The treatment of SCIs with stem cells and specialised cells can be traced back to early animal studies that examined the regenerative capabilities of various stem cell types, including MSCs, NSCs, and iPSCs. These studies have revealed the potential of these cells to improve motor and sensory functions and facilitate neural repair. Initial clinical trials conducted in the early 2000s focused on the safety and feasibility of MSC transplantation, demonstrating that MSCs derived from sources such as the bone marrow and adipose tissue are safe and can modulate immune responses and promote tissue repair.^10–13 Advances in iPSC technology in the 2010s have enabled the reprogramming of somatic cells into pluripotent stem cells, offering new avenues for neural repair.^14,15 NSCs derived from foetal tissues or iPSCs have been tested for their ability to differentiate into neurons and glial cells, aiding in neural repair and functional recovery.^14,16–18

Specialised cell types, such as olfactory ensheathing cells (OECs) and stem cell-derived exosomes, have also been investigated for their regenerative potential.^19–22 OECs are known for their ability to support axonal growth, while exosome therapy offers a cell-free therapeutic approach by carrying neuroprotective and regenerative factors to the injury site.^20,21

Despite promising results, challenges such as immune rejection, tumorigenesis, and the optimisation of cell delivery methods remain.^23,24 Recent studies have endeavoured to enhance these therapies and establish consistent guidelines for their clinical application, which could significantly advance the treatment of SCI and promote better patient outcomes.^25,26

MSCs possess immunomodulatory and regenerative properties. Derived from bone marrow, adipose tissue, and umbilical cord, MSCs show potential in improving motor and sensory functions in SCI patients.^24,27 Levi et al. demonstrated the safety and feasibility of transplanting 20 million human central nervous system stem cells (HuCNS-SC) into the thoracic spinal cord of 12 patients with chronic motor-complete and sensory-incomplete SCI in a multi-site phase I/IIa clinical trial. The six-year study revealed no severe adverse effects or tumour formation, and while sensory improvements were observed in five patients, motor function recovery was not detected, emphasising the need for further research to enhance cell engraftment and integration.²⁸ Sykova et al. illustrated that MSCs from various sources have shown promise in treating neurodegenerative diseases such as SCI and ALS, owing to their multilineage differentiation potential and immunomodulatory properties.^29,30 They release neuroprotective cytokines, migrate to lesion sites, and enhance neural plasticity, leading to improved function in animal models.^27,31 Clinical studies have confirmed the safety and modest benefits of MSCs in promoting neural repair and functional recovery, particularly umbilical cord-derived MSCs with high neurotrophic factor secretion.^29,32,33,34 Tahmasebi et al.’s review, reflects that although improvements in sensory and bladder functions have been noted, the effects on motor function remain unclear, requiring further research to optimise and assess the application of these therapies in humans.³⁴

NSCs can differentiate into neurons, astrocytes, and oligodendrocytes, making them suitable for repairing neural damage.^35–38 Additionally, it has been suggested that genetically modified NSCs could overcome certain limitations, such as low migration and survival rates, thereby enhancing their therapeutic potential.³⁹ Preclinical studies using NSCs derived from fetal tissues and iPSCs have shown promising results in promoting neurogenesis and functional recovery in animal models of SCI.^18,40–42 However, several challenges persist that must be addressed before the clinical application of this technology can be realised, including the regulation of cell differentiation and proliferation, as well as ensuring patient safety.^18,43 Further research is needed to optimise these therapies and ensure their efficacy and safety for potential use in humans.^41,42,44

Another technology that has been explored is the conversion of human fibroblasts into NSCs using single zinc-finger transcription factors, which represents a significant advancement and provides deeper insights into neural development and potential therapeutic applications.^45,46 This method allows the generation of long-term self-renewable and multipotent NSCs, which are similar to control NSCs in terms of their characteristics and functionality. Induced NSCs exhibit the capacity to survive, migrate, and differentiate into neural phenotypes post-transplantation without tumour formation, which is crucial for any therapeutic application.⁴⁵ However, while this advancement is promising, it is important to consider the broader context of SCI treatment and the various approaches being explored. For instance, Yu et al. and Pereira et al. elaborate on the opportunities presented by NSCs derived from iPSCs and their capacity for cell transplantation therapy aimed at addressing SCI.^47,48 Lu et al. and Ao et al. emphasised the survival and integration of NSCs in severe SCIs and the potential synergistic effects of co-transplanting NSCs with other cell types, such as OECs, to promote regeneration and functional reconstruction.^49,50 Furthermore, Kiani et al. indicated the potential of employing human-induced neural stem cells (hiNSCs) for cell-based therapy in rats with spinal cord injury (SCI), as evidenced by the enhanced cell viability and locomotor function observed following transplantation.⁵¹

