Cell therapy for stroke and spinal cord injury in clinical trials

Abstract

Brain injury describes a variety of injuries to the tissues and blood vessels in the head. It can be external such as in road accident or physical assaults or internal such as a stroke. Regardless, they are largely incurable with a long route to recovery with symptoms-relieving medications and rehabilitation. As such, many therapies were explored including cell therapy. However, not all were evidence based and in many instances banking of patients’ desperation, many treatments were done without any evidence from clinical trials. Here, we reviewed clinical trials on clinicaltrials.gov for stroke and spinal cord injury where there are cellular therapies transplanting neural, mesenchymal, and haemopoietic cells. We present and discuss 40 trials involving cell therapies for stroke and 32 for spinal cord injuries that are either completed or active. Although some trials began as long as 20 years ago and have shown encouraging improvements in various scale scores for both stroke and spinal cord injury, cell transplantation for brain injuries remains an evolving field that requires further research before it can be established as a standard treatment.

Graphical abstract

Graphical Abstract.

Significance Statement.

This timely concise review present and discuss all clinical trials involving cellular therapies for stroke and spinal cord injuries that are either completed or active on clinicaltrials.gov. First, we provide a contemporaneous review of cellular therapies for these two major brain injuries, along with a comprehensive discussion on the key trials to give an unbiased insight into this field. Finally, we provide suggestions on necessary improvements that is required to move the field and improve the ability of cellular therapies to impact upon patients suffering with stroke and spinal cord injuries.

Introduction

Stroke, spinal cord, and traumatic brain injuries are the most prevalent among brain injuries. They impact on hundreds of millions worldwide, and there is generally no effective cure. Current management options for these neurological conditions are limited with most treatments targeted at ameliorating symptoms rather than cure. Little can be done to improve functional outcome once brain damage has set in. Rehabilitation is generally long term, and in addition to pharmacological management of comorbidities, it is a massive burden to the patient, society, and healthcare systems.¹ The progress made with cell therapy offers hope to radicalize treatment for brain injuries as its success could potentially bring about an actual permanent or long-term ‘cure’ by means of (1) integration and differentiation into functional neural cells, (2) neuroprotection from inflammatory changes, and (3) enhancement of survival of affected cells.

The focus of this review is to detail the latest clinical trials using neural stem cells (NSCs) and cells of neural lineage for the treatment of brain injuries, specifically stroke and spinal cord injury (SCI), as a follow-up of such a review we did on neurodegenerative diseases.² Clinical trials involving the delivery of neural-lineage cells for stroke and SCI were reviewed alongside cellular therapies using mesenchymal stem cells (MSCs), mononuclear cells (MNCs), endothelial cells, and others in established clinical trials.

Methods

A systematic search of the brain injury (Stroke or SCI), NSCs, neural cells, and cell therapy were first performed on clinicaltrials.gov for all existing trials up to October 2022 by one reviewer (Y.F.). This is subsequently updated by two reviewers (Y.F. and S.T.W.) independently for the same search words for all existing trials up till May 2025. Trials involving cell therapy with neural cells will be listed in the tables followed by the non-neural lineage cell clinical trials for each disease type. For this purpose, only interventional and not observational studies are included. Studies that were terminated, withdrawn, suspended, or unknown (past completion dates but status not verified for more than 2 years) were excluded. Similarly, studies not registered in clinicaltrials.gov were omitted from this study. We used a standard data extraction form based on the one recommended by the Cochrane Handbook for Systematic Reviews of Interventions to extract the following information: injury, sponsor, cell types, route of administration, cell dose, number of participants (planned or published), year of trial initiated, phase of clinical trial, and clinical trial number. Data is extracted from the clinicaltrials.gov site and/or published articles listed in PubMed of the specified clinical trial number. Discrepancies are resolved by discussion and in the event of discrepancy of information, the information from the published peer-reviewed article is extracted and presented in the tables.

Stroke

Stroke occurs when blood supply to a part of the brain is interrupted due to the obstruction (ischemic stroke, 85%) or the rupture of a blood vessel (hemorrhagichemorrhagic stroke).³ In both cases, reduced or interrupted blood flow results in cerebral damage due to oxygen and nutrient deprivation.⁴ Stroke is a major and increasing cause of mortality and morbidity worldwide, with substantial healthcare and societal costs.⁵ Fifteen million people suffer a stroke each year worldwide, of whom a third succumbs, and another third left permanently disabled.⁶ Approximately 75% of stroke occurred in individuals above 65 years old, although it can occur at any age.³ The underlying premise of a stem cell approach is to create a favorable environment to regenerate and repair, replace injured cells through differentiation and proliferation, upregulate growth factors and promoters of angiogenesis, and mobilize endogenous NSCs in the patient.^7-10

In 2022, there have been 41 trials listed on clinicaltrials.gov. At last update in April 2025, 7 of these trials have moved into unknown status with no findings on internet/PubMed, with another 6 new trials added including 1 of human forebrain progenitors, 1 of endothelial progenitors, and 4 with MSCs derived from bone marrow and umbilical cords, bringing the eventual count to 40 (Table 1). The first one in 2005 using bone marrow (BM) mononuclear cells (MNCs) demonstrated homing of the labelled MNCs delivered intraarterial (IA) to the brain after stroke, more than 2 months after the onset of symptoms.¹¹ Majority of the trials (37 out of 40) are specifically for ischemic strokes, segregated by acute (13), chronic (11), and unspecific or across phases (13). The majority of the trials utilized BM cells, with four trials transplanting human neural stem/progenitor cells.

