Next Article in Journal
Use of Tissue Specimens from Stereotactic Biopsies for Patient-Derived GBM Organoid-Based Drug Testing
Previous Article in Journal
Dauricine Impedes the Tumorigenesis of Lung Adenocarcinoma by Regulating Nrf2 and Reactive Oxygen Species
Previous Article in Special Issue
Hypothermia Shifts Neurodegeneration Phenotype in Neonatal Human Hypoxic–Ischemic Encephalopathy but Not in Related Piglet Models: Possible Relationship to Toxic Conformer and Intrinsically Disordered Prion-like Protein Accumulation
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 14
Issue 10
10.3390/cells14100700
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes

by
Madison C. B. Paton
1,2,*,
Alexandra R. Griffin
1,
Remy Blatch-Williams
1,
Annabel Webb
1,
Frances Verter
3,
Pedro S. Couto
3,4,
Alexey Bersenev
5,
Russell C. Dale
6,7,
Himanshu Popat
8,9,
Iona Novak
10 and
Megan Finch-Edmondson
1
1
Cerebral Palsy Alliance Research Institute, Speciality of Child and Adolescent Health, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
2
Department of Paediatrics, Monash University, Melbourne, VIC 3800, Australia
3
Parent’s Guide to Cord Blood Foundation, Brookeville, MD 20833, USA
4
Department of Biochemical Engineering, University College London, London WC1N 3QS, UK
5
Cell Therapy Laboratories at Yale, New Haven Hospital, Yale University, New Haven, CT 06520, USA
6
Department of Neurology and Neurosurgery, Children’s Hospital, Westmead, NSW 2145, Australia
7
Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
8
Grace Centre for Newborn Care, The Children’s Hospital at Westmead, Sydney, NSW 2006, Australia
9
The Children’s Hospital at Westmead Clinical School, The University of Sydney, Sydney, NSW 2006, Australia
10
Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
*
Author to whom correspondence should be addressed.
Cells 2025, 14(10), 700; https://doi.org/10.3390/cells14100700
Submission received: 28 March 2025 / Revised: 24 April 2025 / Accepted: 8 May 2025 / Published: 12 May 2025
(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)
Browse Figures
Review Reports Versions Notes

Abstract

:
Mesenchymal stromal cells (MSCs) have been under clinical investigation for the treatment of cerebral palsy (CP) for over a decade. However, the field has been limited by study heterogeneity and variable reports of efficacy. We conducted a scoping review of published and registered reports of MSC treatment for CP, with meta-analysis of Gross Motor Function Measure (GMFM) outcomes to summarize research and provide future recommendations. Thirty published reports and 10 registered trials were identified, including 1292 people with CP receiving MSCs. Most received ≥2 doses (72%) of umbilical cord tissue MSCs (75%), intrathecally (40%) or intravenously (38%), and 31% were treated via compassionate/Expanded access. MSC treatment was safe and meta-analyses demonstrated that MSCs conferred significant improvements in GMFM at 3 − (1.05 (0.19–1.92), p = 0.02), 6 − (0.97 (0.30–1.64), p = 0.005) and 12 months (0.99 (0.30–1.67), p = 0.005) post-treatment. Whilst MSCs are safe and improve GMFM outcomes in CP with large effect sizes, study and participant variability continues to confound data interpretation and limits subgroup analyses. With no published Phase 3 trials and high rates of compassionate access, the field would benefit from well-designed trials with unified outcomes. Additionally, data sharing to enable Individual Participant Data Meta-Analysis would support the determination of optimal source, route and dose to progress towards regulatory approval.

