Clinical Efficacy of Stem Cell Therapy in Neurotraumatic and Neurodegenerative Conditions: A Comparative Review

Abstract

BACKGROUND:

Neurotraumatic conditions, such as spinal cord injury, brain injury, and neurodegenerative conditions, such as amyotrophic lateral sclerosis, pose a challenge to the field of rehabilitation for its complexity and nuances in management. For decades, the use of cell therapy in treatment of neurorehabilitation conditions have been explored to complement the current, mainstay treatment options; however, a consensus for standardization of the cell therapy and its efficacy has not been reached in the medical community. This study aims to provide a comparative review on the very topic of cell therapy use in neurorehabilitation conditions in an attempt to bridge the gap in knowledge.

METHODS:

Studies were searched from the PubMed database published from 2014 to 2024 employing the terms including but not exclusive to “spinal cord injury,” “brain injury,” “amyotrophic lateral sclerosis,” “regenerative medicine,” “cell therapy,” and “stem cell.” Following the PRISMA 2020 statement, the studies were screened, included, and excluded. Thirty three studies were identified and selected for this review.

RESULTS:

Countless researchers investigated the efficacy of various stem cell products for the treatment of numerous neurotraumatic conditions, such as spinal cord injury, traumatic brain injury, and neurodegenerative conditions such as amyotrophic lateral sclerosis. The recent decade of studies suggest that in neurotraumatic conditions, bone-marrow-derived and neural stem cells can be effective, and in neurodegenerative conditions, such as ALS, mesenchymal and neural stem cells can be efficacious.

CONCLUSION:

Emerging data from the latest research is encouraging to the patients suffering from neurotraumatic and neurodegenerative conditions, which present themselves as a need for further studies with improved standardization in study design, including cell source specification, differentiation and culture method, and outcome measures to ensure a wide applicability.

Introduction

The patient population that suffered neurological conditions, whether traumatic or non-traumatic in nature, often undergo rehabilitation in the forms of physical, occupational, or speech therapy, in addition to the medical care and attention at various levels of acuity and intensity depending on the severity of the condition and co-morbidities. Often, rehabilitation goals are to reduce the length of hospitalization, maximize the functional capacity of an individual via either recovery of lost functions or adaptation to the new baseline of functions, while meticulously considering a safe discharge plan with an appropriate disposition. Regenerative medicine has been attracting significant interest and popularity in the treatment of various neurorehabilitation diseases, namely spinal cord injury, brain injury, demyelinating disorders, and neuropathy.

Spinal cord injury (SCI) is a devastating condition that often results in a combination of motor, sensory, and autonomic dysfunctions, the pathophysiology which is thought to involve acute and chronic phases, via ischemia, oxidative stress, inflammatory events, apoptotic pathways, and locomotor dysfunctions as illustrated by Anjum et al. [1]. Despite the development of various rehabilitation strategies to facilitate recovery, due to the complexity of the condition and healing mechanism, a definitive therapeutic option that expedite the rehabilitation is still be identified. Papa et al. suggested the role of stem cell in the treatment of spinal cord injury by targeting the disease process on a cellular level [2]. The metrics frequently used to evaluate the severity and the recovery of spinal cord injury is AIS grading system, in which a complete injury is denoted grade A, incomplete as B, C, or D dependent on the sensory and motor involvement as well as urinary and bowel incontinence status.

Traumatic brain injury and cerebrovascular accident are neurorehabilitative conditions that also pose significant challenges in management to facilitate a meaningful recovery. In both conditions, the level of spasticity, a symptom that can be disabling to the activities of daily living, can be assessed employing modified Ashworth scale (MAS), a numerical value assigned to each affected muscle based on the extent of a particular range of motion inhibited. It is denoted as 0 for no increase in muscle tone, as 1 for slight increase in muscle tone with a catch and release at the end of the range of motion, as 1 + for a catch followed by minimal resistance less than half of the range of motion, as 2 for more marked increase in muscle tone through most of the range of motion, as 3 for a muscle tone that renders passive movement difficult, and 4 for affected part rigid in flexion or extension.

Among various regenerative medicine treatment options, numerous investigators explored the effectiveness of stem cell therapy for its exciting therapeutic potential. Multiple pre-clinical studies report the potential role of stem cells in the treatment of various neuromusculoskeletal conditions. For instance, 3D-spheroids of bone marrow-derived mesenchymal stem cells can be employed in enhancing the efficacy of spinal fusion surgery in terms of angiogenesis, bone regeneration, and mechanical stability. Furthermore, a combination use of epidural electrical stimulation and umbilical cord mesenchymal or neural stem cells in treatment of spinal cord injury have been described [3, 4]. As such, stem cell use in treatment of neurorehabilitation conditions is widely acknowledged, but due to the lack of solid clinical evidence, it is not currently covered by medical insurance and recommended by professional society treatment guidelines.

Stem cell has a potential in that it can overcome the hurdle that cannot be cured by the conventional pharmacologic treatment and interdisciplinary efforts; however, non-standardized culture method and various cell sources and reservoir still present as a source of hesitation to clinicians from choosing stem cell as a first-line complementary treatment option. This review explores the current available literature on PubMed on the topic of cell therapy in the treatment of neurotraumatic and neurodegenerative conditions and intends to delineate which cell type is efficacious in the treatment of spinal cord injury, traumatic brain injury, and amyotrophic lateral sclerosis.

Materials and methods

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement was followed to screen, include, and exclude the studies in conducting this comparative review. Of the 40 records identified, 3 duplicate records were removed, 1 was removed for other reasons, then the remainder of 36 records were screened, sought for retrieval, and assessed for eligibility. A total of 33 studies pertaining to the topic of spinal cord injury, brain injury, and amyotrophic lateral sclerosis were identified and selected for this review (Fig. 1).

Fig. 1.

