAG).
Western blot, immunofluorescence, and PCR are the primary methods utilized to verify their expression [127]. Additionally, other assessments such as evaluating the secretion of neurotrophic factors, co-culturing with dorsal root ganglion neurons and assessing myelination can be conducted [126, 128].
Studies involving MSCs from rats and humans have demonstrated an increase in the secretion of neurotrophic factors, including BDNF, GDNF, NGF, and VEGF-A, following transdifferentiation [129, 130]. Furthermore, a significant upregulation in the expression of BDNF and GDNF was observed after
9. Therapeutic potential of Schwann-like cells derived from mesenchymal stem cells for peripheral nerve injuries
The evaluation of SLCs transplantation in peripheral nerve injuries is constantly evolving, and the promising results have been reported. In this topic, assessments have been divided, considering the different sources of MSCs to obtain SLCs.
9.1 Bone marrow MSCs-derived SLCs
Bone marrow-derived MSCs (BM-MSCs) have been extensively researched for peripheral nerve regeneration. Studies highlight the promising results achieved with BM-MSCs-derived SLCs. In models of sciatic nerve transection in rats with a 12 mm gap, BM-MSCs derived SLCs from rats were transferred to hollow fibers and cellular transplantation was performed [97]. This intervention resulted in significant improvements in motor nerve conduction velocity, sciatic nerve function, reconstruction of Ranvier’s nodes, and myelination [97]. Additionally, no tumor formations were detected within six months after transplantation [97]. Another study, also employing a rat model with a 12-mm gap lesion, utilized chitosan nerve conduits seeded with SLCs, resulting in improvements in remyelination and axonal regrowth [94]. However, no significant results were observed compared to treatment with SCs derived from the sciatic nerve [94]. Using human BM-MSCs, a study conducted the transplantation of hollow conduits seeded with SCLs and treated with tacrolimus in rats with a 10 mm gap lesion, resulting in functional recovery of the sciatic nerve [123].
Moreover, in a model of transection of the buccal branch of the rabbit facial nerve with a 1-cm gap, it was evidenced that rabbit SLCs within the autologous vein graft accelerate axonal regeneration and promote better remyelination [103]. Another study, utilizing rat SLCs incorporated into a polyglycolic acid tube, revealed promising results in nerve regeneration following neurotmesis of the mandibular branch of the rat facial nerve [115].
9.2 Adipose tissue MSCs-derived SLCs
Adipose tissue-derived MSCs (AT-MSCs) have garnered interest in regenerative medicine due to their widespread availability and ease of obtainment. In experimental models of rat sciatic nerve transection with a 10-mm gap [116, 130, 132, 133] and 15-mm gap [134], the transplantation of AT-MSCs transdifferentiated into SLCs, from both rats [116, 132, 133, 134] and humans [130], into nerve fibrin conduits [130, 132, 133], aligned collagen matrix [134] and silicone [116] has shown improvements in axonal regeneration [116, 130, 132, 133, 134], increased neurotrophic factors, vascularization [130], myelination [116] and reduction in muscle atrophy [133].
A study compared the transplantation of rat AT-MSCs, SLCs, and SCs incorporated into silicone nerve conduits with collagen gel in a 7-mm gap model of rat facial nerve and concluded that the groups exhibited a similar potential for nerve regeneration [108].
Additionally, the use of sheep as an animal model showed promising results by employing acellular nerve allografts recellularized with ovine SLCs after experimentally inducing a 30-mm gap in the animals’ peroneal nerve [86].
In crush models, positive results were also observed. The capacity for myelination formation was demonstrated after the transplantation of human SLCs in an experiment involving tibial nerve crush injury in athymic nude rats [135]. Another study demonstrated that the transplantation of SLCs from rats obtained through the approach utilizing a conditioned medium with factors secreted by the rat sciatic nerve assisted in peripheral nerve regeneration in a rat sciatic nerve crush injury model [79].
9.3 Wharton’s jelly MSCs-derived SLCs
Wharton’s jelly-derived MSCs can be easily obtained in abundance and have been widely investigated [136]. The use of human MSCs transdifferentiated into SLCs, combined with Matrigel grafting in a rat sciatic nerve transection model with an 8-mm gap, promoted myelination and enhanced nerve regeneration [125]. Moreover, acellular nerve grafts combined with SLCs have been shown to promote peripheral nerve regeneration in a rat sciatic nerve injury model with 6-mm nerve defects [12].
9.4 Umbilical cord blood MSCs-derived SLCs
Umbilical cord blood-derived MSCs (UCB-MSCs) are widely investigated due to their extensive availability and non-invasive collection process [137]. Transplantation of human UCB-MSCs-derived SLCs, organized into three-dimensional (3D) cellular spheroids using a methylcellulose hydrogel system, in a rat sciatic nerve crush injury model, stimulated nerve structure regeneration and promoted motor function recovery [138].