1. Introduction

Mesenchymal stromal cells (MSCs) are multi-potent, heterogenous, non-hematopoietic stromal cells that are commonly derived from umbilical cord tissue, bone marrow and adipose tissue [1]. MSCs were discovered >30 years ago and since then, our understanding, characterization and use of these cells within medicine has evolved and been refined [2,3]. MSCs are now under investigation as a treatment for a range of neurological conditions including cerebral palsy (CP). CP describes a group of permanent disorders affecting posture and movement, resulting from damage to the developing brain [4]. Available treatments for CP are limited, with a focus on motor training-based rehabilitation to optimize motor potential. MSCs are emerging as a potential intervention with substantial interest across research and the CP community.
MSCs act via anti-inflammatory and immunomodulatory properties and do not require donor-matching due to low immunogenicity, with limited potential for in vivo differentiation [5]. Taken together, these features have enabled widespread use of repeat dose allogeneic MSC products. Research supports that MSCs mainly produce changes in brain outcomes via paracrine signaling [6]. Systemic administration does not lead to MSCs crossing the blood–brain barrier in significant numbers. Despite this, some studies have administered MSCs directly into the brain, although the majority administer MSCs intravenously and intrathecally [7,8]. Across more than two-decades of preclinical research, MSCs for perinatal and adult brain injury have been shown to be potent immunomodulators, secreting anti-inflammatory chemokines, cytokines and growth factors that result in smaller brain infarct sizes, amelioration of damage to oligodendrocyte progenitors, improved myelination, neovascularization, reduced brain cell death and altered brain and systemic inflammation [9,10,11,12,13]. MSCs also directly interact with immune cells to skew macrophage polarization towards anti-inflammatory phenotypes and downregulate immune responses [14]. An important recent discovery was that MSC cell death is required for functional benefit in a range of preclinical models of inflammatory injury [15]. Specifically, when administered intravenously, MSCs are metabolized via first pass in the lungs where alveolar macrophages engulf MSCs and are rapidly cleared. Without cell death and cell clearance, MSCs have impaired efficacy in immunomodulation and paracrine signaling. Immunomodulation is particularly important when considering how to best treat CP. The available evidence supports that there is a pathogenic role of inflammation in CP which should be considered a comorbidity of the condition, with changes in inflammatory status and immune function likely present years after the initial brain injury that may be amenable to treatment [16].
With supportive preclinical efficacy and therapeutic rationale, it has been documented that nearly 50,000 participants over a range of conditions are being, or have been, enrolled across >1000 registered clinical trials using MSC treatment [17]. Encouragingly, a robust safety profile of MSCs is established across a range of conditions [18]. MSC use for CP has been documented in two systematic reviews with meta-analyses [19,20]. These concluded that, from four controlled studies, MSC treatment improves gross motor function (measured via the Gross Motor Function Measure, GMFM) and Comprehensive Function Assessment in children with CP compared to controls. However, Phase 2 trials have suggested inferior benefit compared to other treatments, such as umbilical cord blood [21]. Whilst the evidence of efficacy appears mixed, children continue to be treated in research across various phases of research, as well as via compassionate/Expanded Access Programs, using various methods, dosing, routes and sources of MSCs. Future research directions remain unclear. We conducted a scoping review to better describe the clinical landscape, the number of people treated in clinical studies, and to provide recommendations to direct research efforts. In addition, we also aimed to report on the treatment effect of MSCs for improving gross motor function measured on the GMFM to help provide up-to-date information on efficacy.

2. Materials and Methods

We followed the Population, Concept, and Context keywords search method to formulate our scoping review question [22]. The study protocol was published on the Open Science Framework (DOI 10.17605/OSF.IO/GZ9TF) and is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Guidelines (PRISMA-ScR) [23]. The PRISMA-ScR Checklist can be found in Supplementary Table S1.

2.1. Search Strategy

The search strategy was informed via previously published systematic reviews [19,20] and preliminary journal searches to optimize term selection. We ran database searches on 20 May 2024 using MEDLINE (1946 to 20 May 2024), Cochrane Central (The Cochrane Library, May 2024) and Embase (1947 to 20 May 2024) via Ovid using the following strategy: (cerebral palsy).tw; (mesenchymal).tw. Searches were de-duplicated. Registered reports/trials were identified using published methodology with searches of 12 international trial registries up to 2023 [24], that included registered compassionate, Expanded or alternate access programs. Registry searches as well as searches of gray literature via Google Scholar were conducted simultaneously and updated on 13 February 2025. A full electronic search strategy can be found in Supplementary Table S2.

