Stem cell therapies for spinal cord injury in humans: A review of recent clinical research

Abstract

Recently, cell transplantation has emerged as a promising treatment for spinal cord injury (SCI). Over the past decade, numerous clinical studies of SCI have been conducted using various types of cells, including fetal neural stem/progenitor cells (NS/PCs), pluripotent stem cell-derived NS/PCs, mesenchymal stem/stromal cells (MSCs), olfactory ensheathing cells, and Schwann cells. Promising results have been reported for patients with subacute SCI, especially in studies involving MSCs, such as those conducted with Stemirac, although no universally recognized breakthroughs have been achieved. Allogenic NS/PCs may offer advantages over autologous MSCs because they have the potential for cell engraftment within the spinal cord and can be prepared in advance, facilitating their administration during the hyperacute phase. Recent advances achieved with induced pluripotent stem cells indicate their promise potential to be used in future therapies. This review provides an overview of recent clinical studies and discusses potential advancements anticipated in the future.

Highlights

• •Several clinical trials using stem cells to treat SCI have been conducted.
• •Developing cell therapies for SCIs is challenging due to its complexity.
• •Cell therapy plus neurorehabilitation and imaging may lead to new findings.

Abbreviations

ADL

Activities of daily living

AIS

American Spinal Cord Injury Association Impairment Scale

ASIA

American Spinal Injury Association

BM-MSC

Bone marrow-derived mesenchymal stem cell

BM

Bone marrow

C

Cervical

CNS

Central nervous system

ES cell

Embryonic stem cell

FDA

Food and Drug Administration

iPS

Induced pluripotent stem

ISNCSCI

International Standards for Neurological Classification of Spinal Cord Injury

ITT

Intention to treat

jRCT

Japan Registry of Clinical Trials

L

Lumber

MSC

Mesenchymal stromal/stem cell

Muse

Multilineage-differentiating stress enduring

n

Number of patients

NA

Not available

NBD

Neurological breathing dysfunction

NS/PC

Neural stem/progenitor cell

OEC

Olfactory ensheathing cell

QOL

Quality of life

SAE

Serious adverse event

SCI

Spinal cord injury

SCIM

Spinal cord independence measure

SSEA

Stage-specific embryonic antigen

T

Thoracic

UC-MSC

Umbilical cord-derived mesenchymal stem cell

UC

Umbilical cord

ZPP

Zone of partial preservation

1. Introduction

Spinal cord injury (SCI) is a devastating condition that can suddenly leave a healthy individual severely paralyzed, with little chance of spontaneous recovery. Over 15 million people are affected by SCIs worldwide (World Health Organization, 2024). SCIs are primarily caused by trauma (including falls, traffic accidents, injuries during sports, and violence). However, non-traumatic causes, such as degenerative conditions, vascular conditions, and tumors, also lead to SCIs. As the population ages, more cases with SCI from minor injuries (such as falls at ground level) are anticipated (Miyakoshi et al., 2021) due to underlying spinal degeneration and spinal canal stenosis.

No promising treatments have been developed for SCI. Various potential drugs, including glucocorticoids (Hejrati et al., 2023), riluzole (Fehlings et al., 2023), hepatocyte growth factor (Nagoshi et al., 2020), and granulocyte-colony stimulating factor (Koda et al., 2021), have been suggested as possible treatments; however, conclusions regarding their effectiveness are not well supported. The difficulty in finding an effective treatment reflects the complex pathology of SCI. Owing to the delicate structure of the spinal cord, even a slight deviation in the position of the injury can significantly affect the symptoms. Limb injuries, organ damage, the method and degree of rehabilitation, psychological situations, and pre-existing conditions can further complicate treatment outcomes. Therefore, recruiting a large number of patients or conducting clinical trials with strict exclusion criteria is necessary for demonstrating reliable results in clinical trials for SCI.

In this context, cell transplantation has garnered attention as a new treatment approach. Clinical studies on regenerative treatments for SCI have increased since 2000, and remarkable progress has been made in recent years. Various cell types, including fetal neural stem/progenitor cells (NS/PCs) (Curt et al., 2020), pluripotent stem cell-derived NS/PCs (Sugai et al., 2021; Fessler et al., 2022; Mckenna et al., 2022), Schwann cells (Gant et al., 2022), olfactory ensheathing cells (OECs) (Zamani et al., 2022), and mesenchymal stromal/stem cells (MSCs) (Honmou et al., 2021; Bydon et al., 2024), are under clinical research for transplantation therapies. Among these cell types, the first four show efficacy through mechanisms that include the replacement of the damaged tissue. These therapies require the surgical delivery of cells to targeted sites, where the transplanted cells mature and integrate with the damaged host tissue to reconstitute damaged neural circuits. Among these, Schwann cells and OECs are considered to pose a low risk for tumorigenesis.