10. Future perspectives of fabricating nerve guidance conduits (NGCs) for peripheral nerve injuries
To promote the regeneration of peripheral nerve injuries, various strategies are being investigated, including the use of NGCs in defects with long gaps [139]. These tubular structures provide a suitable microenvironment between the ends of the injured nerve, favoring neuroregeneration [43]. NGCs can be constructed from non-biological materials, as well as autogenous and allogeneic biological materials [140].
NGCs may originate from synthetic or natural origin, a blend of both, and exhibit structural variations related to porosity and filament presence [25]. The material is chosen based on its biocompatibility, permeability, resorption time, strength, and surface characteristics [141, 142]. NGCs are designed and manufactured to provide different mechanical, biological, and biochemical stimuli (Figure 3) [25, 143].
Figure 3.
Schematic illustration of NGC fabrication featuring various configurations and integrated with biochemical, biological, and mechanical cues for peripheral nerve regeneration. Created with Biorender.com
Several techniques, such as micro-patterning, injection molding, unidirectional freezing, electrospinning, and 3D printing, have been employed in the fabrication of NGCs [25]. The emergence of 3D bioprinting allows for the construction of NGCs aimed at regenerating tissues with complex architectures and specific production for each case [139]. In bioprinting, bioink is prepared with living cells that are employed as fundamental elements, while support materials serve as a base structure, enabling the creation of 3D tissue structures [144].
The use of 3D bioprinting allows for greater mechanical stability, high porosity, reproducibility, and adaptability to various polymers, mimicking the structural details of the nerve region to be replaced [144, 145, 146]. Bioprinting shows great potential; however, it faces some challenges that need to be overcome to acquire the precise architecture of nervous tissue. This involves reproducing nerve microanatomy, precisely depositing different types of cells in a controlled environment within the hydrogel, in addition to the composition and mechanical properties of the bioink [144]. A futuristic area is the use of the four-dimensional (4D) technology approach, which may allow for material adaptation in response to stimuli, mimicking physiological variations of the body [25, 147]. The primary goal of future research on NGCs is to make them functional, and the combination with SLCs represents potential future research that could further enhance the neureregenerative capacity after injury.
11. Conclusions
The regeneration of the PNS remains a major challenge. SCs are the main glial cells present in the PNS and are of the utmost importance in its regeneration. SC transplantation has emerged as a promising cellular therapy for the treatment of peripheral nerve injuries. However, due to the limitations associated with its use, research has advanced toward alternative approaches to overcome these constraints, such as the transdifferentiation of MSCs into SLCs. Several sources of MSCs, from different species, have been transdifferentiated into SLCs and have become a great promise as substitutes for SCs in nerve regeneration.
Several studies have provided evidence of the beneficial effects of SLC transplantation for treating peripheral nerve injuries. However, there are still significant issues to address. Further research is needed to investigate different doses, application frequencies, long-term assessments post-transplantation, potential immune responses, transplantation in chronic injuries, and the use of several biomaterials as cell carriers. Therefore, conducting more preclinical studies is crucial before advancing to clinical application. SC-based therapy has the potential to become an even more attractive and effective strategy for treating PNS injuries.
Conflict of interest
The authors have no conflict of interest.
Acronyms and abbreviations
three-dimensional | |
four-dimensional | |
adipose tissue-derived mesenchymal stem cells | |
brain-derived neurotrophic factor | |
basic fibroblast growth factor | |
beta-mercaptoethanol | |
bone marrow-derived mesenchymal stem cells | |
central nervous system | |
ciliary neurotrophic factor | |
epidermal growth factor receptor 3 | |
fibroblast growth factor 2 | |
forskolin | |
glial-derived neurotrophic factor | |
glial fibrillary acidic protein | |
glial growth factor-2 | |
hepatocyte growth factor | |
heregulin | |
indoleamine 2,3-dioxygenase | |
insulin-like growth factor | |
interleukin | |
leukemia inhibitory factor | |
myelin-associated glycoprotein | |
myelin basic protein | |
monocyte chemoattractant protein-1 | |
mesenchymal stem cells | |
nerve guidance conduits | |
nerve growth factor | |
nerve growth factor receptor | |
neurotrophins | |
oligodendrocyte 4 | |
protein zero | |
platelet-derived growth factor | |
prostaglandin E2 | |
peripheral myelin protein 22 | |
peripheral nervous system | |
retinoic acid | |
S100 calcium-binding protein | |
Schwann cells | |
Schwann-like cells | |
transforming growth factor beta | |
tumor necrosis factor | |
umbilical cord blood-derived mesenchymal stem cells | |
vascular endothelial growth factor A |
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