2.2. Study Eligibility Criteria

Eligible studies included all published clinical reports and registered reports/trials (including any available posted results) across any research phase, as well as publicly available information about registered compassionate, Expanded or alternate access programs. Included reports had to administer MSCs (any source) to participants with CP, for the treatment of their CP, but could include a mixed population with no minimum proportion of CP participants. Conference abstracts, posters and full text articles were included in any language where online translation could be utilized.
We excluded MSC secretome products including extracellular vesicles and supernatant, studies with a treatment arm that exclusively administered a mixed cell therapy (like bone marrow alongside MSCs in the same treatment), umbilical cord blood without specific expansion/enrichment of MSCs, and unexpanded/unenriched bone marrow mononuclear cells. We excluded registered trials that had a status of no longer available, suspended or withdrawn with no available posted results. We also excluded registered trials that did not explicitly recruit those with CP even if the keywords provided contained “cerebral palsy”.

2.3. Study Selection

De-duplicated database results were exported into Covidence Systematic Review Software (Veritas Health Innovation, Melbourne, Australia, available at: http://www.covidence.org, accessed on 20 May 2024). Additional de-duplication was conducted before titles and abstracts were screened by two independent reviewers (MCBP, MFE). Full texts of studies were then retrieved and independently assessed for eligibility.

2.4. Data Extraction, Analysis and Reporting

2.4.1. All Included Reports

Data from trial registries, as well as those from included reports, were extracted by MCBP into a Microsoft Excel spreadsheet developed specifically for this review. Extracted information included study details (year, location, design, author details and registration), participant details (sample size, age, type/topography and severity of CP) and details of the MSC treatment (source, route, dose, how dosing was calculated and treatment regimen/timing).

2.4.2. For Controlled Studies

Meta-analysis was performed on studies that had a control group and reported on outcomes from the GMFM (including all versions such as the -66 and -88), where data were available from two or more studies collecting results at the same timepoint. The GMFM is a gold-standard outcome measure for gross motor function in CP. Review Manager (RevMan, Version 5.4, The Cochrane Collaboration, 2020) was used to conduct quantitative meta-analysis, with outcome data extracted and analyzed for mean, standard deviation (SD) and sample size. When data were reported in other forms (e.g., median with confidence intervals (CI)), the calculator function on RevMan was used to calculate mean and SD. We used a random-effects model with standardized mean differences (SMD) and 95% CI with two-sided p values for each outcome.
Subgroup analysis was performed when there were two or more studies collecting the GMFM with similar features at the same timepoint. Subgroup analysis was used to determine potential sources of heterogeneity based on prespecified factors including participant demographics, MSC source, administration route and dose. Heterogeneity between the studies was assessed using the I2 statistic, where I2 > 50% or >75% was interpreted as moderate or substantial heterogeneity, respectively.
Two review authors (MP, AG) independently assessed the risk of bias using the Cochrane criteria (Cochrane Risk of Bias 2) for studies that were included in the meta-analysis. Other studies were not assessed for risk of bias.

2.5. Data Reporting

Studies were reported based on the level of evidence (e.g., defined as being published Phase 2, Phase 1 or unpublished registered trials). Compassionate access reports were defined as those that self-reported as providing treatment under regulated Expanded or compassionate access.
Studies were grouped and reported based on report type, publication status and participant information, as well as MSC details. Records were categorized as reported by original authors, however in the instance of registered clinical trials or published reports with missing information, those without a control group were designated Phase 1, and those with a control group were designated Phase 2. In instances where there were multiple reports of the same participants, study authors were contacted to confirm data. Included studies were cross-checked with recent reviews to validate comprehensiveness and accuracy [19,20,25].

3. Results

Following database searches, a total of 360 records were identified. After title and abstract screening, 42 full texts were assessed for eligibility. In addition, 29 reports from registries and gray literature were identified. A total of 30 published reports and 10 registered trials were included in this review [5,21,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. There was duplication in participants reported across two records [30,44]. These two records are presented with collated data received via correspondence from authors to account for all participants. The PRISMA Flow Diagram of the search process is presented in Figure 1.

3.1. Study Characteristics

A summary of the 40 included studies is presented in Supplementary Table S3. These comprise 16 case series/reports (15 published, 1 published abstract), eight Phase 1 trials (three published, four unpublished, one published abstract), 12 Phase 2 trials (7 published, 4 unpublished, 1 published abstract), two Phase 3 trials (unpublished) and one compassionate access program across two reports (one published, one published abstract, Figure 2).