Table 1.

Clinical trials listed on clinicaltrials.gov for stroke.

No.	Disease	Sponsor	Cell type	Route	Cell dose	Planned participants	Year	Phase	Clinical trial no.
1	Chronic ischemic stroke (6 months-5 years)	ReNeuron	fNSC (CTX0E03)	Intracerebral	2-20 M	11	2010	1	NCT01151124
2	Ischemic stroke (2-13 months)	ReNeuron	fNSC (CTX DP)	Intracerebral	20 M	23	2014	2	NCT02117635
3	Chronic ischemic stroke (6-60 months)	Gary Steinberg	ESC-derived NPC (NR1)	Intracerebral	Not mentioned	30	2021	½	NCT04631406
4	Chronic ischemic stroke (6-60 months)	Hopstem Biotechnology Inc.	Human Forebrain NPC (hNPC01)	Intracerebral	15, 30, and 60 M	21	2023	1	NCT06299033
5	Ischemic stroke (3 h-90 days)	Universidade Federal do Rio de Janeiro	Autologous BM MNC	IV and intra-arterial	500 M	12	2005	1	NCT00473057
6	Acute ischemic stroke (≤7 days)	Imperial College London	Autologous BM CD34+ cells	Intra-arterial	1.2-2.8 M	5	2007	1,2	NCT00535197
7	Acute stroke (5-7 days)	Hospital Universitario Central de Asturias	Autologous BM MNC including CD34+ cells	Intra-arterial	159 M of which 3.38 M CD34+	20	2008	1,2	NCT00761982
8	Acute ischemic stroke (24-72 h)	University of Texas Health Science Center, Houston	Autologous BM MNC	IV	10 M/kg	25	2009	1	NCT00859014
9	Subacute ischemic stroke (7-30 days)	All India Institute of Medical Science, New Delhi	Autologous BM MNC	IV	30 to 500 M	120	2009	2	NCT02425670
10	Chronic stroke (6-60 months)	China Medical University Hospital	Autologous peripheral blood CD34+ SC	Intracerebral	2-8 M	30	2009	2	NCT00950521
11	Ischemic stroke (<6 weeks)	University Hospital, Grenoble	Autologous BM MSC	IV	100 and 300 M	31	2010	2	NCT00875654
12	Acute ischemic stroke (≤7 days)	University Hospital, Grenoble	Adipose-derived MSC	IV	1-3.1 M/kg	95	2018	1	NCT03570450
13	Ischemic stroke (7-30 days)	Manipal Acunova	Autologous BM MNC	IV	60-160 M	118	2011	2	NCT01501773
14	Acute ischemic stroke (1-2 days)	Athersys, Inc	BM multipotent PC (Multistem)	IV	400 and 1200 M	134	2011	2	NCT01436487
15	Acute ischemic stroke (≤7 days)	Southern Medical University, China	Autologous endothelial PC OR autologous BM SC	IV	5M/kg	20	2011	1,2	NCT01468064
16	Chronic ischemic stroke (>6 months)	Stemedica Cell Technologies, Inc.	BM MSC	IV	0.5-1.5 M/kg	38	2011	1,2	NCT01297413
17	Chronic ischemic stroke (6-60 months)	SanBio, Inc	Genetically modified BM MSC (SB 623)	Intracerebral	2.5, 5, and 10 M	18	2011	1/2a	NCT01287936
18	Chronic ischemic stroke (6-90 months)	SanBio, Inc	Genetically modified BM MSC (SB 623)	Intracranial	2.5 and 5 M	153	2016	2	NCT02448641
19	Ischemic stroke (14 days)	Instituto de Investigación Hospital Universitario La Paz	Adipose MSC	IV	1 M/kg	19	2014	½	NCT01678534
20	Chronic ischemic stroke (6-60 months)	Southern Medical University, China	Autologous endothelial PC	IV	Not mentioned	12	2014	1,2	NCT02605707
21	Acute ischemic stroke (≤7 days)	CHABiotech CO., Ltd	UC MSC	IV	200 and 400 M	18	2015	½	NCT02378974
22	Ischemic stroke (3-10 days)	Joanne Kurtzberg	CB	IV	0.5-50 M nucleated cells/kg	10	2015	1	NCT02397018
23	Ischemic stroke (3-10 days)	Joanne Kurtzberg	CB	IV	0.5-50 M nucleated cells/kg	83	2017	2	NCT03004976
24	Ischemic stroke (≤14 days)	Postgraduate Institute of Medical Education and Research	Autologous BM MNC	Intra-arterial	51-60 M	20	2015	1	NCT03080571
25	Acute ischemic stroke (1-7 days)	Andalusian Initiative for Advanced Therapies	Autologous BM MNC	Intra-arterial	2 or 5 M/kg	76	2015	2	NCT02178657
26	TBI, stroke, Parkinson/ALS/dementia/Alzheimer’s (>6 months)	MD Stem Cells	Autologous BM SC	IV and intranasal	Not mentioned	500	2016	1,2	NCT02795052
27	Chronic ischemic stroke (6 months-10 years)	Gwo Xi Stem Cell Applied Technology Co., Ltd	Autologous adipose-derived SC (GXNPC1)	Stereotactic implantations	100 M	3	2017	1	NCT02813512
28	Acute ischemic stroke (≤36 h)	Healios K.K.	BM multipotent PC (HLCM051/Multistem)	IV	1200 M	220	2017	2,3	NCT02961504
29	Acute hemorrhagic stroke (≤72 h)	Mayo Clinic	BM MSC	IV	IV (0.5, 1, and 2 M/kg)	9	2017	1	NCT03371329
30	Acute ischemic stroke (2-7 days)	Meridigen Biotech Co., Ltd	UC MSC (UMC119-06)	IV	Low, medium, and high dose	9	2019	1	NCT04097652
31	Acute ischemic stroke (≤48 h)	Teijin Pharma Limited	Allogenic dental pulp–derived SC	IV	100 and 300 M	79	2019	½	NCT04608838
32	Perinatal ischemic stroke/neonatal stroke (≤7 days)	UMC Utrecht	BM MSC	Nasal	50 M	10	2020	½	NCT03356821
33	Acute ischemic stroke (≤36 h)	Ever Supreme Bio Technology	UC MSC (UMSC01)	Intra-arterial and IV	Not mentioned	14	2020	1	NCT04434768
34	Ischemic stroke (6-24 h, 1-3 days, 4-7 days, 1-4 weeks, 1-6 months)	General Hospital of Shenyang Military Region	UC MSC	IV	100 M	200	2021	2	NCT04811651
35	Ischemic stroke (≤24 months)	Vinmec Research Institute of Stem Cell and Gene Technology	UC MSC	IV/intrathecal	3 M/kg	48	2021	1,2	NCT05292625
36	Ischemic stroke (≤4 weeks)	Cytopeutics Sdn. Bhd	UC-MSC (Neuroncell-EX)	IV	2 M/kg	80	2023	2,3	NCT06129175
37	Acute ischemic stroke (≤7 days)	Allife Medical Science & Technology Co., Ltd	Endothelial progenitor cells	IV	Single dose	27	2023	1	NCT05993884
38	Convalescent ischemic stroke (12-24 weeks)	Shanghai IxCell Biotechnology Co., LTD	UC-MSC (IxCell hUC-MSC-S)	IV	50, 100, and 200 M	18	2023	1	NCT05697718
39	Ischemic stroke (≤1 month)	National Engineering Center of Cell Products	UC-MSC	IV	Not mentioned (1× or 1× weekly for 3 weeks)	18	2024	1	NCT06518902
40	Chronic ischemic stroke (6 months-5 years)	Hokkaido University Hospital	Autologous BM MSC (HUNS001-01)	Intracerebral	40 M in 2 sites	8	2024	2	NCT06752720