OECs have been identified as promising agents in treating SCIs because of their unique ability to support axonal growth and facilitate neural regeneration.^59,60 These cells, which share characteristics with both Schwann cells and astrocytes, can migrate within the damaged spinal cord, secrete neurotrophic factors, and potentially carry exogenous genes to promote neuronal regeneration.^61,62 Olfactory mucosa cells have been found to be effective in restoring motor function due to their capacity to remyelinate and regenerate axons. Furthermore, they express neurotrophic factors essential for nerve tissue recovery following SCI.⁶³ Additionally, OECs have been shown to interact with astrocytes, regulate inflammatory reactions, and contribute to myelination, which is a critical process in nerve repair.⁵⁹

However, there are challenges in the application of OECs, such as inconsistency in therapeutic outcomes, which may be attributed to the variability in cell populations used for transplantation.⁶⁴ Moreover, while OECs have demonstrated neuroprotective and repair roles, the mechanisms by which they mediate anti- inflammatory effects remain a subject of debate.⁶⁵ The potential of OECs is further complicated by the need for improved purification procedures to achieve their full therapeutic potential.⁶⁴

In summary, OECs offer a multifaceted approach to SCI treatment by promoting axonal regeneration, myelination, and modulation of the inflammatory response. Despite promising evidence, further research is required to standardise cell preparations and fully understand the mechanisms of OEC-mediated repair to optimise their therapeutic application.^64,65

Exosome therapy presents a novel cell-free approach to treating spinal cord injuries (SCIs) by capitalising on the intrinsic ability of exosomes to transport neuroprotective and regenerative factors to the site of injury. Exosomes are extracellular vesicles that facilitate intercellular communication and possess the potential to modify the injured spinal cord’s environment by delivering bioactive molecules that promote neuroprotection and regeneration.^20,21,66 Numerous studies have demonstrated the therapeutic potential of exosomes. Zhou et al., in their study, revealed that exosomes derived from human placental MSCs possess the ability to promote recovery from SCIs by stimulating endogenous neurogenesis and improving locomotor and bladder functions via the MEK/ ERK/CREB signalling pathway.⁶⁷ In addition, a study by Xue et al. showed that human umbilical cord mesenchymal stem cell (hUC-MSC)-derived small extracellular vesicles (sEVs) have the potential to repair disrupted blood-spinal cord barriers in SCI through the regulation of Endothelin-1 and the enhancement of tight junction proteins. These findings further support the idea that sEVs may offer a promising cell-free therapeutic strategy for treating SCI.⁶⁸ Another study demonstrated that exosomes derived from UC-MSCs enhanced motor function recovery and reduced inflammation by inhibiting the NF-κB/MAPK signalling pathway.⁶⁹ Lee et al. demonstrated that targeted delivery of MSC-derived nanovesicles (MF-NVs) enhances neuroprotection, anti-inflammation, and angiogenesis in SCI treatment, offering an effective cell-free therapeutic approach.⁷⁰ A study by Mu et al. showed that an emergency treatment strategy using MSC-derived exosomes encapsulated in fibrin glue resulted in significant functional recovery in SCI, suggesting potential benefits in urinary function recovery.⁷¹

Recent research has suggested that combining different stem cell types may enhance therapeutic outcomes.⁶² Co-transplantation of NSCs and MSCs has demonstrated synergistic effects, resulting in improved motor and sensory function. Furthermore, scaffolds and growth factors facilitate stem cell transplantation by establishing a favourable microenvironment that promotes tissue regeneration.^72–75 Notably, while the advantages of employing a combination of stem cells have been emphasised, the literature also recognises the intricacy of spinal SCI pathophysiology and the necessity for precision medicine approaches. This indicates that the efficacy of combined stem cell therapies may be contingent upon customised treatment to the unique features of the injury and the patient.^24,76,77

Integrating stem cell transplantation with rehabilitation and neurotrophic factors has yielded encouraging outcomes.

Rehabilitation enhances the effects of cell transplantation by promoting neural plasticity and functional recovery. Studies have shown that rehabilitation when combined with stem cell transplantation, can lead to significant improvements in functional recovery, particularly when initiated during the chronic phase of SCI.⁷⁸ This synergistic effect is thought to be the result of the rehabilitation’s capacity to facilitate neuronal plasticity within transplanted stem cells and sensorimotor circuits, which is crucial for functional recovery.⁷⁹ Furthermore, it has been demonstrated that the integration of rehabilitation and neural progenitor cell (NPC) transplants leads to enhanced functional results because rehabilitation promotes the growth of host corticospinal axons into grafts.⁷⁸ This suggests that rehabilitation not only supports the integration of transplanted cells but also enhances endogenous repair mechanisms.