In contrast, the efficacy of MSCs primarily stems from their ability to improve the host tissue microenvironment by releasing bioactive factors or modulating the host immune system. Therefore, MSC transplantation does not always require surgery and is also considered to pose a low risk for tumorigenesis; however, the exact mechanisms underlying functional recovery remain unclear (Wu et al., 2023). The principles of cell transplantation therapy are illustrated in Fig. 1, Fig. 2.

Fig. 1.

Differences in the transplantation methods used with different cell types. Abbreviations: neural stem/progenitor cells (NS/PCs); olfactory ensheathing cells (OECs); mesenchymal stromal/stem cells (MSCs).

Fig. 2.

Progression of spinal cord injury (SCI) and the mechanisms underlying the therapeutic effects expected from cell transplantations with different cell types. Abbreviations: neural stem/progenitor cells (NS/PCs); olfactory ensheathing cells (OECs).

The results of the first clinical study using fetus derived NS/PCs for SCI were reported in 2006 (Curt et al., 2020; Moviglia et al., 2006). Subsequently, the first clinical study using embryonic stem (ES) cell derived NS/PCs was initiated in 2009. The final results (reported in 2022) confirmed the safety of the protocol but indicated that its efficacy needs to be assessed further (Fessler et al., 2022; Mckenna et al., 2022), highlighting the difficulty associated with developing cell therapies for SCI. Our research group initiated the first clinical study using induced pluripotent stem (iPS) cells in 2020 (Sugai et al., 2021), which is currently ongoing. No Food and Drug Administration (FDA)-approved stem cell-based therapies are available for SCIs (Kirkeby et al., 2025); however, one therapy involving MSCs (described below) has received conditional public approval in Japan (Cyranoski et al.).

This review provides an overview of recent advances in cell transplantation therapy, focusing on patients involved in clinical research.

2. Methods

From May to November 2024, the Pubmed database (https://pubmed.ncbi.nlm.nih.gov) was searched using the keywords “cell transplantation”, and “spinal cord injury”, and the filters “Clinical Trial” and “in the last 10 years” to identify recent and relevant clinical studies. As a result, 34 publications were retrieved. All of them were reviewed, and seven which were considered irrelevant were excluded. From the remaining 27 publications, 17 were selected as references for this manuscript based on their high impact factor, scientific importance, and originality. Studies were also searched on the world's largest clinical research registration site (ClinmicalTrials.gov; https://clinicaltrials.gov), using the keywords “spinal cord injury” and “cell transplantation”. Furthermore, additional publications from distinguished names in the field and related to the publications previously identified were retrieved and used as references for this manuscript.

3. NS/PC clinical studies

Recent research has clarified that a small number of NS/PCs remain in the central nervous systems of adult humans (Ma et al., 2009). However, these stem cells lack sufficient activity to repair damage to the brain or spinal cord. Thus, neonatal tissue-transplantation therapy has gained attention since the 1980s (Bjorklund and Stenevi, 1984), and clinical research using NS/PCs has been actively conducted since 2010. NS/PCs can be derived from three sources—neonatal tissues, ES cells, and iPS cells. The results of recent clinical studies on NS/PCs are summarized in Table 1 (Curt et al., 2020; Sugai et al., 2021; Fessler et al., 2022; Mckenna et al., 2022; Levi et al., 2018, 2019; Curtis et al., 2018).

Table 1.

Recent major clinical trials using human fetal NS/PCs and human pluripotent stem cell derived NS/PCs.

Product name	Type of product	Cell origin	SCI target phase	Target level∗ (number of participants receiving transplants)	Trial name	Phase	Status	Reported efficacy	Sponsor or main institute	Reference
HuCNS-SC	Neural stem cell line derived from a human fetal brain	Human fetus	Chronic	T2–T11 (n = 12)	NCT01321333 NCT01725880 NCT03069404	Phase 1/2	Completed	5 of 12 patients showed reliable sensory improvements.	StemCells, Inc.	Levi et al., 2018 Curt et al., 2020
HuCNS-SC	Neural stem cell line derived from a human fetal brain	Human fetus	Chronic	C5–C7 (n = 12)	NCT02163876	Phase 2	Completed. Early safety was observed, but efficacy was below the required threshold set by the sponsor, resulting in early termination of the study.	A trend toward improvement of upper extremity function was observed, but the magnitude was below the required clinical efficacy threshold.	StemCells, Inc.	Levi et al., 2018 Levi et al., 2019
NSI-566	Neural stem cell line derived from a human fetal spinal cord	Human fetus	Chronic	T2–T12 (n = 4)	NCT01772810	Phase 1	Enrollment is finished. The study is scheduled to continue for 60 months. The current status on the registry is “unknown"	3 of 4 patients showed improved motor function. No significant change in quality-of-life scores was reported.	Neuralstem, Inc.	Curtis et al., 2018 Martin et al., 2024
LTCOPC1 (GRNOPC1 or AST-OPC1)	Oligodendrocyte progenitor cells	Human ES cells	Subacute	T3–T11 (n = 5)	NCT01217008 NCT05919563	Phase 1	The original observational study is completed. A subsequent 15-year observational study is active.	All participants maintained at AIS A. 3 of 5 participants experienced at least one level of improvement in their ZPP.	Lineage Cell Therapeutics, Inc.	Mckenna et al., 2022
LTCOPC1 (GRNOPC1 or AST-OPC1)	Oligodendrocyte progenitor cells	Human ES cells	Subacute	C4–C7 (n = 25)	NCT02302157NCT05975424	Phase 1/2	The original observational study is completed. A subsequent 15-year observational study is active.	96% of the ITT group recovered one or more levels of neurological function on at least one side of their body, and 32% recovered two or more levels of neurological function on at least one side of their body.	Lineage Cell Therapeutics, Inc.	Fessler et al., 2022
–	iPS cell-derived neural stem cells	Cord blood	Subacute	C4–T10 (n = 4)	jRCTa031190228	Phase 1	One-year follow-up of the four patients have been completed.	The results are currenly being analyzed.	Keio University	Sugai et al., 2021