Cells transplanted are allogenic unless stated.

Abbreviations: BM, bone marrow; CB, cord blood; ESC; embryonic stem cells; fNSC, fetal neural stem cells; h, hours; IV, intravenous; M, million; MNC, mononuclear cells; MSC, mesenchymal stem cells; PC, progenitor cells; SC, stem cells; UC, umbilical cord; UCB, umbilical cord blood.

Transplantation with cells of neural lineage

The first human neural cell transplantation performed in stroke patients was with NT2N cells, an immortalized cell line derived from a human teratocarcinoma cell line.^6,12 While this Phase I Food and Drug Administration approved trial established the safety and feasibility of N2TN transplantation, the lack of significant motor improvements and underlying concerns about the cell source and postulated therapeutic dose of at least 35 million cells halted the study at Phase 2.^13,14 The second Phase I trial utilized NSCs for treatment of ischemic stroke in the United Kingdom in 2010. This was performed with a conditionally immortalized fetal brain–derived NSC line, CTX0E03, in 2010 (NCT01151124).¹⁵ CTX0E03 NSCs were delivered to male participants with chronic ischemic stroke that established improved neurological function with no immunological or cell transplant–related adverse events (AE) up to 2 years post-transplant, albeit with transplantation-related AE in four patients.¹⁵ ReNeuron proceeded with a prospective, multicenter, single-arm, open-label Phase 2 trial, stereotactically implanting 20 million CTX0E03 NSCs into the ipsilateral putamen of the cerebral infarct. Improvements in upper limb function were observed at 3, 6, and 12 months, albeit only in participants with residual upper limb motor function at baseline.¹⁶ A third clinical trial involving human embryonic stem cells (ESCs)-derived neural progenitors (NR1) commenced in 2021 for 30 participants to determine safety and feasibility of intracerebral implantation of these cells as well as signs of improvement in locomotion (NCT04631406). This trial has since stopped recruiting and we await the sharing of the results. The final trial utilizing human forebrain neural progenitors (hNPC01) was initiated in 2023 and aims to investigate the efficacy of the cells at increasing doses, up to 60 million, the highest neural cell dosage for stroke. These four clinical trials involving intracerebrally-delivered neural cells for ischemic strokes are all Phase 1 and/or 2 trials involving small numbers of 11 to 30 participants. The only Phase III trial was registered in 2018, with ReNeuron as a randomized double-blind trial (PISCES 3) with CTX0E03 on the back of promising Phase I/II results¹⁶ but has since been terminated due to the COVID pandemic.¹⁰ Nine participants in that trial who has received 20 million CTX0E03 are currently in a long-term (4 years) observational study (NCT05598775).