3.2. Participants Characteristics

The total number of participants with CP treated with MSCs in identified reports was n = 1292 (Figure 2). Nearly a third of all participants were treated via compassionate access (31%), with 27% treated in Phase 2 trials. Participants treated ranged in age from 6 months to 45 years (Supplementary Table S3). Severity, type and topography of CP varied considerably and was often not reported.

3.3. MSC Characteristics and Treatment Regimen

Most participants received MSCs from allogeneic origins (either related or unrelated) (Figure 3). Various sources of MSCs were used, with the most frequent being umbilical cord tissue-derived MSCs. Other sources included bone marrow, umbilical cord blood, adipose and dental pulp. A portion of participants were missing MSC source information (21.9%).
MSC dose varied considerably across reports and could not be collated or averaged due to the wide range of dosing selected, repeat dosing and overall differences in total dose (Supplementary Table S3). Ten studies did not provide any dosing information. The method for dose calculation varied, but most participants (69%) received a standard dose of cells regardless of body weight. Some participants did not have information on the number of doses received; however, the majority were reported as receiving two or more doses of MSCs rather than a single dose (Figure 3).
Across all studies, 11 routes of MSC administration (including different combinations of routes) were utilized. The most common routes were intrathecal, intravenous or intrathecal and intravenous (Figure 3). Other lesser common routes included intracranial (1.4% of participants), intraventricular (3.9% of participants), a mixture of routes such as intrathecal in combination with intraparenchymal, or a selection of methodologies across participants in the same study (e.g., intravenous or intranasal or intrathecal, Supplementary Table S3). Percentages of participants receiving each type of route within the same study were not commonly reported and therefore not able to be presented in detail.

3.4. Meta-Analyses of Controlled Studies

Eight controlled studies were considered for meta-analysis of GMFM [21,27,29,35,38,40]. Six studies had adequate outcome data reported and could be collated for meta-analysis, with all other motor-focused efficacy outcomes listed in Supplementary Table S4. Timepoints of data collection varied, with at least two studies available for meta-analysis at 1, 3, 6 and 12 months post treatment.
No effect was detected 1-month after treatment on the GMFM (SMD 0.00 (95% CI: −0.65–0.66) p = 1.00, Figure 4), with only two studies available for meta-analysis at this earlier timepoint. A statistically significant improvement in GMFM was detected after MSC treatment compared to controls at 3 − (1.05 (0.19–1.92), p = 0.02), 6 − (0.97 (0.30–1.64), p = 0.005) and 12 months (0.99 (0.30–1.67), p = 0.005) post treatment. Using Cohen’s standard, these effect sizes are considered large. However, substantial heterogeneity was detected across all timepoints, with I2 ranging from 64 to 90%, meaning the observed effect varied considerably across studies.

3.5. Subgroup Analyses

There was sufficient data to analyze the effect of repeat dosing (one dose versus more than one dose) and route of administration (intravenous versus intrathecal) at the 12-month timepoint, as well as the effect of MSC source (bone marrow versus cord tissue) at 3 months post treatment. There was insufficient data to explore the effect of participant age, type or severity of CP, or dose of MSCs. The test for subgroup differences did not identify significant differences in effect between studies administering one or multiple doses (p = 0.38, Figure 5) or studies administering MSCs via intrathecal or intravenous routes (p = 0.47) at 12 months post treatment. Similarly, at 3 months post-treatment, no difference was detected in effect size between studies utilizing bone marrow MSCs versus cord tissue MSCs (p = 0.33). However, with 0% residual heterogeneity found (Figure 5), repeat dosing, route of administration and MSC source are all plausible sources of heterogeneity.

3.6. Risk of Bias Assessment

Figure 6 demonstrates the results from Risk of Bias-2 assessment from the five studies reported and included in the meta-analysis [21,27,35,38,40]. One study was determined to have some risk of bias in the domains of deviations from intended interventions that resulted in an overall score of some concerns [40]. Two studies had overall high risk of bias from selection of the reported results [21], in addition to deviations from the intended interventions [38].