The use of neurotrophic factors, such as neurotrophin-3 (NT-3), in conjunction with stem cell therapies, has been shown to improve outcomes in patients with spinal cord injuries (SCI). The combination of these two therapies has demonstrated synergistic effects, leading to improved locomotor function and reduced SCI pathology.^80,81 In particular, the use of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), in conjunction with stem cell therapies has demonstrated the potential to mitigate damage and facilitate recovery in preclinical models of SCI.⁸⁰

In conclusion, evidence suggests that neurotrophic factors, including NT-3, can effectively improve outcomes after SCIs when combined with stem cell treatments. This joint approach benefits from the neuroprotective and regenerative qualities of neurotrophins and the extensive therapeutic potential of stem cells, presenting a promising strategy for improving recovery in SCI.^77,80,81

Clinical trials have established the safety and feasibility of stem cell transplantation in SCI. Rong et al. study highlights that stem cell transplantation has been performed at various stages of SCI and is safe and feasible, with the potential to alleviate inflammation and restore the function of damaged nerve cells.⁸² Similarly, Digma et al. reported that early clinical trials demonstrated the safety and feasibility of stem cell transplantation in patients with SCI, with observed improvements in sensory and motor functions.⁸³ Silvestro et al. also supported these findings, indicating that clinical trials have demonstrated the safety and efficacy of stem cell therapy in patients with SCI.^82–84 However, despite these positive indications, challenges and limitations remain to be addressed. Agosti et al. pointed out that, while stem cell therapies show promise, some potential adverse events and limitations necessitate careful optimisation of transplantation conditions.⁸⁵ Moreover, there is a need for a deeper understanding of SCI pathophysiology and concerns, such as tumourigenicity and immunogenicity, before its widespread clinical adoption. Goel et al. and Kan et al. echo the sentiment that more rigorous, large-scale clinical trials are needed to fully understand the safety, efficacy, and long-term viability of stem cell therapies for SCI.^85–87

Although the safety of stem cell therapies has been well documented, their efficacy remains variable. The efficacy of these therapies is less consistent, as clinical studies have not always yielded encouraging results, and the translation of preclinical success to clinical practice has been challenging.⁸⁸ This discrepancy may be due to the heterogeneity of SCI pathophysiology, timing of intervention, and types of stem cells used.⁷⁶ Moreover, despite the promise shown in animal models, the limitations of preclinical data and the complexity of translating these findings into successful clinical outcomes have been acknowledged.⁸⁹

Various studies have reported improvements in motor and sensory functions post-SCI have been reported in various studies, particularly with the use of MSCs and NSCs. MSCs have been shown to promote repair through immunomodulation, neuroprotection, and nerve regeneration,²⁴ whereas NSCs have demonstrated the ability to form synapses with host axons and extend new axons from the injury site.⁷⁹

However, the extent of recovery is variable and dependent on factors such as the type of stem cells used, the severity of injury, and the therapeutic approach. The promising results from MSC and NSC therapies underscore the potential of stem cell-based interventions in SCI treatment, although further research is needed to optimise these therapies and understand their mechanisms of action.^24,90

The advent of iPSC technology has mitigated ethical concerns, particularly with the use of embryonic stem cells (ESCs) and fetal tissues.⁴⁰ Although stem cells are not a complete solution for neural repair, their combination with other therapies, such as rehabilitation and nanotechnology, may enhance their effectiveness.⁹⁶

Integrating innovative technologies and comprehensive treatment strategies is fundamental to advancing SCI treatment and achieving substantial functional recovery.^97–99 Technologies, such as biomaterials, scaffolding, and gene editing, are being explored to enhance the effectiveness of stem cell therapies. Biomaterials can provide a supportive environment for stem cells, promoting their survival and integration into the host tissues.^{74,75,99–101}

Scaffolding techniques help guide the growth and organisation of new cells, whereas gene editing can be used to enhance the regenerative capacity of stem cells.^44,74,93,100 Moreover, integrating complementary technologies, such as neurorehabilitation, electrical stimulation, and pharmacological treatments, can maximise the benefits of stem cell therapy.^102,103 Neurorehabilitation can help patients relearn motor skills and improve functional outcomes. Electrical stimulation can enhance the activity of spinal circuits and promote nerve regeneration.^103–105 Pharmacological treatments can address inflammation and other secondary complications, creating a more favourable environment for stem cell therapy.¹⁰⁶