Intracerebral administration is the only route utilized by trials administering cells of neural lineage (4 out of 4) and in a minority of trials administering other cell types (5 out of 36), possibly due to concerns whether neural lineage cells are being able to cross the blood–brain barrier that is required for intravenous (IV) or IA delivery. It has been reported that only 0.6%-0.9% of cells delivered IV or IA are detectable in the human brain and the cells get increasingly difficult to identify within the brain 24 hours post-transplantation.^17-21 Neural SCs and its derivatives may also not have the necessary machinery to migrate into areas of inflammation or injury. Intracerebral administration allows direct delivery of a large quantity of cells to the injured area and is less dependent of homing factors, particularly important for patients where the stroke had occurred sometime ago and where areas of brain injury are no longer/less active in secreting chemotactic factors in response to the injury, although it may not always be possible such as in the case of inaccessible sites of injury.²² However, stereotactic injections also carry a small but not negligible (1-2%) risk of AE such as hemorrhage.²³

Transplantation with bone marrow mononuclear cells

Prior to the use of NSCs transplantation for stroke, both autologous and allogenic BM-derived cells have been used for stem cell therapy for stroke.^24-26 Twelve trials listed involved the use of BM MNCs/SC, which very likely contained a mixture of hematopoietic SC (HSCs) and MSCs, and 19 trials involving MSCs from various sources ranging from BM to adipose tissue to umbilical cord (UC) and dental pulp. BM MNCs have been used for stroke via stereotactic intralesional injections of 14-55 million cells,²⁷ IV at a dose of 70-100 million cells per kilogram,²⁸ and IA between 125 and 500 million BM MNCs (Table 1).¹⁸ All these methods were found to be safe, with brain biodistribution of BM MNCs via IA and IV comparable.^19,20 Stereotactic injections, although likely to be the most efficient mode of delivery, are also especially challenging in the context of stroke, given the risk of anesthesia worsening cerebral inflammation and edema whereas IV administration means that majority of the transplanted cells will be filtered by nontarget organs, particularly the lungs, spleen, and liver before reaching the brain.^29-33 Henceforth, some teams have chosen IA delivery as an intermediate strategy as it is more directed compared to IV and has lower risk than stereotactic intracerebral injections,³⁴ although there have been studies that showed similar biodistribution rates and outcomes.²⁰ Two Phase I trials involving autologous BM-derived cells yielded beneficial effects^28,35 but were not corroborated at the Phase II trial with a larger sample size of 120 participants.²⁴

Transplantation with mesenchymal stem cells

MSCs act predominantly through paracrine mechanisms, secreting neurotrophic, mitogenic, and angiogenic factors.^36-38 They are comparably safe and easy to harvest and are also abundant, allowing sufficient quantities for transplantation use.³⁹ Efficacy of autologous MSCs transplant have been mixed. Several teams have found no significant benefits between the transplanted and control groups after IV administration of MSCs⁴⁰ as well as between MSCs compared with HSCs.⁴¹ In the comparison between MSCs and endothelial progenitor cells (EPCs) (NCT01468064), Fang et al. showed that EPCs group had fewer serious AE and a better Scandinavia Stroke Scale score at 3 months compared to the placebo group. Comparatively, MSCs group has a similar Scandinavia Stroke Scale compared to placebo. Allogenic MSCs present an advantage where cells are already available, without the need for a lag time for cell processing and is useful when early intervention is crucial for improving clinical outcomes.^39,42 In terms of allogenic MSCs, a study on 10 patients demonstrated safety when delivered intra-nasally in neonates with MRI-confirmed perinatal arterial ischemic stroke.⁴³ Durand and team looking at three different IV doses of 0.5. 1 and 2 million/per kg of subject also showed safety and tolerability with favorable cytokines outcomes 3 days post injection for hemorrhagic stroke.⁴⁴

The highest cell dose administered was 1.2 × 10⁹ allogenic BM multipotent progenitor cells via IV in the MASTERS trial (NCT01436487) where it has been shown to be safe and well tolerated albeit no significant improvement in neurological outcomes at 90 days time point.⁴⁵ However, the Phase 3 study with the same cell dose (NCT03545607) initiated in 2018 has had its status switched to unknown with no publications as yet.

Transplantation of HSCs and EPCs

The first was a phase 1/2 trial that commenced in 2007 using BM-derived CD34+ cells, delivered through the middle cerebral artery, which showed promising results with five out of the five participants achieving functional improvement and reduction in lesion volume.³⁴ The other trial initiated in 2009 delivered G-CSF mobilized peripheral-blood CD34+ cells delivered via direct intracerebral injection, which showed significant improvements in stroke scales (National Institutes of Health Stroke Scale, European Stroke Scale (ESS), ESS Motor Subscale) and modified Rankin Scale at end of 12 months follow-up.⁴⁶ Transplantation of endothelial cells first by IV with autologous EPCs (NCT02605707) and then allogenic EPCs derived from induced pluripotent stem cells (iPSCs) (NCT05993884) were performed although the results are not yet available. It would be important to detail the identity of the endothelial cells, which can be highly heterogeneous.⁴⁷