∗Abbreviations: C, cervical; ITT, intention-to-treat; L, lumber; iPS, induced pluripotent stem; n, number of patients; NS/PC, neural stem/progenitor cell; T, thoracic; ZPP, zone of partial preservation.

3.1. Human fetal NS/PCs

The first major clinical study involving NS/PCs used a human fetal (16–20 gestational weeks) central nervous system-derived stem cell line (HuCNS-SC®) developed by StemCells, Inc. This cell line has been clinically investigated with various diseases, including neuronal ceroid lipofuscinosis, age-related macular degeneration, Pelizaeus–Merzbacher disease, and SCI. The first transplantation of this product for SCI occurred in 2006 as part of a phase 1/2 clinical trial involving 12 patients with chronic thoracic injury. Safety data were reported for a follow-up period of up to 6 years; however, the lower-limb motor scores did not change (Curt et al., 2020).

In a subsequent randomized, single-blind, phase 2 dose-escalation study, 15–40 million cells were transplanted into 12 participants with chronic cervical SCI. The results of the study confirmed early safety, and a trend toward gains in upper-extremity motor function was observed. However, the gains were below the required clinical efficacy threshold set by the sponsor, resulting in early study termination (Levi et al., 2018, 2019).

Another clinical study was conducted using spinal cord-derived NS/PCs (NSI-566) obtained from human fetuses. This cell line has been used for clinical trials of amyotrophic lateral sclerosis and ischemic stroke (Zhang et al., 2019). This clinical study started in 2013, targeting patients with chronic thoracic SCI. It was conducted as an open-label phase 1 study. Four patients underwent transplantation with NSI-566 cells and received a cocktail of immunosuppressants for 12 weeks post-transplantation. Up to 27 months of follow-up data showed the safety of the transplantation protocol in all four participants. Also, one-level sensory and motor improvement in one patient and gain of voluntary muscle activity by electromyography in another two patients were reported (Curtis et al., 2018). The results of a follow-up as long as five years showed late additional changes in electromyography and brain motor control assessment in some patients, but it is still plausible that these changes could be attributed to spontaneous recovery (Martin et al., 2024). Studies involving larger patient populations are necessary.

3.2. Human pluripotent stem cell-derived NS/PCs

Pluripotent stem cells can differentiate into any cell type in the body, and they are an important resource for applications in regenerative medicine. There are two types of human pluripotent stem cells widely allowed to be used in clinical trials: ES cells and iPS cells. ES cells are pluripotent stem cells typically obtained from the inner cell mass of unused artificially inseminated eggs that have reached the blastocyst stage. iPS are a new type of pluripotent stem cells first generated in 2006 by introducing four genes into somatic cells (Takahashi and Yamanaka, 2006). iPS cells can be obtained from differentiated somatic cells in the adult human body, such as skin or blood cells. Cord blood cells or adult peripheral blood cells are considered ideal cell sources for these cells (Nakagawa et al., 2014). The major difference between iPS and ES cells is that it is possible to generate iPS cells that are patient-specific using their own somatic cells, and this advantage is utilized in research into various diseases (Okano et al., 2023).

3.2.1. ES cell-derived NS/PCs

The first human pluripotent stem cells that could be used in clinical trial were ES cells. One study involved the use of human ES cell-derived oligodendrocyte progenitor cells (LTCOPC1, also known as GRNOPC1 or AST-OPC1), which attracted global attention as the first human trial using ES cells. Despite challenges posed by the complexity of SCI and the high treatment costs, the research persisted through several sponsor changes. The study was conducted in two parts, focusing on thoracic SCI (NCT01217008) and cervical SCI (NCT02302157). The first part of the study was planned as a single-dose, multicenter phase 1 clinical trial and designed to assess safety in patients with American Spinal Injury Association Impairment Scale (AIS) A thoracic injuries with injured levels T3 to T11. The first patient was enrolled in October 2010, and five patients received LTCOPC1 2 × 10⁶ cells between 7 and 14 days after injury, along with low-dose tacrolimus for 60 days. In 2022, 10-year follow-up data were reported, showing no unanticipated serious adverse events (SAEs) related to the LCTOPC1 cells (Mckenna et al., 2022).