Flowchart of records selection using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

Studies published from January 2014 to December 2024 were searched from the PubMed, Cochrane Library, SCOPUS, Science Direct, SAGE databases electronic database employing the terms such as “neural stem cells,” “mesenchymal stem cells,” “bone marrow-derived stem cells,” “Wharton’s jelly stem cells,” “fetal brain-derived stem cells,” “adipose-derived cell cells,” “human central nervous system stem cells,” “oligodendrocyte progenitor cells,” “neurorehabilitation,” “spinal cord injury,” “SCI,” “brain injury,” “TBI,” “amyotrophic lateral sclerosis,” “ALS,” “regenerative medicine,” “cell therapy,” “stem cell,” “efficacy,” “safety,” “adverse events,” “case,” “case-series,” and “clinical trial.” Combinations of these terms were used to search by utilizing Boolean operators “or” and “and.”

Inclusion criteria for study types include case report, case-series, case–control, and clinical trials, both randomized and nonrandomized. The studies identified were human studies, in varying stages of clinical trials, but pre-clinical animal studies were excluded from the search. In terms of the acuity of each condition, both acute and chronic injury characteristics were included; however, the majority of the cases were chronic in nature. Exclusion criteria include studies involving conditions that are not related to neurorehabilitation, treatments other than any form of cell therapy, and are in forms of books, articles, and responses.

The tables were created by categorizing each study into different neurorehabilitation conditions, spinal cord injury, traumatic brain injury, and amyotrophic lateral sclerosis. Then the key elements of each study, including study type, allogenic vs. autologous, cell type, concentration, administration route, size, major functional outcome, and major adverse events, were summarized and listed to aid the readers with comparison.

Results

Spinal cord injury

Dozens of investigations have been reported for the treatment of intractable spinal cord injury using cell therapy (Table 1). Autologous mesenchymal stem cells (bone marrow-derived cells, adipose-derived cells), allogenic mesenchymal stem cells, neural stem cells, Wharton’s jelly-derived cell, and oligodendrocyte progenitor cells were used in the cases of cervical, thoracic, lumbar spinal cord injury.

Table 1.

Stem cell types and different therapeutic effects in the treatment of spinal cord injury [3–14]

Study Type	Allogenic vs Autologous	Cell Type	Concentration (cells)	Administration Route	Injury Level	Size (n)	AIS Grade Change	Other Changes	Major Adverse Events	Ref.
Case report	Autologous	Bone marrow nucleated cells (BMNCs)	3.2 × 109 (IV) 0.5 × 109 (IT)	Intrathecal Intravenous	Thoracic (T2-3)	1	A > C/D; sensation level expanded to T1 - L3–4	Restoration of bladder filling sensation and control, and anal sensation	Hemorrhagic necrosis initially observed at T2-3 level on MRI	[5]
Clinical trial	Autologous	BMNCs	Unspecified (5 mL)	Intrathecal	Lumbar (L1/L2)	10	Improvements in 6/10 cases	Improvements in 8/10 cases for VTC, walking	–	[6]
Clinical trial	Autologous	Bone marrow mesenchymal stem cells (BM-MSCs)	1.0 × 108	Intrathecal (9) Intralesional (11)	Cervical (7) Thoracic (13)	20	A > B; improvements in 5/8 cases	–	–	[7]
Clinical trial	Autologous	Adipose- derived mesenchymal stem cells (AD-MSCs)	9 × 107	Intrathecal	Cervical; Cervico -thoracic; Thoracic; Lumbar	14	Improvements in 5/14 cases at 8 months	Improvements in VAC in 2/14; in ASIA sensory score in 10/13	UTI; headache; nausea, vomiting	[8]
Case series	Autologous	BM-MSCs	0.84–1.6 × 108	Intravenous	Cervical (C3–C5)	13	A > B/C B > C/D C > D; Improvements in 12/13 cases at 6 months	–	–	[9]
Clinical trial	Allogenic	Fetal neural stem cells (spinal cord-derived; NSI-566)	2 × 105 (/10uL)	Motor cortex Nucleus ruber	Thoracic (T2, T5, T7, T8)	4	–	T5: sensory and motor improvements in T5–T7 up to 18 months; T7 paraspinal EMG activity T7: T6–T8 paraspinal EMG activity, T6–T9 sensation development at 18 months	–	[13]
Clinical trial	Allogenic	Fetal brain- derived Neural stem cells (HuCNS-SC)	4 × 107	Perilesional Intramedullary	Cervical (C5–C7)	6	–	Improvements in UE Motor Score 1.25 > 2.83 at 9 months; in GRASSP strength; prehension ability by 4.17	Surgical incision site Staph. epidermidis wound infection; non-surgical incisional hematoma	[15]
Clinical trial	Allogenic	Fetal brain- derived Neural stem cells (HuCNS-SC)	2.0 × 107	Perilesional	Thoracic (T2–T11)	12	Improvements in 5/12 cases for sensation at 1 year	Development of sensation below the lesion in 2/7 cases for the AIS A group	CSF leak; moderate pseudo- -meningocele	[14]
Non- randomized controlled trial	Allogenic	Fetal brain- derived neural stem cells (hNSPCs)	1.0 × 105 (/uL)	Intraparenchymal	Cervical	19	A > B/C B > D; Improvements in 5/19 cases	–	–	[12]
Case report	Allogenic	Wharton’s jelly mesenchymal stem cells (WJ-MSCs)	3 × 107 (× 5, q3mos)	Intrathecal	Thoracic (T11–T12)	1	A/B > C/D; sensation level decreased from T12 to L3–L4	Recovery of bladder control and anal sensation; improvement in LE strength	–	[10]
Case report	Allogenic	WJ-MSCs	1.18 ± 4 × 108 (× 6)	Intrathecal	Thoracic (T10-T12)	1	A > C at 3 months	VAC at 3 months; partial urinary control at 12 months	–	[11]
Clinical trial	Allogenic	Oligodendrocyte progenitor cells (LCTOPC1)	2 × 106 1 × 107 or 2 × 107	Intraparenchymal	Cervical (C4-7)	25	–	Recovery of > 1 levels of neurological function on at least one side of body in 21/22 cases at 1 year	CSF leak; bacterial infection	[16]