3.7. Safety Assessment

Overall, MSC treatment was deemed safe in all studies that reported on it, with no serious adverse events. However, of the 30 published reports, 7 did not contain any information on the capture of safety or side effects.
Studies using intravenous administration of MSCs included reports of fever, diarrhea, vomiting and dyspnea, and were mainly associated with mild, transient infusion reactions. Meanwhile, intrathecal administration of MSCs included safety events of fever, irritability, headache, low back pain, vomiting, nausea and meningism, aligning with increased or decreased cerebrospinal/intracranial fluid pressure. All events were treatable and resolved within days after treatment. One study that assessed donor-specific antibody formation after treatment noted the development of asymptomatic donor-specific anti-HLA class I antibodies in two participants [21].

4. Discussion

In this scoping review of MSCs for CP, we present all published and unpublished reports, as well as perform a meta-analysis of controlled trials with subgroup analysis of efficacy for improving gross motor skills on the GMFM. We identified 30 published reports and 10 registered trials, with a total of 1292 people with CP treated with MSCs. A large portion of treated individuals have participated in early-stage research including case series/reports, Phase 1 and 2 studies. However, whilst two Phase 3 trials have been registered and marked as complete [54,55], these have not been published. Phase 3 trials remain an integral part of establishing definitive efficacy evidence to support regulatory approval. Strikingly, there are two published reports of compassionate/Expanded access of MSC treatment for CP that contribute the highest relative proportion of participants treated to date (31%, n = 401). This number is likely underrepresented as compassionate access schemes are not routinely published. It is interesting that teams have moved to exploring implementation and alternative access to MSC treatment via compassionate access when there has not been a single MSC candidate or treatment regimen (including dose, route and dose frequency) driven from preclinical to Phase 3 research. Perhaps this is reflective of the lack of commercial interest in MSCs for CP that is required to support costly and resource intense Phase 3 trials (including Phase 3 registration trials) and implementation. Without commercialization opportunities, depending on the country and its regulatory environments, implementation and widespread availability of treatment may be deemed appropriate. For example, the Conditional Early Approval can be granted after supportive Phase 2 research in countries like Japan [56]. These frameworks can be helpful to fast-track approval of promising treatments and deliver them to those who need them. However, the Conditional Early Approval pathways have also been met with some criticism [57], especially when a treatment becomes available in the absence of proven safety and early efficacy signals. In other settings such as the United States, to achieve regulatory approval and reimbursement, the field must focus on streamlining trials to completed Phase 3 trials for treatment approval. In this context, people with CP should not need to rely on compassionate access for treatment access in the long-term and emphasis should be placed on research establishing the comprehensive safety and efficacy profile of MSC treatment for CP.
Promisingly, MSC treatment for CP is safe, and our meta-analysis of GMFM concluded that MSCs confer a large, clinically meaningful improvement in gross motor function at 3, 6 and 12 months after treatment compared to controls [58]. Notably, whilst the GMFM is a gold-standard outcome measure for CP, and widely measured in intervention trials, gross motor is only one outcome that may be improved by MSC treatment. Indeed, there have been calls for exploration of other outcomes, especially those that are considered of high importance to those with lived experience of CP (e.g., quality of life and social participation) [59]. Whilst outside the scope of this scoping review, early evidence from Phase 1 and Phase 2 trials of MSCs for CP do discuss the benefit of treatment for outcomes such as cognition and language [35,49]. Overall, combining these outcomes with those of interest to our community could substantially improve our understanding of the benefits of MSC treatment for CP and also support increasing cost-effectiveness across multiple domains of improvement. Additionally, whilst we do not expect results of MSC treatment to be lost over time, we note that in this scoping review that most reports do not collect outcome measures beyond 12–24 months post-treatment. Long-term follow-up of MSC treatment within CP studies has not been conducted although clinical research has been active for many decades. Whilst this may be entirely appropriate for some patient cohorts, for younger children who are yet to reach their motor potential or for outcomes that are age-dependent, follow-up studies may support confirmation around the sustained or changing benefit of treatment across a range of important outcome measures over time. Nevertheless, the results from this study on GMFM up to 12 months post-treatment remain a timely and important finding, especially