The second study was a phase 1/2, dose-escalation, multicenter clinical trial with intervention performed between 2015 and 2017. In that study, patients with C4 to C7 injuries with severity of AIS scores A or B were recruited, and 25 enrolled patients received 2 × 10⁶, 1 × 10⁷, or 2 × 10⁷ cells as intramedullary injections between 21 and 42 days post-injury. To assess the treatment efficacy, the study's intention-to-treat (ITT) population was defined as 22 participants who received 1 or 2 × 10⁷ cells. Notably, 95.5 % of the ITT population showed at least one motor-level improvement from the baseline, based on the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), with no correlation observed between the level of improvement and the cell dose.

However, the authors concluded that it is difficult to specifically attribute the degree of recovery to cellular therapy versus natural recovery due to the small sample size. They recommended further study with rehabilitation involving novel strategies to maximize the benefits of cellular treatments (Fessler et al., 2022). Spontaneous neurological recovery can occur up to approximately three months post-injury in patients with SCI, highlighting the need for a control group to determine the effectiveness of the treatment accurately, especially in the treatment of subacute patients.

3.2.2. iPS cell-derived NS/PCs

In Japan, a clinical study entitled “Regenerative Medicine using iPSC-derived Neural Progenitor Cells for Subacute SCI” (UMIN000035074) is ongoing (Sugai et al., 2021). This trial was designed to focus on the effects of transplanting NS/PCs derived from donor iPS cells into four patients with subacute complete SCI (AIS-A). Four patients with injuries ranging from C3/4 to T10 were enrolled within 24 days of injury. The study adhered to protocols approved by Japan's Ministry of Health, Labor, and Welfare and was registered under the Japan Registry of Clinical Trials (jRCT; trial number jRCTa031190228). This study is the first to use iPS-derived cells for treating SCI. One concern with using iPS cells is that they show abnormal proliferation due to genetic mutations and genetic instability (Sugai et al., 2016). To reduce the risk of abnormal proliferation after transplantation, the cells used in the clinical study were subjected to rigorous checks, including chromosomal analysis, genetic analysis, and in vivo evaluation. In addition, a γ-secretase inhibitor was used to further promote cell differentiation (Okubo et al., 2016). The first patient underwent transplantation in 2020, and the completion of the study was reported in November 2024. Treatment-related serious adverse effects are not observed at this point.

4. MSCs

NS/PCs are typically transplanted intralesionally, whereas MSCs are generally transplanted intrathecally or intravenously. MSCs are expanded from extracts obtained from the bone marrow, adipose tissue, or umbilical cord blood. Transplanted MSCs are thought to exert their effects by homing to damaged sites and inducing neurotrophic and protective effects via neurotrophic factors as well as anti-inflammatory effects. MSCs contribute to neuroprotection by stabilizing the blood–spinal cord barrier and indirectly contributing to nerve regeneration and remyelination, by creating an environment that is permissive to regeneration. More accessible sources are available for MSCs than for NS/PCs, and several clinical trials with MSCs are ongoing, a few of which have advanced to phase 2 or 3. Recent reports regarding these clinical trials are summarized in Table 2 (Honmou et al., 2021; Bydon et al., 2024; Oh et al., 2016; Vaquero et al., 2016, 2017, 2018; Koda et al., 2024; Awidi et al., 2024; Saini et al., 2022; Albu et al., 2021; Akhlaghpasand et al., 2024). Most of these studies demonstrated limited efficacy; however, treatments that are likely to be effective have been recently described. The data suggest that MSCs exert their effects through nutritional factors. Moreover, novel MSC exosome-based approaches that are likely to be effective have emerged recently (Akhlaghpasand et al., 2024).

Table 2.

Recent major clinical trials involving MSCs.