Based on the results above, it is likely that the maximal benefit will be realized with an immediate transplantation approach, although the systematic review by Boncoragli found treatment of stroke to be more effective when performed during the chronic instead of acute or subacute phase.¹ The use of autologous BM MSCs has been the preferred cell source thus far based on the number of trials carried out for each cell type, possibly due to its ease of isolation and delivery and lack of toxicity (Table 1). Only three trials planned to recruit 200 or more participants of which only two are exclusively for stroke patients (UMSIS and Multistem^®) and of which Multistem^® was the only one to reach Phase 3. Since 2022, the clinical trial has since switched to unknown status after an interim analysis showed that even at the sample size of 300, the study is still underpowered to achieve statistical significance for the primary endpoint analysis.⁴⁸ This can be due to a small effect size and high outcome variability; therefore, future studies should consider large multicenter trials, with sample size calculations based on realistic effect sizes. Stem cell therapy in stroke has been largely safe¹⁰ with promising therapeutic effects reported between 6 months and 2 years post-transplantation.^{1,16,22,34,49} This highlights that a longer term of follow-up is necessary as the results contrasted with a trial reporting no significant improvements after just 90 days.⁴⁵ Another unique characteristic of this trial being that it required a very large dose of 1,000 million BM multipotent cells. This in combination with a long term of follow-up would require a much larger financial budget consideration in designing and following up a trial, forming one of the several hurdles/challenges for cellular therapy to be established as the main mode of therapy.

Spinal cord injury

Severe traumatic SCI where motor, sensory, and autonomic functions are affected, affects 250 000 to 500 000 people per year.^50,51 Traumatic SCI is more common in males (79.8%) than females (20.2) with majority of the injuries at the cervical (∼60%), thoracic (32%), and lumbosacral regions (9%).⁵² The primary injury perforate the cell membranes leading to ions and small molecules dysregulation, which then sets off a secondary injury cascade that gives rise to more permanent damage.⁵³ Cell therapy has been proposed to work via multiple avenues. Transplanted cells may firstly replace the damaged neural cells, secondly help to regenerate the injured site via a supportive role on the surviving cells; directing/enhancing the endogenous progenitor cells and supplying vital neurotrophic/growth factors to support regeneration. The final and third mode of mechanism would be to modulate immune responses, reducing the inflammation.⁵⁴ Following encouraging results in experimental SCI models,^55-66 several clinical trials had taken place with more currently occurring worldwide (Table 2). Saremi et al. reported 23 clinical trials since 2016 using SC therapy for SCI,⁵⁴ which at the time of this manuscript (May 2025) revealed one termination and 13 switching to unknown status. Our first search back in 2022 yielded 62 results (accessed on August 11, 2022) of which three were withdrawn, four terminated, two suspended, four studies that are no longer available, and 17 of unknown status. Two and a half years later, there are 76 studies, of which trials of unknown status increased to 23, trials terminated increase to 5, while 3 remain withdrawn (accessed on March 4, 2025). In the last two and a half years (Aug 2022 to March 2025, two new active trials emerged while five active trials have switched to unknown status and one terminated, bringing the eventual count of valid clinical trials of cellular therapy within the criteria for this review for SCI to 32 at 2025. At both timepoints, it is apparent there are always a high number of unknown trials, ranging between 27% and 30% of the total number of trials. While its understood that unknown status does not mean termination of the trial, such status tend to suggest a lack of follow-up, possibly with the absence of beneficial outcomes. All these allude to the challenges in pursuing SC therapy for SCI. In this review, we identified 32 trials, of which 8 utilize cells of neural lineage (Table 2).

Table 2.

Clinical trials listed on clinicaltrials.gov for spinal cord injury.