CSF cerebrospinal fluid; VTC virtual time to contact; VAC voluntary anal contraction; UE upper extremity; LE lower extremity; GRASSP graded and redefined assessment of strength, sensibility, and prehension

Autologous mesenchymal stem cells

Autologous bone marrow-derived cells have demonstrated a therapeutic potential in the treatment of thoraco-lumbar SCI patients, the notion of which initially started with a case report in 2015 by Jarocha et al. [5]. The case report illustrates the use of bone marrow nucleated cells (BMNCs) for a patient who suffered a T2–T3 thoracic SCI. Ten weeks after the injury, the patient was injected 3.2 × 10⁹ BMNC intravenously and 0.5 × 10⁹ BMNC intrathecally, followed by five round of mesenchymal stem cell administration every three to four months via lumbar puncture, at the concentration of 1.3–3.65 × 10⁷. AIS grading improved from grade A to grade C/D, with sensation level expanding from T1 thoracic to L3–L4 lumbar levels. In addition, the patient displayed recovery of bladder filling sensation, control, and anal sensation by the time of the follow-up. A major adverse event of hemorrhagic necrosis was initially observed at T2–T3 thoracic level on magnetic resonance imaging.

The use of bone-marrow derived cells in SCI patients was also explored by Bansal et al. who evaluated the efficacy of autologous bone marrow-derived stem cells in ten patients with lumbar SCI. 5 mL of processed sample was administered at the L1–L2 lumbar level by lumbar puncture [6]. Of the ten participants, AIS grading improved in six, ambulation improved in eight, bladder control restored in three, and sexual functions recovered in five. No major adverse events were reported by the authors.

The aforementioned studies were followed by a single-center, open-label, parallel-group randomized clinical trial was conducted by Awidi et al. in 2024 who identified and randomized 20 patients with SCI into two groups to examine the therapeutic effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) [7]. Group A consisted of four cervical and seven thoracic SCI patients who received 1.0 × 10⁸ perilesionally, while group B of three cervical and six thoracic SCI patients injected the same concentration intrathecally. In group A, five patients with the baseline AIS grade of A improved to AIS B at the one-year follow-up, and all three AIS B patients saw improvement to AIS C; in group B five of the AIS A patients improved to AIS B grading. No long-term adverse events were reported in both groups by the authors.

Though the use is not reported in abundance, autologous adipose-derived mesenchymal stem cells can also be beneficial in the treatment of SCI of all levels. Hur et al. conducted a clinical trial examining the role of adipose-derived mesenchymal stem cells (AD-MSCs) in acute to chronic SCI [8]. A total of 14 patients with varying levels of spinal cord injury were examined (6 cervical, 1 cervico-thoracic, 6 thoracic, and 1 lumbar) received 9 × 10⁷ of AD-MSCs intrathecally via lumbar tapping. At eight-month follow-up, five out of 14 patients saw improvement in AIS grading, two out of 14 patients experienced improvement in anal contraction, and ten out 14 patients gained recovery of ASIA sensory score. Four adverse events were reported in three patients of urinary tract infection, headache, nausea, and vomiting.

Honmou et al. reported the use of autologous mesenchymal stem cells at 0.84—1.6 × 10⁸ concentration in 13 patients with cervical (C3–C5 level) SCI [9]. At six-month follow-up post-infusion, AIS grade improvement was observed in 12 out of 13 participants, in which three of six AIS A patients improved to AIS B and two of six to AIS C, one of two AIS B improve to AIS C and one of two to AIS D. No serious adverse events associated with MSC injection was observed.

Of the studies using autologous mesenchymal stem cells, the intrathecal, intravenous, and intraspinal administration of the cells have demonstrated efficacy of the cell therapy in the treatment of spinal cord injury in all levels, though at a varying level. While most of the earlier works focused on the thoracolumbar levels, a recent work expanded the level to the cervical. In most cases, at least one AIS grade improvement was seen in patients, and at times, two or more grades.

Allogenic mesenchymal stem cells

Allogenic Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) have been suggested by two case reports on its use to treat the patients with thoracic SCI [10]. Interestingly, both cases illustrate the potential therapeutic role of WJ-MSCs in lower levels of thoracic SCI. Despite positive results of both cases, the route of administration and the concentration of the cells used varied significantly. A patient with thoracic SCI at the level of T11–T12 with an incomplete, AIS grade A/B, deep paraparesis, and sphincter palsy received 3 × 10⁷ WJ-MSCs over five rounds every three months via lumbar puncture. The patient saw AIS grading improvement from A/B to C/D at the follow-up, sensation level descended from T12 thoracic to L3–L4 lumbar, regained bladder control and anal sensation, and saw improvements in left lower extremity strength. The authors of the case reported no complication during the 18-month follow-up.

Akin to the Miczarek et al.’s report of a case, Jamali et al. also suggested the utility of WJ-MSCs with cases of thoracic (T10–T12) SCI [11]. In this case, the cells were administered intrathecally at 1.18 ± 4 × 10⁸ concentration over six doses. In comparison to the baseline AIS grading of A, at three-month follow-up, AIS grade was improved to C, which plateaued throughout the 22 months of the study. The patient recovered a voluntary anal contraction at three months and partial urinary control at 12 months. No serious adverse effects related to the treatment were reported during the 25-month follow-up period.

Neural stem cells (NSCs)

Neural stem cells (NSCs) have been demonstrated to be effective in treatment of chronic spinal cord injuries encompassing all major levels of cervical, thoracic, and lumbar spine, as evidenced by four clinical trials in the recent decade. Shin et al. [12]. conducted a phase 1, 2a open-label, non-randomized controlled trial with 19 patients who suffered from cervical SCI, 17 sensorimotor complete and 2 motor complete, sensory incomplete, by administering fetal brain-derived neural stem/progenitor cells (hNSPCs), at the concentration of 1.0 × 10⁵, directly into the spinal cord. Among the 19 participants, AIS improvement was seen in five patients whose grading improved from grade A to grade C in two, grade A to grade B in one, and grade B to grade D in two. No major adverse event was observed, including evidence for cord damage, syrinx or tumor formation, neurological deterioration, exacerbating neuropathic pain, or spasticity at one-year follow-up.