Product name	Type of product	Cell origin	SCI target phase	Target level∗ (number of participants receiving transplants)	Injection route	Trial name	Phase	Status	Reported efficacy	Sponsor or main institute	Reference
Muse cell (CL2020)	SSEA-3-positive cells	Allogenic Bone marrow	Subacute	C4–C7 (n = 10)	Intravenous	JRCT1080224764	Phase 1/2a	Completed	The ISNCSCI, ADL, and QOL scores showed statistically significant improvements when compared with the baseline data	Life Science Institute	Koda et al., 2024
–	Adipose-derived MSCs	Autologous adipose tissue	Chronic	C4–T12 (n = 10)	Intrathecal	NCT03308565	Phase 1	Completed	Seven patients demonstrated improved AIS grades following injection.	Mohamad Bydon, Mayo Clinic	Bydon et al., 2024
–	Allogeneic exosomes from UC-MSCs	Allogenic UC	Subacute	C5–T12 (n = 9)	Intrathecal	IRCT20200502047277N	Phase 1	Completed	Significant improvements in ASIA pinprick and light-touch scores, total SCIM III scores, and NBD scores were observed.	Shahid Beheshti University of Medical Sciences	Akhlaghpasand et al., 2024
–	MSCs of autologous BM (BM-MSCs) or allogeneic UC origin (UC-MSCs)	Autologous BM or allogenic UC	Chronic	C5–T11 (n = 20)	Perilesional (with BM-MSCs only) and Intrathecal	NCT04288934	Phase 1/2	Completed	Significant improvements in total ASIA scores.	University of Jordan	Awidi et al., 2024
–	BM-derived stem cells	Autologous BM	Subacute	NA (n = 7)	Intralesional	–	Phase 1/2	Completed	ASIA sensory-score improvement, improved bladder sensation,decreased spasticity, and improved posture control	NA	Saini et al., 2022
Stemirac	BM-MSCs	Autologous BM	Subacute	C3–C5 (n = 13)	Intravenous	JMA-IIA00154	Phase 2	Completed	Neurologic improvement based on the ASIA grade in 12 of 13 patients at 6 months post-MSC infusion	Nipro Corporation	Honmou et al., 2021
XCEL-UMC-BETA	Wharton's Jelly MSCs	Allogeneic Wharton's Jelly	Chronic	T3–T11 (n = 10)	Intrathecal	NCT03003364	Phase 1/2a	Completed	Statistically significant improvement in pinprick sensation. Significant improvement of bladder function at the individual level	Banc de Sang i Teixits	Albu et al., 2021
–	BM-MSCs	Autologous BM	Chronic	C3–C6 (n = 16)	Intralesional and intrathecal	–	Phase 3	Completed	2 patients showed improvements in the neurological status.	Asan Medical Center, Korea	Oh et al., 2016
–	BM-MSCs	Autologous BM	Chronic	C–L (n = 11)	Intrathecal	NCT02570932	Phase 2	Completed	Improvements in sensitivity, motor power, spasms, spasticity, neuropathicpain, sexual function, or sphincter dysfunction, including bladder compliance	Puerta de Hierro University Hospital	Vaquero et al., 2018
–	BM-MSCs	Autologous BM	Chronic	C3–L2 (n = 10)	Intrathecal	NCT02165904	Phase 2	Completed	All patients showed improved sensitivity and motor function. Improvements in sexual function, pain, bladder and bowel control, and spasms were observed at the individual level		Vaquero et al., 2017
–	BM-MSCs	Autologous BM	Chronic	T (n = 12)	Intralesional and intrathecal	NCT01909154	Phase 1/2	Completed	All patients showed improvement, primarily in sensitivity and sphincter control. Intralesional motor activity was achieved by most patients.		Vaquero et al., 2016

∗Abbreviations: ADL, activities of daily living; ASIA, American Spinal Injury Association; BM, bone marrow; BM-MSC, bone marrow-derived mesenchymal stem cell; C, cervical; ISNCSCI, International Standards for Neurological Classification of Spinal Cord Injury; L, lumber; n, number of patients; NA, not available; NBD, neurological breathing dysfunction; MSC, mesenchymal stem cell; QOL, quality of life; SCIM, spinal cord independence measure; SSEA, stage-specific embryonic antigen; T = thoracic; UC, umbilical cord; UC-MSC umbilical cord-derived mesenchymal stem cell.

In Japan, the regenerative medicine product Stemirac has been recognized by the Ministry of Health, Labor, and Welfare as effective for patients with subacute SCI and has received conditional insurance coverage. To our knowledge, Stemirac is the only SCI treatment in the world that is covered by national insurance. The raw materials in Stemirac consist of the bone marrow fluid and serum of the patient. MSCs are obtained from the bone marrow of the patient, and the culture medium is prepared from the serum of the patient. Over a period of 2–3 weeks, the bone marrow-derived MSCs of the patient are expanded by approximately 10,000-fold in culture (to 100 million cells), after which they undergo safety and quality tests before being returned to the patient. The cells are infused into the peripheral vein over approximately 60 min.

In the pre-approval trial, 6 months after MSC infusion, 12 of 13 patients showed neurological improvement based on the AIS. Five of six patients classified as AIS A before MSC infusion improved to AIS B (3/6) or AIS C (2/6), two patients with AIS B improved to AIS C (1/2) or AIS D (1/2), and five patients with AIS C improved to the functional status of AIS D (5/5) (Honmou et al., 2021). Based on these results, Stemirac was approved for subacute traumatic SCI with an AIS severity of A, B, or C. This approval attracted worldwide attention and sparked discussions on whether it should be accepted (Cyranoski, 2019; Miyamoto, 2019). As this was a conditional and time-limited drug approval, only a limited number of hospitals in Japan have started treating patients with Stemirac, and data for up to 1 year after treatment are still being collected. Moreover, the current approval is limited to patients in the acute phase within 31 days post-injury, leaving many chronic SCI patients unable to take advantages of this treatment. Non-clinical trials (Hirota et al., 2024) showed efficacy in chronic phase models, leading to an ongoing clinical study of chronic phase patients (jRCT2013230003).