No.	Disease	Sponsor	Cell type	Route	Cell Dose	Planned Participants	Year	Phase	Clinical Trial #
1	Spinal cord injury Acute (7-14 days)	Lineage Cell Therapeutics	ESC OPC (GRNOPC1)	intraparenchymal into spinal cord	2M	5	2010	1	NCT01217008
2	Spinal cord injury Subacute (21-42) days	Lineage Cell Therapeutics	ESC OPC (AST-OPC1)	intraparenchymal into spinal cord	2, 10 and 20M	25	2015	1,2	NCT02302157
3	Spinal cord injury Subacute (21-42) days	Lineage Cell Therapeutics	ESC OPC (LCTOPC1)	injection to injured site	10M	10	2025	1b	NCT06841770
4	Spinal cord injury >6 weeks	StemCells, Inc	CNS SC	intramedullary	not mentioned	12	2011	1/2	NCT01321333
5	Spinal cord injury <30 days	W. Dalton Dietrich	Autologous Schwann cells	intraspinal	5,10,15M	9	2012	1	NCT01739023
6	Spinal cord injury Chronic (>1 yr)	W. Dalton Dietrich	Autologous Schwann cells	intraspinal	not mentioned	8	2015	1	NCT02354625
7	Spinal cord injury Chronic (1-2 yrs)	Neuralstem	Fetal spinal cord NSC (NSI-566)	intraspinal	not mentioned	8	2014	1	NCT01772810a
8	Spinal cord injury Subacute (7-30 days)	S-Biomedics	ESC NPC	IT	not mentioned	5	2021	1,2a	NCT04812431
9	Spinal cord injury (10 months-3 yrs)	Cairo University	Autologous adherent BM cells	IT	2M/kg	80	2005	1,2	NCT00816803
10	Spinal cord injury <2 weeks, 2-8 weeks, >6 months	International Stemcell Services Limited	Autologous BM SC	IT	not mentioned	12	2008	1,2	NCT01186679
11	Spinal cord injury >2 months	R-Bio	Autologous adipose MSC	IV	400M	8	2009	1	NCT01274975
12	Spinal cord injury >3 months	R-Bio	Autologous adipose MSC	IV, IT and intraspinal	200M (IV), 50M (IT), intraspinal (20M)	15	2013	1,2	NCT01769872
13	Spinal cord injury Not mentioned	Hospital Sao Rafael	Autologous BM MSC	intraspinal	not mentioned	14	2010	na	NCT01325103
14	Spinal cord injury >1 year	General Hospital of Chinese Armed Police Forces	UC MSC	IT	not mentioned	300	2012	3	NCT01873547
15	Spinal cord injury Not mentioned	Bukwang Pharmaceutical	Autologous adipose MSC	IT	90M	15	2012	1	NCT01624779
16	Spinal cord injury chronic > 6 months	Puerta de Hierro University Hospital	Autologous BM stromal cells	IT	130M	12	2013	1	NCT01909154
17	Spinal cord injury chronic > 6 months	Puerta de Hierro University Hospital	Autologous BM MSC	IT	300M	10	2015	2	NCT02570932
18	Spinal cord injury Subacute <6 months Chronic >6 months	National Institute of Bone and Marrow Transplant	Autologous BM MSC	IT	2.4-3.6M/kg	9	2013	1	NCT02482194
19	Spinal cord injury Acute (<3 days)	Sklifosovsky Institute of Emergency Care	UCB MNC	IV	300M	20	2013	1/2a	NCT04331405
20	Spinal cord injury Acute (<7 days)	Sklifosovsky Institute of Emergency Care	UCB MNC	IV	500 +/- 50M 7-day Interval	80	2022	1/2	NCT05693181
21	Spinal cord injury Chronic	Hospital Sao Rafael	Autologous BM MSC	percutaneous	20M	5	2015	1	NCT02152657
22	Spinal cord injury Chronic	Banc de Sang i Teixits	WJ MSC	IT	10M	10	2016	1/2a	NCT03003364
23	Spinal cord injury >2 weeks	University of Jordan	Autologous BM and adipose MSC	IT	not mentioned	14	2016	1,2	NCT02981576
24	Spinal cord injury >12 weeks	University of Jordan	Autologous BM MSC and allogenic WJ MSC	into the spinal medulla	4x100M/3x100M(monthly)	20	2017	1	NCT04288934
25	Spinal cord injury Not mentioned	MD Stem Cells	Autologous BM SC	paraspinal, IV, intranasal	not mentioned	40	2017	na	NCT03225625
26	Spinal cord injury 2 weeks to 1 year	Allan Dietz	Autologous adipose MSC	IT	100M	10	2017	1	NCT03308565
27	Trauma-induced spinal cord injury >2 months	Limin Rong	UC MSC	IT	1M/kg	102	2018	1,2	NCT02481440
28	Spinal cord injury Within a year	Mayo clinic	Autologous adipose MSC	IT	not mentioned	40	2020	2	NCT04520373
29	Spinal cord injury 1-5 yrs	Neuroplast	Autologous BM Cells (Neuro-Cells)	IT	not mentioned	10	2020	1	NCT04205019
30	Spinal cord injury 6-10 weeks	Neuroplast	Autologous BM Cells (Neuro-Cells)	IT	not mentioned	16	2022	2,3	NCT03935724
31	Spinal cord injury Not mentioned	Foundation for Orthopaedics and Regenerative Medicine	UC MSC	IT and IV	100M	20	2022	1	NCT05152290
32	Traumatic spinal cord injury Chronic (>3 months)	Kunming Tongren Hospital	Stromal vascular fraction containing include adipose-derived stem cells, endothelial cells, endothelial progenitor cells, pericytes, T cells, and other immune cells with hydrogel	transplantation into spinal cord	not mentioned	15	2023	na	NCT05967325

Cells transplanted are allogenic unless stated.

Abbreviations: BM, bone marrow; CNS, central nervous system; ESC, embryonic stem cells; IV, intravenous; IT, intrathecal; M, million; MNC, mononuclear cells; MSC, mesenchymal stem cells; na, not applicable; NPC, neural progenitor cells; NSC, neural stem cells; OPC, oligodendrocyte progenitor cells; SC, stem cells; UC, umbilical cord; UCB, umbilical cord blood; WJ, Wharton Jelly.

^aUnknown status.