The use of NSCs can also be extended to the treatment of patients with thoracic SCI. In 2018, Curtis et al. performed a phase 1 clinical trial with spinal cord-derived neural stem cells (NSI-566) in the treatment of four thoracic (T2, T5, T7, T8) SCI patients [13]. 2 × 10⁷ cells/10uL were injected per injection into the motor cortex and nucleus ruber. While the patients who suffered a T2, T7 thoracic SCI saw no change in ISNCSCI (International Standards for Neurological Classification of Spinal Cord Injury) neurological score up to 12 months after the cell grafting, the patients with T5 and T8 thoracic level injuries displayed one level of sensory and motor (in right T5–T6, left T5–T7) and motor improvement respectively at 6, 12, and 18 months. Despite the lack of improvement in ISNCSCI score in a T7 thoracic injury patient, EMG analysis showed a new voluntary activity in the right rectus abdominus, left T6–T8 thoracic paraspinal muscles, bilateral development of sensation in T6–T9 thoracic at 18 months. No immediate or delayed complication was observed in the aftermath of the injections.

Another study suggested the therapeutic potential of neural stem cells in patients with thoracic SCI. Curt et al. in its multi-site, phase I/IIA clinical trial, injected 2.0 × 10⁷ fetal brain-derived, human central nervous system stem cells (HuCNS-SC) into thoracic cord for 12 patients with thoracic SCI over T2–T11 thoracic with AIS grading of either A or B [14]. Five out of 12 participants demonstrated sensory improvements over at least the first year of follow-up and two of seven with AIS grade A developed some sensation below the lesion. The authors mentioned four severe adverse effects in three subjects (CSF leak at 11 days post-transplant, moderate pseudomeningocele at 13 days post-transplant).

The use of neural stem cells in the treatment of spinal cord injury was not limited to the cervical and thoracic levels. Levi et al. conducted a phase 2, single blind, randomized, proof-of-concept clinical trial with allogenic neural stem cell (fetal brain-derived; HuCNS-SC) that were injected perilesionally and intramedullary into six patients with cervical SCI patients with C5–C7 tetraplegia, either with AIS grade of A or B [15]. In this study, unlike the studies by Curtis et al. and Curt et al., upper extremity motor score (UEMS) and Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) ability score were employed to assess for the improvement. In comparison to the baseline UEMS score of 1.25, at the nine-month follow-up, UMES score improved to 2.83, and GRASSP score was improved by 4.17 and 1.08 points for strength, prehension ability and motor gains respectively. Two serious adverse events were reported such as surgical incision-related Staphylococcus epidermidis wound infection and non-surgical incisional hematoma.

Despite the emerging encouraging results of the studies employing neural stem cells for the treatment of spinal cord injury of all major levels, a standardized, ideal dosage of the NSCs have yet to be identified, depending on the administration route. In addition, though most studies used AIS grading change as the metric to assess the efficacy of the treatment, other scores (ISNCSCI, UEMS, GRASSP) utilized varied by the author, rendering it difficult to comparatively assess the studies.

Oligodendrocyte progenitor cells

A recent report suggests human embryonic stem cell derived-oligodendrocyte progenitor cells (formerly known as APC-OPC1) have demonstrated a therapeutic potential for treatment of cervical spinal cord injury. Fessler et al. conducted an open-label, dose-escalation, multi-center clinical trial in which 25 patients with cervical SCI over C4–C7 level with AIS A or B grade of injury were injected 2 × 10⁶, 1 × 10⁷, or 2 × 10⁷ LCTOPC1 cells intraparenchymally [16]. At one-year follow-up, 21 of 22 intention-to-treat groups recovered one or more levels of and seven of 22 recovered two or more levels of neurological function on at least one side of the body. A total of 29 serious adverse events were reported, including cerebrospinal fluid leakage and bacterial infection.

Traumatic brain injury

It has been suggested that traumatic brain injury can also be treated with cell therapy, using WJ-MSCs, bone marrow mononuclear cells, and gene-modified MSCs (Table 2).

Table 2.

Different cell types in the treatment of traumatic brain injury [15–19]

Study type	Allogenic vs autologous	Cell type	Concentration (cells)	Administration route	Size (n)	Major functional outcome	Major adverse events	Ref.
Case report	Allogenic	WJ-MSCs	1 × 106 (/kg)	Intrathecal; Intramuscular; Intravenous	1	At the baseline, tetraplegic with high-degree of muscle spasms, inability to speak and control sphincter FIM score improved from 22/126 to 76/126 at 12 months; MAS: 44 to 16 at 12 months	–	[17]
Clinical trial	Allogenic	WJ-MSCs	1 × 106 (/kg)	Intrathecal; Intramuscular; Intravenous	6	All 6 participants demonstrated improvements in cognitive abilities (FIM scale), muscle spasticity (MAS), muscle strength, performance scores (Karnofsky), and motor skills (FIM);	Early, transient complications: subfebrile fever, mild headache, muscle pain due to IM injection	[18]
Clinical trial	Autologous	BMNCs	6 × 106 9 × 106 12 × 106 (/kg)	Intravenous	25	Quantitative analysis of the high-resolution 3D T1-weighted images demonstrated preservation of supratentorial volumes in the treated group at 6 months; dose-dependent suppression of TNF-alpha and reduction of IL-1beta, IL-10, IFN-gamma in high-dose group	–	[19]
Clinical trial	Autologous	BMNCs	6 × 106 10 × 106 (/kg)	Intravenous	37	3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days, and 3-day. (14%) reduction in ICU days; preserved white matter volume, placebo group displayed reduction in corpus callosum streamlines compared to the BMMNC group	Death due to sepsis before 1 month	[20]
Clinical trial	Allogenic	BM-MSCs transiently transfected intracellular domain of human Notch-1 (SB623)	2.5 × 106 5.0 × 106 10 × 106	Intraparenchymal	63	Significantly improved motor status at 24 weeks as demonstrated by significantly greater change of the FMMS score in the SB623 pooled group in comparison to the control group (p = 0.04); continued improvement of function and ADL at 48 weeks	–	[21]

