Perspectives on Schwann-like cells derived from bone marrow-mesenchymal stem cells: Advancing peripheral nerve injury therapies

Abstract

Peripheral nerve injuries are clinical conditions that often result in functional deficits, compromising patient quality of life. Given the relevance of these injuries, new treatment strategies are constantly being investigated. Although mesenchymal stem cells already demonstrate therapeutic potential due to their paracrine action, the transdifferentiation of these cells into Schwann-like cells (SLCs) represents a significant advancement in nerve injury therapy. Recent studies indicate that SLCs can mimic the functions of Schwann cells, with promising results in animal models. However, challenges remain, such as the diversity of transdifferentiation protocols and the scalability of these therapies for clinical applications. A recent study by Zou et al provided a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells in the treatment of peripheral nerve injuries. Therefore, we would like to discuss and explore the use of SLCs derived from bone marrow-derived mesenchymal stem cells in more detail as a promising alternative in the field of nerve regeneration.

Key Words: Cell therapy; Nerve repair; Peripheral nervous system; Transdifferentiation; Transplantation

Core Tip: Schwann-like cells (SLCs) derived from bone marrow-mesenchymal stem cells have emerged as a promising therapeutic approach for peripheral nerve regeneration. However, further in vitro and in vivo studies are needed to optimize transdifferentiation and transplantation methodologies, as well as to explore the efficacy of SLCs in different injury models. The development of strategies that integrate SLCs could enhance neuroregeneration, promoting cell survival and therapeutic success.

TO THE EDITOR

We would like to express our sincere appreciation for the publication of the review entitled “Bone marrow-mesenchymal stem cells in treatment of peripheral nerve injury” by Zou et al[1], which provides a comprehensive overview of the role of bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of peripheral nerve injuries (PNI). In addition to highlighting the relevance of BM-MSCs, we would like to commend the authors and offer a more in-depth perspective on the use of Schwann-like cells (SLCs) derived from BM-MSCs as a promising alternative in the field of nerve regeneration.

PNI represents a significant clinical challenge in both humans and animals[2,3], due to the complexity of the neural microenvironment and the limited regenerative capacity, especially in severe injuries[4-6]. In long-gap injury, autograft is the gold standard treatment; however, it presents several limitations, including incomplete functional recovery, donor nerve morbidity, scar tissue formation, and the risk of neuroma formation[7,8]. Given these challenges, new therapeutic strategies are constantly being investigated.

Mesenchymal stem cells (MSCs) have attracted considerable attention for peripheral nerve regeneration[9]. Their ease of expansion in culture, the ability to differentiate into various cell types[10], and their neuroprotective, anti-inflammatory, immunomodulatory, and pro-angiogenic properties highlight MSCs as a strategy with great therapeutic potential, as reported by Zou et al[1]. The transplantation of BM-MSCs in PNI has been investigated in small and large animal models, such as rats[11], dogs[12], rabbits[13], sheep[14], and horses[15]. Furthermore, studies have demonstrated the potential for the transdifferentiation of BM-MSCs into SLCs, as highlighted by Zou et al[1].

Different protocols are described for performing transdifferentiation and exploring the potential of the transplantation of SLCs derived from BM-MSCs into animal models (Figure 1). In this manuscript, we also present in vitro approaches that utilize exosomes derived from different cell sources[16] and conditioned medium containing secreted factors from the peripheral nerves of both rats[17] and horses[18]. The method using conditioned medium enhances the gene expression of neurotrophic factors following transdifferentiation[18]. This recent approach still needs to be further explored to determine which factors specifically trigger the transdifferentiation process, which could open new avenues for research and experimental methodologies.

Figure 1 Schematic representation of the transdifferentiation of bone marrow-derived mesenchymal stem cells into Schwann-like cells using different protocols and their potential in vivo application. Protocols involving chemical agents, growth factors, exosomes derived from various cell sources, and secreted factors from equine and rat peripheral nerves are used for the in vitro transdifferentiation of bone marrow-derived mesenchymal stem cells into Schwann-like cells. Studies involving the transplantation of Schwann-like cells into animal models generally use chemical agents and growth factors to induce transdifferentiation. Created with Biorender (https://BioRender.com/p72z610). BM-MSCs: Bone marrow-derived mesenchymal stem cells.

Schwann cells (SCs) are the main glial cells in the peripheral nervous system and play a crucial role in neuroregeneration through proliferation, formation of Büngner bands, secretion of neurotrophic factors, phagocytosis of myelin debris, and recruitment of macrophages[19]. While protocols for SCs isolation are well-established and their transplantation has shown benefits in treating PNI[20,21], this approach has limitations. These include the need to sacrifice a functional nerve for cell harvesting and the extended time required for cell expansion, which can delay treatment[22]. In this context, SLCs have emerged as a promising alternative to mimic SCs. The generation of SLCs from MSCs reduces complications associated with donor nerve harvesting. However, potential challenges in translating SLC therapies to clinical applications must be addressed. Issues related to cell quality, phenotypic instability, immune compatibility, and long-term safety remain significant concerns. Moving forward, it will be essential to reach a consensus on the criteria to characterize these cells, ensuring reproducibility and reliability across different studies. Although various methodologies and protocols have been developed, offering promising strategies for nerve regeneration, further investigations are necessary. Studies focusing on BM-MSC-derived SLCs and comparative analyses of different approaches are crucial to optimize and enhance the therapeutic potential of SLCs.