Another clinical study conducted in Japan generated positive results using a subtype of MSCs known as multilineage-differentiating stress-enduring (Muse) cells. Muse cells are endogenous pluripotent bone marrow stem cells characterized by an approximately 0.03% positivity for surface marker stage-specific embryonic antigen-3 (Kuroda et al., 2010). They are non-tumorigenic and possess multipotent, self-replicating abilities. As Muse cells are naturally present in the body, the risk of developing tumors is extremely low, making them a promising candidate for clinical trials targeting various diseases, including cerebral infarction, acute myocardial infarction, and amyotrophic lateral sclerosis.

In a clinical study targeting SCI, 10 patients with cervical SCI classified as B1 or B2 on the modified Frankel scale received a single infusion of allogeneic CL2020 cells (1.5 × 10⁷ cells), a Muse cell-based product generated from human MSCs (JRCT1080224764) (Koda et al., 2024). Their ISNCSCI motor scores, activities of daily living, and quality of life scores were significantly higher than the corresponding baseline values. Although it is difficult to assess the validity of this study, given the potential for natural recovery, Koda et al. (2024) concluded that the effects of CL2020 were comparable to those reported by Honmou et al. regarding Stemirac (Honmou et al., 2021). Although the results were positive, the sponsor withdrew, and no prospects for continuing the research have been reported.

The Neurological Cell Therapy Group of Puerta de Hierro University Hospital, Spain, reported the efficacy of MSC transplantation. They conducted clinical studies using multiple doses of autologous bone marrow MSCs transplanted on various schedules, targeting patients with chronic SCI. In a study reported in 2016 (NCT01909154), 12 patients with chronic complete SCI (mean chronicity period: 13.86 years) were treated with intralesional and intrathecal injections of MSCs (1.3 × 10⁸ to 2.3 × 10⁸ cells/patient), depending on the size of the suspected injury, as determined from magnetic resonance images (Vaquero et al., 2016). In another report published in 2017 (NCT02165904), 10 patients with incomplete SCI received four intrathecal injections of 3.0 × 10⁷ MSCs (total of 1.2 × 10⁸ MSCs/patient) (Vaquero et al., 2017). Another report published in 2018 (NCT02570932) described three intrathecal injections of 1.0 × 10⁸ MSCs administered to 11 patients with chronic SCI (Vaquero et al., 2018). Although the authors reported efficacy for each method, cell-transplantation studies rarely demonstrate therapeutic effects in patients with chronic SCI. Furthermore, their group has not submitted any clinical trials to ClinicalTrials.gov, and the progress of their research is unknown.

5. Schwann cells

Schwann cells form and maintain the myelin sheath that surrounds the axons of peripheral nerves and produce cytokines important for maintaining motor and sensory neurons. In addition, Schwann cells play major roles in guiding and repairing the axons during axon regeneration after nerve injury (Nagoshi et al., 2011). Schwann cells are considered possible candidates for transplantation therapies intended to repair nervous system damage. However, few clinical studies have been conducted to investigate this treatment due to difficulty in culturing the tissue and concerns over the invasiveness of nerve harvesting. Given the scarcity of clinical research on Schwann cell transplantation, future studies are needed to evaluate its efficacy and safety.

In 2017, Anderson et al. published results from a phase 1 clinical trial assessing the safety of autologous human Schwann cell transplantation into the injury epicenter of a patient with subacute thoracic complete SCI, confirming its safety (Anderson et al., 2017). In 2022, Grant et al. (part of the same research group) reported a similar approach targeting patients with chronic SCI (NCT02354625) (Gant et al., 2022). They combined transplantation with fitness and rehabilitation training, addressing the functional decline due to disuse of the body and aiming to stimulate coordinated neural activity and thereby enhance neuroplasticity, which is key for promoting recovery following SCI. A standardized pre- and post-transplantation training protocol was implemented for each participant to avoid confounding factors between transplantation and rehabilitation. No SAEs were related to the protocol, and functional evaluations conducted 6 months post-transplantation showed partial improvement in sensory and motor functions for certain patients.