FIM functional independence measure; MAS modified Ashworth scale; IM intramuscular; ADL activities of daily living; FMA Fugl-Meyer Assessment

WJ-MSCs

As shown to be efficacious in the treatment of spinal cord injury, the use of WJ-MSCs in treatment of traumatic brain injury (TBI) has been explored since 2020. Kabatas et al. first reported a case of a TBI patient with tetraplegia, high-degree of muscle spasm, inability to speak, and control sphincter [17]. 1 × 10⁶ WJ-MSCs were injected intrathecally, intramuscularly, and intravenously over six doses in total. At the 12-month follow-up, the patient saw improvements in functional independence measure (FIM) scores from 22/126 to 76/126 and modified Ashworth scale (MAS) from 44 to 16. No adverse event was reported in this case.

The case report was followed up four years later by the clinical trial of six patients with a similar treatment set up with intrathecal, intramuscular, and intravenous administration of 1 × 10⁶ WJ-MSCs [18]. All participants of the study demonstrated improvements in cognitive abilities and motor skills by FIM score, muscle spasticity by MAS, muscle strength, and performance scores by Karnofsky. Early, transient complications were reported, such as subfebrile fever, mild headache, muscle pain due to the intramuscular injection.

Bone marrow mononuclear cells

Another cell type that has shown a therapeutic potential to complement the treatment of traumatic brain injury is bone marrow mononuclear cells (BMMNCs). Cox et al. initially investigated the efficacy of autologous BMMNCs in 2017 in its phase 1/2a clinical trial of 25 patients [19]. 6 × 10⁶ cells/kg, 9 × 10⁶ cells/kg, and 12 × 10⁶ cells/kg were administered intravenously, and at six months, high-resolution three-dimensional T1-weighted images were employed to perform a quantitative analysis, which demonstrated preservation of supratentorial volumes in the treated group. In addition, a dose-dependent suppression of tumor necrosis factor-alpha and reduction of interleukin-1beta, interleukin-10, interferon-gamma in the high dose group. No adverse events were reported in this study.

Building on the previous phase 1/2a clinical trial, the authors conducted a randomized, double-blind, placebo-sham-controlled, Bayesian dose-escalation clinical trial. 37 severe TBI (i.e., Glasgow coma scale < 8) were selected, of which 14 were assigned to the placebo group, and treated intravenously with 6 × 10⁶ cells/kg if assigned to the low-dose group and with 9 × 10⁶ cells/kg for the high-dose group [20]. The treatment groups resulted in near 3-day (23%) reduction in ventilator days, 1-day (16%) reduction in intracranial pressure monitoring days, and 3-day (14%) reduction in intensive care unit (ICU) days. At the one-year follow-up, the BMMNC group demonstrated significantly preserved white matter volume (mean difference of − 20,600; p = 0.01); in addition, the placebo group displayed reduction in corpus callosum streamlines compared to the BMMNC group (mean difference − 394; p = 0.055), which was not statistically significant due to the high variability. No episodes of significant hemodynamic changes, pathological intracranial pressure elevations, infusion-related toxicity or organ injury were reported.

The clinical trials conducted over multiple phases have suggested the therapeutic role of BMMNCs in the treatment of traumatic brain injury, as evidenced by the brain volume and pro-inflammatory cytokine assessment. However, since the conclusion drawn from the findings was the result of an aggregate results of the groups of differing cell concentration, the discovery of the optimal cell dosage would be the direction of the future studies.

Gene-modified allogeneic BM-MSCs

The latest development in the use of cell therapy for the treatment of traumatic brain injury is showcased by the double-blind, randomized, prospective, surgical sham-controlled, phase 2 clinical trial carried out by Okonkwo et al. [21]. 63 TBI patients were treated with SB-623, allogeneic BM-MSCs transiently transfected with cytoplasmic domain of Notch-1, at 2.5 × 10⁶, 5.0 × 10⁶, and 10 × 10⁶ cell concentration administered intracranially via stereotactic surgery. At the 24-week follow-up, a significant improvement in motor status was seen as demonstrated by the greater change in FMMS score in the SB623 pooled group in comparison to the control group (p = 0.04). The participants were tracked at 48 weeks, whose function and activities of daily living continued to improve. No deaths or withdrawals due to adverse events were reported.

Amyotrophic lateral sclerosis

The conventional management of amyotrophic lateral sclerosis (ALS) can be complemented with cell therapy (Table 3). Fetal spinal cord-derived neural stem cells, neural stem cell-derived motor neuron, fetal human neural stem cells, BM-MSCs, WJ-MSCs, and GDNF-overexpressing human fetal neural progenitor cells have demonstrated an optimistic results in treatment of ALS.

Table 3.

Therapeutic effects of cell therapy according to cell types in amyotrophic lateral sclerosis [23–34]