as recent publications have questioned the future of MSC research for CP with variable efficacy reported in comparative analyses with other available cell therapies like umbilical cord blood [21,60]. Whilst these recent studies were not powered to detect changes between the two cell therapy arms, it was determined that umbilical cord blood may have a larger effect size than MSC treatment, with earlier detectable changes in GMFM. However, our meta-analysis confirms a large effect size of MSC treatment across timepoints as early as 3 months post treatment (with SMD around 1), and supports the role of MSC treatment as a strategy for improving gross motor outcomes in CP. Not to mention, MSCs may be a favorable therapy especially considering its low immunogenicity and off-the-shelf features that enable safe and frequent repeat dosing, plus feasible high-dosing targets using a manufactured allogeneic product that can be standardized [61]. These MSC characteristics may support their use across a broader treatment window of individuals (potentially across broader age ranges and severity), and this will be important to investigate in more research with well-defined patient populations.
With such variability noted within Phase 2 research, it was critical to explore the effect of repeat dosing, administration route and source of MSCs in subgroup analysis. For the first time in the published literature, there was sufficient data on the GMFM at 12 months to assess the effect of repeat dosing (one dose versus more than one dose) and route of administration (intravenous versus intrathecal), as well as the effect of MSC source (bone marrow versus cord tissue) at 3 months post treatment. Though, due to high heterogeneity and small sample size, no subgroup differences were detected. Our analysis did reveal, however, that repeat dosing, administration route and MSC source reduced residual heterogeneity to 0%, and are therefore plausible contributing factors to heterogeneity. Whilst we did not have enough data to draw any substantial conclusions, it is likely that these MSC treatment characteristics will impact effect size on the GMFM. We are aware of other trials that aim to assess the comparative effectiveness of different cell therapies and administration routes [62]. However, this study has an unknown status and has not been updated since 2018. It also remains critical to better elucidate the effect of repeat dosing and dose per treatment. For instance, one study included in the meta-analysis with the largest treatment effect [38] administered the highest number of doses within the controlled trials (eight doses). The field would benefit from more well-designed, powered trials with the ability to share de-identified data to contribute to a global individual participant data meta-analysis (IPDMA). This would enable addressing research aims such as identifying the best route, dose and dosing threshold, and identification of responder criteria.
Published IPDMA avoids duplication of research, encourages sharing of findings and reduces the burden on finite research resources, supporting knowledge integration [63,64]. We have recently seen the significance of works of this nature in the field, with the world’s first IPDMA of umbilical cord blood for CP being published to help direct who should be receiving treatment, when and at what dose [65]. All MSCs are not equal, and there is no doubt that product variables can impact efficacy, along with participant characteristics such as age, severity, etiology and type of CP. For instance, the IPDMA for umbilical cord blood revealed that treatment is likely to benefit those of a younger age (under 5) with ambulant CP [65]. It is plausible that similar findings may exist within the MSC trial data. It is often hypothesized that as MSCs are highly immunomodulatory, repeat administration at a younger age when inflammation may be higher could confer greater gains [16,21,66]; however, we do not yet have sufficiently powered clinical evidence to draw any definite conclusions.
With the current absence of individual participant data, global data sharing platforms, notable missing data and alternate strategies such as unifying outcome collection via the development of consensus recommendations for reporting standards in future research may be useful. The MSC field has focused over many decades to develop structured methodologies to better characterize products, and establish consistent nomenclature, functional characterization and biobanking standards [2,67,68]. These methods, combined with a minimum dataset within clinical trials treating CP that extends to participant characteristics, outcome selection and reporting, may also support harmonization in published reports and future clinical research. Similar consensus recommendations for data reporting exist within neurology fields undertaking research in neonatal encephalopathy and adult stroke [69,70,71]. This strategy may assist in overcoming missing data that was noted in this scoping review. It also supports movement to unified intervention frameworks based on preclinical and clinical trial results. In future, this could mean that a standardized MSC dose, source, route, participant groups and study outcomes are prioritized, and this could direct later phase clinical trials.