SLCS TRANSPLANTATION

Studies evaluating the transplantation of SLCs derived from BM-MSCs in PNI have demonstrated significant therapeutic benefits (Table 1). There is considerable evidence that the use of these cells can assist in nerve regeneration, underscoring their therapeutic potential. However, further investigations are still needed to establish effective protocols for clinical application. Although MSCs are considered immune evasive[23], the use of immunosuppressants such as tacrolimus and cyclosporine has been adopted in some studies to prevent immune rejection in xenogeneic transplants[24,25]. In addition, many studies have combined cell transplantation with biomaterials, optimizing treatment efficacy by creating a favorable microenvironment for regeneration[26,27].

Table 1 Transplantation of Schwann-like cells derived from bone marrow-mesenchymal stem cells in peripheral nerve injuries.

Model	Cells/grafts	Method of transdifferentiation	Outcome	Limitations	Ref.
Rat sciatic nerve (12 mm gap)	SLCs (rats). Hollow fiber	Chemical and growth factors	Improvements in motor conduction, sciatic nerve function index, regeneration of the nodes of Ranvier, and remyelination. No tumor formation was detected 6 months post-transplantation	Lack of detailed sensory functional analysis and gene expression evaluation of SLCs and nerve regeneration markers	[35]
Rat sciatic nerve (10 mm gap)	SLCs (humans). Transpermeable tube. Immunosuppressants used	Chemical and growth factors	Improvements in nerve regeneration and functional recovery	Lack of detailed sensory functional analysis, gene expression evaluation of SLCs and nerve regeneration markers, no electroneuromyography, assessed for three weeks	[25]
Rat sciatic nerve (12 mm gap)	SLCs (rats). Chitosan conduits	Neurosphere induction, incubation with growth factors and co-culture	Improvements in remyelination and axonal growth. No significant difference was observed compared to the transplantation of Schwann cells derived from the sciatic nerve	No undifferentiated BM-MSC transplantation group, lack of detailed sensory functional analysis and gene expression evaluation of SLCs and nerve regeneration markers	[26]
Buccal branch of the facial nerve in rabbits (1 cm gap)	SLCs (rabbits). Vein graft	Chemical and growth factors	Acceleration of axonal regeneration and improvement in remyelination	Lack of detailed sensory functional analysis of the facial nerve and gene expression evaluation of SLCs markers	[27]
Rat sciatic nerve (12 mm gap)	SLCs (humans). Chitosan conduits. Immunosuppressants used	Neurosphere induction, incubation with growth factors and co-culture	Improvements in axonal regeneration and myelination	No undifferentiated BM-MSC transplantation group, lack of detailed motor and sensory functional analysis, electroneuromyography, and gene expression evaluation of SLCs and nerve regeneration markers	[24]

The studies are predominantly conducted using laboratory animal models, while there is a lack of research evaluating the regenerative potential of Schwann-like cells derived from bone marrow-derived mesenchymal stem cells in large animal models. These larger models are particularly relevant for translational studies, as the size of the peripheral nerve in these animals allows for larger lesions, providing more realistic data on the nerve regeneration process, which can be applied to human treatments[4]. SLCs: Schwann-like cells; BM-MSC: Bone marrow-derived mesenchymal stem cell.

Biomaterials have been widely studied for the construction of nerve guidance conduits (NGCs), which may be natural or synthetic, exhibiting a wide range of characteristics that play crucial roles in nerve regeneration[28]. NGCs are designed to provide structural support and create a favorable microenvironment for axonal growth[3]. Physical properties, such as porosity, stiffness, and biocompatibility, as well as incorporated bioactive components, are key determinants for successful neural regeneration[29,30]. The use of 3D printing has revolutionized the design and fabrication of NGCs, enabling customization with complex architectures[31]. This technology allows the creation of NGCs with geometries tailored to different types of nerve injuries, while precisely controlling features such as pore size, fiber orientation, and material composition[32,33]. In this context, the combination of SLCs with 3D-printed personalized NGCs represents a promising approach for the treatment of PNI, enhancing functional recovery and opening new perspectives for nerve tissue engineering. These findings highlight the importance of continuing to explore the transdifferentiation capacity of BM-MSCs and conducting new studies in combination with different approaches aimed at improving the efficacy of cell-based therapy in neuroregeneration.

CONCLUSIONS AND PERSPECTIVES

Despite evidence suggesting that SLCs are a promising alternative for nerve regeneration, several challenges remain to be addressed. Issues such as the quantity of cells to be used, the most efficient methodology for transdifferentiation, the application frequency, long-term safety, potential immune responses, dedifferentiation after the removal of the inducing medium, and efficacy in different types of injuries require further investigation.

To advance in this field, it is essential to standardize transdifferentiation protocols and establish a consensus on the characterization of SLCs. This will assist in ensuring reproducibility and clinical applicability. Preclinical studies utilizing large animal models to evaluate the safety and effectiveness of SLC-based therapies, followed by clinical trials, are also crucial to translate these findings into clinical practice. The combination of cellular therapy with biomaterials and other technologies has the potential to further enhance neuroregeneration. In this context, future studies should investigate the 3D bioprinting of NGCs incorporated with BM-MSCs, as demonstrated by Liu et al[34], or with SLCs, aiming to develop better therapeutic approaches for PNI. It is vital to create an optimal microenvironment that promotes cell survival and integration after transplantation. Moreover, incorporating and distributing stimulating factors that influence the phenotype of SLCs will be crucial for the therapeutic success of these approaches. Thus, we would like to highlight future perspectives toward therapies based on SLCs derived from BM-MSCs, which have great potential for the treatment of PNI.