Study type	Allogenic vs autologous	Cell type	Concentration (cells)	Administration route	Size (n)	Major functional outcome	Major adverse events	Ref.
Clinical trial	Autologous	BM-MSCs	–	Intravenous Intrathecal	25	At 12 month follow-up, 10 patients receiving cell therapy displayed slowing of disease progression	–	[26]
Clinical trial	Autologous	BM-MSCs	1.0 × 106 (/kg)	Intrathecal	20	1st & 2nd injections: ALSFRS-R improved (> 25%) in 15/19 cases 2nd & 3rd injections: improvement in 11/12 cases 3rd & 4th injections: improvement in 8/10 cases	–	[27]
Clinical trial	Autologous	BM-MSCs secreting high neurotrophic factor (NTF) (NurOwn® cells)	125 × 105 (/5 mL; intrathecal) 48 × 106 (/mL; intramuscular)	Intrathecal Intramuscular	48	The change in ALSFRS-R score slope was greater in MSC-NTF group in comparison to the placebo group at both 2 and 4 weeks	9/36 in MSC-NTF cells group and 2/12 in placebo group developed serious adverse events with headache and procedural headache being the most common followed by back pain	[28]
Clinical trial	Autologous	NurOwn® cells	125 × 106	Intrathecal	196	Improvements in cerebrospinal neuroinflammation, neurodegeneration, and neurotrophic factor related biomarkers; the primary endpoint evaluating efficacy was not met	The majority of the participants experienced treatment-emergent adverse events, the most common of which was pain	[29]
Clinical trial	Allogenic	Fetal spinal cord-derived neural stem cells	1.0 × 105 (/injection)	Intraspinal (cervical)	6	Post-operative ALSFRS-R, HHD, and EIM measurements with no acceleration of disease course; slower disease progression seen in cervical injection group	Only minimal preoperative or postoperative complications reported	[22]
Clinical trial	Allogenic	Fetal neural stem cells	7.5 × 105 (/injection)	Intraspinal (lumbar)	6	Up to 18-month after surgery, no increase in disease progression; transient improvement in the ambulation subscore of ALS-FRS-R scale in 2/6 cases	3 patients, who refused PEG and invasive ventilation, died 8 months after surgery related to the evolution of the disease	[24]
Clinical trials	Allogenic	Fetal spinal cord-derived neural stem cells	1.0–8.0 × 105 (/injection)	Intraspinal (cervical  ± lumbar)	15	No differences in mean rates of disease progression observed when compared to three separate historical control groups	Transient pain associated with surgery and to side effects of immunosuppressant medications were reported	[23]
Clinical trial	Allogenic	Fetal neural stem cells	4.5 × 106	Intraspinal (T8/11; C3/5)	18	ALSFRS-R and FVC (%) no acceleration of decline; SEIQoL remained elevated (73%); temporary improvement in ambulation score in 5/18; improvement by one point in the upper limbs score in 4/18 participants	–	[25]
Clinical trial	Allogenic	GDNF gene transducer fetal neural stem cells (CNS10-NPC-GDNF)	0.2 × 106 0.5 × 106	Intraspinal (lumbar)	18	Slower rate of strength loss in the treated leg than the untreated leg on average; no significant changes in CMAP of the tibialis anterior and EIM seen in the treated group	–	[31]
Case–control	Allogenic	WJ-MSCs	30 × 106 (/injection)	Intrathecal	67	All groups resulted in doubling of the median survival time; decreased progression rate seen in 21/67, no change in progression rate in 33/67, and increased progression in 13/67	–	[30]

CMAP compound motor action potential; EIM electrical impedance myography; ALSFRS-R ALS functional rating scale—revised; HHD hand-held dynamometry

Fetal spinal cord-derived neural stem cells

The use of allogenic fetal spinal cord-derived neural stem cells in the cervical intraspinal has been suggested by two clinical trials in 2014 and 2016. Feldman et al. conducted a phase 1 clinical trial of six patients who received 1.0 × 10⁵ cells/injection [22]. The post-operative ALSFRS-R, HHD, and EIM measurements demonstrated no acceleration of the disease course, and the patient who received the cervical injection displayed a slower progression of the disease. No major adverse events were reported, and only minimal perioperative, postoperative complications were seen.

Similarly, Glass et al. performed a phase 1, 2 clinical trials of 15 patients using the same cell lines at concentrations of 1.0–8.0 × 10⁵ cells/ injection [23]. The cells were administered in the cervical spinal cord bilaterally in all groups while one group received injections in the lumbar (L2–L4) level. The study did not include a control group of its own, but instead compared its experimental group with three separate historical control groups, the comparison of which revealed no differences in mean rates of disease progression. The authors reported transient pain associated with surgery and to side effects of immunosuppressant medications as the adverse events of the study.

Fetal human neural stem cells

Targeting the lumbar spinal cord with fetal human neural stem cells in the treatment of ALS was suggested by Mazzini et al. in clinical trials of six patients in 2015 [24] and 18 patients in 2019 [25]. In their initial study, the cells were injected intraspinally at 7.5 × 10⁵ cell concentration, and at the 18-month follow-up after the surgery, no evidence for the increase in disease progression was observed. In two of six participants, a transient improvement in the ambulation subscore of ALS-FRS-R score was seen. In this study, three patients who refused percutaneous-endoscopic gastrostomy placement and invasive ventilation died 8 months after the surgery, deemed related to the evolution of the disease. In the second trial [25], patients receiving intraspinal injection of 4.5 × 10⁶ were monitored up to 60 months with no evidence of adverse events related to the treatment. A significant transitory decline in progression of ALS-FRS-R score were seen within the first month of cell transplantation that continued up to 4 months.

Autologous MSCs

Rushkevich et al. conducted a clinical trial in 2015 assessing the efficacy of autologous BM-MSCs in treatment of ALS [26]. Twenty-five patients were administered intravenously via lumbar puncture. At 12-month follow-up, ten patients who received the cell therapy displayed slowing of disease progression comparatively to the control group. No significant adverse effects were reported.

Petrou et al. followed up in 2021 with a phase 2 clinical trial examining the therapeutic potential of BM-MSCs when administered intrathecally [27]. Twenty ALS patients were injected 1.0 × 10⁶ cells/kg of body weight, one of which was lost to follow up. In 15 of 19 patients, ALSFRS-R monthly rate of progression improved by greater than 25% between the first and second injections, in 11 of 12 patients, an improvement was seen between the second and third injections, and in 8 of 10 between third and fourth injections. Seven of 19 patients saw clinical improvement after the first injection and five of 19 after the second injection. No serious adverse events were reported by the authors.