6. OECs

The olfactory nervous system, spanning from the olfactory mucosa to the olfactory bulb, is an exceptional site where nerve and axon regeneration occurs under physiological conditions (Farbman, 1994). This regenerative effect is thought to be caused by neural stem cells and OECs present in the olfactory mucosa epithelium. OECs ensheathe the non-myelinated axons of olfactory neurons in the same manner as Schwann cells ensheathe the peripheral neurons. Therefore, clinical studies using the olfactory mucosa (Lima et al., 2006; Feron et al., 2005) and olfactory lamina propria (Wang et al., 2016), which contain OECs, have been reported in the last two decades. As functional improvement is limited when OECs are transplanted alone (Wang et al., 2016; Mackay-Sim et al., 2008), clinical studies on the co-transplantation of OECs with MSCs (Zamani et al., 2022) or Schwann cells (Chen et al., 2014) have been initiated in recent years.

Chen et al. have conducted a randomized double-blinded clinical trial using a combination of OECs and Schwann cells in patients with chronic complete cervical SCI (Chen et al., 2014). Seven participants were divided into four groups: three were transplanted with OECs only, one was transplanted with Schwann cells only, one was transplanted with both OECs and Schwann cells, and two patients used as controls received no transplantation. Regarding the origin of the cells, OECs, and Schwann cells were derived from aborted human fetal olfactory bulbs and sciatic nerves, respectively. For the transplantation, one million cells per patient were injected into the spinal cord above and below the center of the lesion. As a result, 6 months after transplantation, all five participants in the treated groups showed some functional neurological improvement, while no changes were observed in the controls. However, the statistical analysis showed no significant difference between the treated and control groups, and the authors concluded that further studies with a large sample size are needed.

In 2021, Zamai et al. published results from a phase 1 clinical trial of intrathecal co-transplantation of OECs and MSCs to three patients with chronic complete thoracic SCI (Zamani et al., 2022). As a result, no serious adverse events were observed during the two years of follow up. One of the participants showed improvement in sensory scores and Spinal Cord Independence Measure III scores, but no motor recovery was observed in any of the participants.

Few reports of clinical studies on OEC transplantation have been published; therefore, future studies are awaited to evaluate its efficacy and safety. The results of recent clinical studies on Schwann cells and OECs are summarized in Table 3 (Gant et al., 2022; Zamani et al., 2022; Anderson et al., 2017; Lima et al., 2006; Feron et al., 2005; Wang et al., 2016; Mackay-Sim et al., 2008; Chen et al., 2014).

Table 3.

Recent major clinical trials involving Schwann cells and OECs.

Type of product	Cell origin	SCI target phase	Target level∗ (number of participants receiving transplants)	Injection route	Trial name	Phase	Reported efficacy	Sponsor or main institute	Reference
Autologous human Schwann cells	Autologous sural nerve	Chronic	C5–T12 (n = 8)	Intralesional	NCT02354625	Phase 1	One patient showed improvement in motor function, sensory function, and the neurological level of injury.	W. Dalton Dietrich	Gant et al., 2022
Autologous human Schwann cells	Autologous sural nerve	Subacute	T3–T11 (n = 6)	Intralesional	NCT01739023	Phase 1	All participants showed improvements to some degree, although this could have been expected in untreated people during the first year post-injury.	W. Dalton Dietrich	Anderson et al., 2017
Autologous OECs	Autologous olfactory mucosa	Chronic	T4–T10 (n = 3)	Intralesional	NA	Phase 1	Safety of up to three year post- transplantation was reported. One participant showed improvement of sensory function.	Griffin University	Feron et al., 2005; Mackay-Sim et al., 2008
Autologous olfactory mucosa	Autologous olfactory mucosa	Chronic	C4-T7 (n = 7)	Intralesional	NA	Phase 1	Every patient showed improvement of neurological function including ASIA motor score. One patient showed sensory decrease.	Hospital de Egas Moniz	Lima et al., 2006
Autologous olfactory lamina propria	Autologous olfactory lamina propria	Chronic	C6–T12 (n = 8)	Intralesional	NA	Phase 1/2	Subjects who received transplants recovered more motor, sensory, and bladder function than sham-operated subjects.	Wenzhou Medical University	Wang et al., 2016
Autologous OECs and BM-MSCs	Autologous olfactory mucosa and bone marrow	Chronic	T10–T12 (n = 3)	Intrathecal	RCT20160110025930N	Phase 1	One patient showed AIS improvement (from A to B) and an improved SCIM III evaluation.	Tarbiat Modares University	Zamani et al., 2022
OECs and Schwann cells	Human fetus	Chronic	C4–C7 (n = 5)	Intralesional	NA	Phase 1	All treated patients (except for one) showed improved electrophysiology test results. All treated patients (5 of 5) showed functional improvements.	Beijing Hongtianji Neuroscience Academy	Chen et al., 2014

∗Abbreviations: BM-MSC, bone marrow-derived mesenchymal stem cell; C, cervical; L, lumber; n, number of patients; NA, not available; OEC, olfactory ensheathing cell; SCIM, spinal cord independence measure; T = thoracic.