Transplantation with cells of neural lineage

The use of exogenous NSCs for cell therapy appears more promising due to the ability of the cells to differentiate into the three neural cell types allowing the replacement of lost or injured cells, as well as to provide a microenvironment that offers appropriate trophic support of the endogenous cells, conducive for neuroprotection and regeneration.^{51,59,61,62,67,68} The earliest completed clinical trials utilizing cells of neural lineage were initiated only in 2010. The use of differentiated cells may seem safer with a reduced risk of tumorigenicity than SC. Lineage Cell Therapeutics have launched three consecutive clinical trials, using ESCs-derived oligodendrocyte progenitor cells (LCTOPC1, formerly known as GRNOPC1 and AST-OPC1) in 2010, 2015, and 2025. Intraparenchymal injection of 2-20 million ESCs OPC into sub-acute SCI in 25 participants in NCT02302157 initiated in 2015 resulted in 96% (21/22) recovery of one or more levels of neurological function on at least one side of the body, and 32% (7/22) recovery of two or more levels of neurological function on at least one side of the body at one year follow-up amongst those injected with 10 to 20 million OPCs (n = 22). Magnetic resonance imaging scans showed no evidence of any enlarging mass or masses in the ventricular system, inflammatory lesions in the spinal cord, or spinal cord damage related to the injection procedure.⁶⁹ Ten-year safety data have also been reported for this direct injection of ESC-OPCs in patients with acute thoracic SCI.⁷⁰ NCT06841770 was hence initiated in 2025 on the basis of those promising results, with the intention to evaluate the safety and utility of a novel delivery device to perform a single injection of 10 million LCTOPC1 cells to a target site of the damaged spinal tissue on just 10 patients, possibly setting the groundwork for a larger clinical trial to study the efficacy of LCTOPC1.

Neural SC, the most primitive cells of the neural lineage, offer differentiation into the required neural cells, such as oligodendrocytes for axon myelination as well as neural signal transition allowing integration into the damaged neural circuits.^54,71 They have been used in two trials. The trial by StemCells, Inc. in 2011 involved 12 SCI patients and was completed in April 2015, although no results have been published.⁷² In the second study, intramedullary injected fetal-derived NSCs (NSI-566) in chronic SCI were shown to be well tolerated with promising efficacy observed in three of the four patients with chronic SCI (NCT01772810).⁷³ While the status is reported as unknown on clinicaltrials.gov, we found a very recent publication that reported well-tolerated therapy in all four participants and improved neurological motor and sensory scores 5 years post transplantation.⁷⁴ There is one trial initiated in 2021 that utilizes ESCs-derived neural progenitor cells (NPCs) for subacute SCI. NCT04812431 planned to investigate cellular therapy of ESCs-derived NPCs, and the fact that it is still in recruitment phase for its five intended participants since the inception of the trial in September 2021 highlights another challenge. In a clinical trial registered in Japan (UMIN000035074), a team at Keio University announced the promising results, reporting significant improvements observed in two out of four participants with subacute SCI participants at a press conference.⁷⁵ Two million iPSCs-derived neural stem/progenitor cells were transplanted into the injured spinal cord parenchyma of each of four patients with subacute SCI, within 28 days of injury.⁷⁶ All participants initially presented with the highest injury classification of American Spinal Injury Association impairment scale (AIS) Grade A. At one year of follow-up, one participant improved to Grade C, with the ability to move some muscles of their limbs and another to Grade D where the participant can stand independently⁷⁵ with no severe AE observed.⁷⁷

Autologous differentiated neural cells known as Schwann cells were used in two of the eight trials. Schwann cells can provide structural scaffolding and promote a favorable environment for regeneration to occur. In preclinical SCI studies, they are shown to reduce cystic cavitation, enhance tissue sparing, and promote remyelination resulting in sensory and motor recovery.^78-82 While they are shown to be safe, the authors advised more precise scrutiny and refinement of the clinical trials, such as selecting participants with less severe injuries or the use of higher cell dose for the transplantation as the results did not present clinical improvement.^83,84

Transplantation with cells of non-neural lineage

Majority of the cell transplantation involved MSCs (17 MSCs, 6 BM cells comprising HSCs and MSCs, and one with stromal vascular fraction including adipose-derived SC out of the 32 trials) which are readily found throughout the body and harvested from accessible tissues such as BM, adipose tissue, and UC.^85-87 Putative mechanisms of benefit from MSCs transplantation include their ability to enhance tissue sparing and functional recovery through immunomodulation, neurotrophic factors secretion, apoptosis and inflammasome inhibition, and pro-angiogenic signaling amongst others.^54,88-90 Majority of the trials involved cell transplants to the spinal cord for direct impact by the cells of interest, except for three which investigated IV injections of autologous adipose MSCs (NCT02152657) and allogenic UC MNCs (NCT04331405 and NCT05693181). Direct administration of the cells to the lesions is associated with increased cell engraftment compared to other routes of administration including intrathecal (IT).⁹¹ All but two of these trials are Phase 1 and/or 2, and all available results suggest that cell therapy with MSCs and MNCs for SCI is safe and well tolerated.^92-98