In 2019, Berry et al. conducted a phase 2, randomized controlled trial to assess the therapeutic utility of NurOwn^® cells, autologous BM-MSCs secreting high levels of neurotrophic factors, for ALS [28]. Forty-eight patients were selected, 36 of whom were administered either intrathecally, with a concentration of 125 × 10⁵ cells/5 mL, or intramuscularly, with a concentration of 48 × 10⁶ cells/mL. At the two-week follow-up, the change in ALSFRS-R score slope was significantly higher in the cell-treated group at + 1.7 points/months than the placebo group at − 0.4 points/month (p = 0.110); at the four-week follow-up, a similar trend was maintained at a lesser degree, with + 0.6 points/month in cell-treated group and − 0.03 points/month in the placebo group. Total of 11 patients developed serious adverse events of headache and back pain. Later, Cudkowicz in 2022, further explored the therapeutic efficacy of repeated NurOwn^® cell treatment of ALS in a phase III study [29]. The randomized, double-blind, placebo-controlled study involved 196 patients, the treatment group of which was injected intrathecally at 125 × 10⁶ cell concentration. A notable improvement in cerebrospinal neuroinflammation, neurodegeneration, and neurotrophic factor related biomarkers was seen in the treated group. It is noteworthy to mention that the primary endpoint evaluating the efficacy of NurOwn^® cells was not met. The majority of the participants experienced treatment-emergent adverse events, the most common of which was pain.

WJ-MSCs

An intrathecal administration of WJ-MSCs been shown to have a therapeutic potential in treating ALS patients in a case–control study by Barczewska et al. [30] 67 patients were selected to participate in the study, of whom the treatment group was injected 30 × 10⁶ cells/injection. The median survival time doubled in all groups, and decreased progression rate was seen in 21 of 67 patients, no change in progression rate in 33 of 67 patients, and increased progression in 13 of 67 patients. No serious adverse events were reported.

GDNF-overexpressing fetal neural stem cells

Baloh et al., in 2022, reported the use of glial cell-derived neurotrophic factor (GDNF) gene transduced fetal neural stem cells (CNS10-NPC-GDNF) in a phase 1/2a clinical trial [31]. 18 participants were allocated to two groups: group A treated with 0.2 × 10⁶ CNS10-NPC-GDNF cells; group B treated with 0.5 × 10⁶ cells. The cells were administered into the transition zone between the dorsal and ventral horns in the lumbar spinal cord. Though no significant changes were observed in compound motor action potential (CMAP) on tibialis anterior and electrical impedance myography (EIM) for the treatment group, a slower rate of strength loss was seen in the treated leg than the untreated leg on average. No serious adverse events attributable to the injected cells were reported.

Discussion

This study is the first review that comprehensively and comparatively outlines the latest developments in regard to specifications and efficacy of cell therapy in treatment of various neurorehabilitation conditions of spinal cord injury, traumatic brain injury, and amyotrophic lateral sclerosis, primarily focusing on the studies published during the past decade (2014–2024).

Efficacy of cell therapy in neurotraumatic conditions

For spinal cord injury, two cell types have been identified to have demonstrated positive results: bone marrow-derived cells and neural (progenitor) stem cells [5–7, 12, 14, 15]. These were suggested by improvement in AIS grading, recovery of sensory and motor function, and bladder and anal controls (Fig. 2).

Fig. 2.

Potential therapeutic effects of bone marrow nucleated cells and bone marrow mesenchymal cells in neurotraumatic and neurodegenerative conditions; AIS: American Spinal Injury Association Impairment Scale, VTC: virtual time to contact, ICU: intensive care unit, FMMS: Fugl-Meyer Motor Scale, UE: upper extremity, ALSFRS-R: ALS Functional Rating Scale – Revised

Autologous bone marrow-derived cells were shown to be efficacious in almost all levels of spine—that is, cervical, thoracic, and lumbar, albeit results of multiple studies—all of which had at least one or greater improvement in AIS grading. It is interesting to note that despite some variation in cell administration, all studies employed intrathecal method via lumbar puncture [5–7]. Similarly, allogeneic neural stem cells were shown to be effective in spinal cord injury recovery, mostly targeting the higher levels of spinal cord, cervical and thoracic [12–15].

One plausible explanation for the therapeutic efficacy of cell therapy may be due to the immunomodulatory effect of stem cells via release of anti-inflammatory cytokines [32, 33]. It has been described that mesenchymal stem cells and neuronal stem cells may induces activation of endogenous M2 macrophages and microglia. In contrast to the iPSCs and neural stem cells that exhibit long-term therapeutic effects and cell survival, long-term survival of MSC is limited; the therapeutic effect is likely due to the paracrine effects of MSC when treated in conjunction with neural stem cells. Furthermore, migration of neutrophils and iNOS + /Mac-2 + cells to the area of spinal cord injury may be suppressed with the administration of neural stem cells, which was concurrently seen with decreased level of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and IL-12 [32, 34].

Efficacy of cell therapy in neurodegenerative condition

In treatment of amyotrophic lateral sclerosis, mesenchymal stem cells and neural stem cells have been shown to be efficacious in facilitating the recovery. Such efficacy was evidenced by slowing of ALS disease progression and either an improvement or absence of disease progression acceleration per revised-ALS Functional Rating Scale [24].

Limitations of the studies

Despite these assuring results, the route of administration (intrathecal vs. intravenous vs. intralesional, intramedullary) and cell concentrations differ significantly depending on the study design [35, 36]. In addition, most studies involved 25 or less participants which also limits the power of the mentioned studies. Therefore, in order to demonstrate the efficacy of the cells with a greater generalizability, a trial with a greater sample size, preferably for a population with similar level of injury, and standardized outcome measures, such as AIS grading at a particular time point in the recovery, is required.

Additionally, a consensus must be reached on the concentration, mode of preparation, namely source and differentiation method, and manufacturer for the specific cells used to treat each condition [37, 38]. In specifics, the cells used in current research are differentiated from a wide-variety of cell types, including induced-pluripotent stem cells, bone marrow cells, and MSCs, which likely is the cause for inconsistent reporting of the results.

The differences in cell culture method, duration, delivery method, whether suspended in fluid or in gel, and manufacturers pose a particular challenge in comparing the outcome of the current studies. Upon standardizing the profile of the cells used and its preparation, the optimal combination of each parameter also needs to be identified. The efficacy of a cell therapy can also vary depending on the state of the cell as a fresh product as opposed to a thawed frozen product, a consideration to be made for future studies. One potential solution to improving the consistency of the stem cell differentiation into a neuron is utilization of biocompatible scaffolds. Specifically, in treating spinal cord injury, the use of porous SilMA hydrogel scaffolds along with paclitaxel nanoparticles (PTX-NPs) may create a favorable environment to direct neural stem cell differentiation into neurons, to facilitate nerve repair, instead of astrocytes [39].