7. Discussion and conclusion

Over 10 years have passed since the clinical application of cell transplantation therapy for SCI began; however, an effective treatment has yet to be identified. This lack of success is likely due to the intricate interplay required to improve patient outcomes in terms of the level of injury, time since the injury, the baseline function of the patient, complications, and the degree of rehabilitation treatment. In addition, the medical burden on each patient is large, making recruiting more patients to clinical trials difficult. Although most patients with SCI have cervical injuries, many treatments are first tried with patients with thoracic SCI. This situation probably reflects the risk of side effects, which can be life-threatening in patients with cervical injury if it causes even mild paresis. Additionally, including patients with cervical SCI would increase the medical burden required to conduct clinical trials. Moreover, assessing functional changes in patients with thoracic SCI is already challenging because no segmental motor nerves are present at the thoracic level to detect slight improvements in function. SCI often results in functional changes long after injury (Kirshblum et al., 2004), making it more difficult to evaluate the efficacy of new treatments. Although most clinical trials have included only patients with traumatic SCI to simplify the study protocol, it is important to remember that patients with other causes (malignancy, vascular, neurological et al.) are also waiting for the new treatment.

It is still difficult to determine which of the various treatments being investigated will become practical in a clinical setting, and there is a possibility that new treatment modalities will be developed in the near future. In addition to the choice of the cell type being transplanted, the injection technique also influences the therapeutic effect. The injection routes used for cell transplantation therapy can be classified into three categories: intralesional, intrathecal, and intravenous. Intralesional injection is the most appropriate to target the injury site itself. However, this method is technically the most difficult of the three, and always carries the risk of worsening the degree of the paralysis caused by the initial injury. In other words, the effectiveness of this method depends greatly on the skill of the surgeon and should therefore only be performed by a trained surgeon, especially for treating chronic cases in which the scarring tissue from the initial injury can potentially interfere. Intrathecal injection is a method commonly used in anesthesia, and its associated risks are low. In this method, the transplanted cells spread via the cerebrospinal fluid. Therefore, the disadvantage of this method is that the percentage of transplanted cells that successfully migrate and survive in the injured site can be low. On the other hand, it may be suitable when the treatment is targeting a widespread injury or when an effect by nutritional factors is expected. The intravenous injection method also carries low risks, but it has the disadvantage that the cells can be easily trapped at the lung (Takahashi et al., 2011). Although pulmonary embolism does not seem to be a severe adverse event in ongoing clinical studies using this method, these potential risks should be considered when planning new clinical trials.

As of August 2024, the FDA had approved 39 cellular or gene therapy products; however, none target neurological diseases, highlighting the difficulty in treating them (U.S.F.D. Administration, 2024). Although complex and challenging, the use of cell transplantation to treat SCI remains an important research topic in the field of medicine. Treatment using a brain–spine interface was reportedly effective for SCIs (Lorach et al., 2023). However, with this type of treatment, the patient is again paralyzed once the device is turned off; therefore, the hope for functional recovery through cell regeneration remains unchanged.

The high costs of developing cell preparations and the scarcity of clear standards for determining their efficacy have led several pharmaceutical companies to withdraw from developing regenerative medicines for SCI. The development costs and challenges of monitoring functional improvements are issues every laboratory faces, highlighting the urgent need for innovative approaches. In recent years, new techniques, such as gene editing, have enabled evasion of the immune system (Meissner et al., 2022) or generating cells with a suicide switch (Amberger et al., 2023) to mitigate adverse effects. The lack of detailed epidemiological data is a limitation of SCI research, although artificial intelligence may fill these data gaps and help interpret the results of clinical studies. Advances in imaging techniques such as functional magnetic resonance imaging and myelin mapping will be useful in assessing functional changes (Matsubayashi et al., 2023; Fujiyoshi et al., 2016). The effectiveness of neurorehabilitation is beginning to become clear, and optimism exists for combining it with cell transplantation therapy (Tashiro et al., 2021; Okawara et al., 2020). Development of new strategies in the future will advance the field to new heights and facilitate the successful treatment of neurological diseases.

Author contributions

Conceptualization, KS. and N.N.; writing—original draft preparation, K.S.; writing—review and editing, N.N. and H.O; supervision, H.O., and M.N.; funding acquisition, K.S., M.N., and N.N. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Japan Agency for Medical Research and Development (AMED) [grant numbers JP24ym0126118 to N.N. and 24bm1223008 to M.N.] and the Japan Society for the Promotion of Science (JSPS) [KAKENHI grant number 23K24464 to N.N. and 24KJ1967 to K.S.].

Declaration of interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masaya Nakamura reports a relationship with K-Pharma, Inc. that includes: consulting or advisory. Hideyuki Okano reports a relationship with San Bio Co., Ltd., K-Pharma, Inc., and intellim Holdings Corporation that includes: consulting or advisory. Hideyuki Okano reports a relationship with SanBio Co., Ltd., and K-Pharma, Inc. that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: Prof F Kandziora