The earliest publications reporting beneficial effects of MSCs on patients with SCI were published in 2014 and are based on transplantation of autologous MSCs for chronic SCI.^99,100 El-Kheir et al. showed sustained functional improvements in 23 out of the 50 (46%) participants at 18 months post treatment. Ten points or more improvement in the American SCI Association (ASIA) score was also observed in 26 participants.⁹⁹ In the case of NCT01325103, all 14 subjects displayed variable improvements in tactile sensitivity 6 months post injury. Eight participants developed lower limbs motor functional gain, while seven presented sacral sparing and improved AIS grades to B or C from A. Nine participants also showed improvement in urologic functions.¹⁰⁰ NCT02152657 also showed improvements in spinal cord independence measure scores and functional independence measures for intralesional administration of autologous BMMSCs in patients with chronic SCI. All participants in the study also have improved bowel regularity.¹⁰¹ Participants in NCT03003364, using WJ-MSCs infused intrathecally, showed significant improvement in pinprick sensations compared to placebo. There is also improvement in bladder maximum capacity and compliance and decrease in bladder neurogenic hyperactivity and external sphincter dyssynergy observed at individual level.¹⁰² Awidi et al. utilizes two different treatment regimens; perilesional administration of expanded autologous BMMSCs, followed by monthly IT BMMSCs for three injections (n = 11), or monthly IT UC MSCs for three injections (n = 9). The basis for repeated dose originated from previously published work where four IT injections at monthly intervals showed improvement in sphincteric control and spasticity that was not observed with a single IT injection.^102,103 Both groups achieved significant improvements in ASIA scores one year post injections with BMMSCs exhibiting more motor improvements.¹⁰⁴ Out of the 32 trials listed, 13 use allogenic cell sources, while 20 use autologous (one trial compared autologous and allogenic MSCs). It is important to note that for SCI, there is a critical time window after the primary injury to do the surgery, providing relief of mechanical compression to prevent secondary injury cascades.¹⁰⁵ The environment at the site of neural injury in SCI is not conducive to neuro-regeneration due to the activation of inhibitory pathways, glial scar formation, and lack of guiding astrocytes necessary for axonal regrowth, adding to the challenges of cell therapy in SCI.¹⁰⁶

Spinal cord injury can be classified into acute (<48h), subacute (48 h to 14 days), intermediate (14 days to 3 months), and chronic (>3 months) phases.^54,107 Majority of the trials are for chronic (10) and intermediate (10) SCI patients, with four more trials for both phases and one trial recruiting patients from subacute through chronic phases. Only one trial recruited patients within 3 days of injury and two recruiting between 48 h and 14 days of injury (less than 7 days and between 7 and 14 days, respectively). Four of the trials did not mention the specific phase of SCI the patients are to be recruited (NCT01325103, NCT01624779, NCT03225625, and NCT05152290). Unbiased improvements in ASIA and/or AIS scores have been reported in clinical trials for both acute and chronic SCI, and hence, it is not possible to conclude if there is only one specific phase at which SCI should be targeted in a cellular therapy.^{75,99,100,104} Silvestro and team have reviewed the SC trials for SCI where they concluded the most common modes of administration are IV, IT, and intramedullary and they are generally safe, with IV and IT being less invasive.¹⁰⁸ A wide range of cell doses, ranging from 2 million to 500 million, have been explored (Table 2) with trials administering high doses IV as well as locally within the injury site. With the success observed by Okano and his team with two million cells,⁷⁵ it would appear that the minimum effective dose does not necessarily need to be high although Phase 2 trials of increasing doses ought to be done to determine if there can be further dose-associated improvement. More research, especially long-term studies, is warranted to ascertain the efficacy of SC for clinical use in SCI. The combinatorial use of SC with biomaterials/scaffolds may improve the efficacy of cell therapy in SCI, and hence, optimization and improvement of the ever-evolving hydrogels and/or nanofibers and/or scaffolds must be continued. Another possible direction would be application of gene editing technologies to engineer SC with enhanced regenerative properties.¹⁰⁹

Discussion

We have found 72 clinical trials involving cell therapy in stroke and SCI within clinicaltrials.gov. The use of cells of neural lineage is more prevalent in SCI trials (8/32) compared to stroke trials (4/40) (Table 3). This is attributed to the fact that the injury in SCI involves traumatic injury to mainly neural cells and its axonal projections, while in stroke, the injury is largely ischemic in nature through a reduction/interruption of the blood flow to the brain that causes the brain damage. NSCs, progenitors, or differentiated neural cells have the advantage of replacing the lost neural cells in SCI, whereas in stroke, an overall therapy involves reducing hypoxia through the increase of blood flow and/or a reduction of inflammation-.

Table 3.

Trials for diseases in this review and the type of cells used.

No.	Disease	Neural stem/progenitors’ cell	Differentiated neural cell	Non-neural cell
1	Stroke	4	0	36
2	Spinal cord injury	5	3	24

It is crucial for the field to proceed with randomized controlled trials with the most promising cell types and approaches in order to establish efficacy. However, this remains challenging as achieving adequate sample sizes will require collaboration across multiple centers. It is imperative that clinical trials should be well documented with full details of the trial including dosage, route of administration, and time and duration of intervention. Long-term follow-up should also be required to establish safety and efficacy of cellular therapy. It is also important to report the findings of listed trials, positive or otherwise and to present the reasons if a trial is terminated early. Ideally, there should be one centralized registry for all clinical trials to ease search and consistency in records. However, this is beset with challenges beyond science. It is also a limitation of this review where we focused only on the largest registry in the world. Another limitation of our review is the inability to detail a risk of bias/quality assessment given our format of review, which encompasses mostly protocol-level information furnished at the discretion of the sponsor, particularly in trials that has not been published. Objective evidence-based assessments of the clinical trials with continued search for the most efficacious therapeutic product that may be by-products of cells such as exosomes should be encouraged and reported promptly so that such clinical interventions can occur without delay and cutting edge translational approaches can advance quickly once backed by sound scientific rigor. Further optimization and fine tuning of the cell/product source, routes of delivery will hopefully make therapy for stroke and spinal cord injuries a reality, improving the health and quality of life of the patients.

Funding

J.C. is supported by National Medical Research Council, Singapore (NMRC STaR22jul-0004).

Conflicts of interest

None declared.

Data Availability

All data are incorporated into the article and its online supplementary material.