While the use of cell therapy in spinal cord injury patients have been widely reported, the number of reports on its use in other neurorehabilitation conditions, such as traumatic brain injury remain scant [19, 21]. The phenomenon is likely attributable to the lack of specificity in the targets for cell therapy in TBI in comparison to SCI, which can address a particular level of injury in the spine. To determine the best use of regenerative medicine in these conditions, prospective studies with specific therapeutic targets for each condition are needed.

The heterogeneity in the pre-treatment status (acute vs. chronic, injury location, severity, cell source and state, administration methods and dosages) and in endpoint outcome measures of each condition poses an additional challenge in comparatively assessing the efficacy of a particular cell therapy. It is likely attributable to the limited number of studies available—which are already small scale with small samples size—especially for neurotraumatic and neurodegenerative conditions. This may be owing to that the conditions such as SCI, TBI, and ALS are rare, but also that the application of stem cell therapy in these conditions is at an early stage. For instance, in cases of SCI, even within the same broad level of spine (e.g., thoracic), the specific level involved (e.g., T2 versus T11), completeness of an injury, and symptomatology (e.g., number of limbs affected) can contribute to the variance in results [5–16]. The majority of the current studies compare the effect of a cell therapy with a control group, often conducted without co-treatment with a conventional management. The effectiveness of a cell therapy can possibly be potentiated when combined with the current, mainstay treatment method, which can vary depending on the stage of the disease.

Safety concerns

In most studies that were cited in this review, the patients at large tolerated various cell therapies well; however, even in a minority of the cases, major adverse events were reported, which in consideration for the translation of the research to the clinical setting, raises genuine safety concerns that cannot be overlooked.

In neurotraumatic conditions, especially pertaining to treatment of spinal cord injury, one of the most serious adverse events include hemorrhagic necrosis of the spinal cord when injected with bone marrow nucleated cells [5]. Moderate pseudomeningocele and cerebrospinal fluid leak were also detrimental adverse events subsequent to perilesional neural stem cells [14], and intraparenchymal oligodendrocyte progenitor cell injections. Less serious adverse events were also reported: surgical incision-related Staphylococcus epidermidis wound infection and non-surgical incisional hematoma after perilesional, intramedullary injections of neural stem cells [16]; headache, nausea, and vomiting in the aftermath of intrathecal adipose-derived mesenchymal stem cells [14]; transient subfebrile fever, muscle pain at the intramuscular injection site of WJ-MSCs [8].

In a neurodegenerative condition of amyotrophic lateral sclerosis, major adverse events that occurred were death eight months post-intraspinal injection of neural stem cells in three patients, who refused PEG placement and invasive ventilation, which the authors deemed to be related to the evolution of the disease. Otherwise, the most common adverse event was pain, which was seen in post-intrathecal administration of mesenchymal stem cells [29], post-spinal injections of neural stem cells [23], and intrathecal placement of bone marrow-derived mesenchymal stem cells which was also accompanied by headache [28].

Despite the aforementioned risks associated with stem cell therapy, neurotraumatic and neurodegenerative conditions, especially spinal cord injury and amyotrophic lateral sclerosis, that had poor responses from the conventional rehabilitation modalities may necessitate such novel treatment option, as the benefit of therapy may outweigh the potential adverse effects associated.

Future perspectives

Despite the encouraging clinical findings on the use of stem cell therapy in neurorehabilitation conditions, a few challenges have been posed in its wide application. These may include varying regulation in different countries and states [40], issues revolving around the ethics of using cell therapy in patients, and difficulties with translating the preliminary data from individual cases and trials into a larger scale clinical setting.

The use of embryonic stem cells (ESCs) can pose an ethical question for the destruction of human embryos while deriving the cells [41]. In addition, when using ESCs, an immune rejection and tumor formation can occur which raises a question of the risks that may potentially outweigh the benefit of the treatment [42]. Potential solution to such ethical concerns for an ESC use can be addressed by the use of induced pluripotent stem cells (iPSCs) which are autologous and has a minimal risk for immune rejection [41].

Additionally, an effective delivery of stem cells to the central nervous system can be hampered by blood–brain, blood-spinal cord barriers [43]. This risk is especially concerning if the delivery of the cell therapy is done intrathecally or intraspinally, which may not reach its full therapeutic potential due to the poor penetrance or migration [44].

Furthermore, it is unclear whether the observed therapeutic benefits of a cell therapy are as a result of replacing lost neurons or the preservation of the existing neurons [45]. Such ambiguity may render it difficult to accurately assess the efficacy of a particular cell line, dosage, and administration route.

Due to the lack of available large-scale randomized controlled studies, the risk of bias in drawing comparative conclusions inevitably exists which is the current state of limitation in the field of neurorehabilitation. Simultaneously, the challenge presents as an opportunity for the future studies which in order to make direct comparison possible, larger-scale studies with standardized disease conditions and outcomes are required.

In addition to the previously described potential of MSCs in neurotraumatic conditions for its paracrine and immunomodulatory effects, new evidence is emerging regarding the use of exosomes and miRNA derived from MSCs that regulates genes and alleviates neuropathological changes in spinal cord injury, which is another possible direction for the future studies [46, 47].

Conclusively, this review critically highlights the recent findings in the therapeutic potential of cell therapy in spinal cord injury, traumatic brain injury, cerebrovascular accident, and amyotrophic lateral sclerosis. Despite the positive results from previous clinical trials and case reports, further studies are necessary with improved standardization of study design and outcome measures to ensure the enhanced applicability of cell therapy in treatment of neurorehabilitation conditions.

Declarations

Conflict of interest

The authors did not receive support from any organization for the submitted work. The authors have no relevant financial or non-financial interests to disclose.