Limitatons

We acknowledge several limitations of this research. As we wanted to summarize the entire research landscape, we included both published and unpublished reports, which may have introduced bias and error. For example, information shared in trial registries (including those translated into English) may differ from actual study methodology. Inclusion of case reports and compassionate access programs also contribute lower-quality evidence, and lower reliability. However, to overcome this, we integrated the meta-analysis and synthesized findings from controlled studies with assessment of study quality using Cochrane criteria.
Widespread missing data also limited interpretation of some study findings. For example, many reports did not clearly publish the type, topography or severity of CP. We know that MSCs, like all cell therapies, will not be a one-size-fits-all, and publishing transparent cohort characteristics in research is essential. Data heterogeneity also impacted study comparison, interpretation of findings and our ability to conduct meta-analysis with subgroup analysis to determine the effect of dose, route and source of MSCs. For instance, whilst 72% of participants received more than one dose of MSCs, these ranged from 2 to 32 administrations, and it was not possible to sensibly dichotomize the data. Total dose and route used was also highly variable, with one study administering up to 750 million cells over 8 treatments, given across 4 different administration routes. As research progresses, study methods that enable IPDMA as well as strive for alignment in core study outcomes will help support overcoming data heterogeneity and enable study comparison. Similar recommendations have been made for the neonatal cell therapies sector [72]. Investigating the contribution of route, dose and MSC source, as well as identifying the right treatment candidates, remains a high priority to better enable regulatory approval of MSC products [73].

5. Conclusions

Whilst MSCs are safe and effective at improving GMFM in CP, an abundance of methods are being utilized that hinder reliability, synthesis of data and interpretation. Research progression from early trials to Phase 3 trials has not been linear, access to MSCs for CP via compassionate access is high and there are no published reports of Phase 3 research. The field would benefit from head-to-head studies as well as robust later stage trials with unified outcome measures. This can enable collaborative IPDMA with knowledge integration that provides recommendations on preferred cell source, route and dose to progress towards regulatory approval of an efficacious MSC therapy for CP.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cells14100700/s1, Table S1: PRISMA-ScR Checklist, Table S2: Search Strategy, Table S3: Summary of Included Reports, Table S4: Motor Function Outcomes and Timepoints.

Author Contributions

Conceptualization, M.C.B.P., M.F.-E. and I.N.; methodology, M.C.B.P., A.W., F.V., P.S.C. and A.B.; analysis, M.C.B.P., M.F.-E., A.R.G. and R.B.-W.; data interpretation M.C.B.P., I.N., M.F.-E., H.P. and R.C.D.; writing, M.C.B.P.; review and editing, M.C.B.P., M.F.-E., I.N., R.C.D., A.R.G., H.P., A.W., F.V., P.S.C., A.B. and R.B.-W. All authors have read and agreed to the published version of the manuscript.

Funding

There was no specific funding acquired for this study.

Data Availability Statement

The original contributions presented in this study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
MSCsMesenchymal stromal cells
CPCerebral palsy
GMFMGross motor function measure
PRISMA-ScRPreferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews Guidelines
RevManReview Manager
CIConfidence intervals
SDStandard deviation
SMDStandardized mean differences
nSample/number of participants
AutoAutologous
AlloAllogeneic
BMBone marrow
CTCord tissue
ITIntrathecal
IVIntravenous
UCBUmbilical cord blood

References

  1. Patel, G.D.; Liu, L.; Li, A.; Yang, Y.-H.; Shen, C.-C.; Brand-Saberi, B.; Yang, X. Mesenchymal stem cell-based therapies for treating well-studied neurological disorders: A systematic review. Front. Med. 2024, 11, 1361723. [Google Scholar] [CrossRef] [PubMed]
  2. Dominici, M.; Le Blanc, K.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.; Krause, D.; Deans, R.; Keating, A.; Prockop, D.; Horwitz, E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8, 315–317. [Google Scholar] [CrossRef] [PubMed]
  3. Horwitz, E.M.; Le Blanc, K.; Dominici, M.; Mueller, I.; Slaper-Cortenbach, I.; Marini, F.C.; Deans, R.J.; Krause, D.S.; Keating, A. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 2005, 7, 393–395. [Google Scholar] [CrossRef]
  4. Rosenbaum, P.; Paneth, N.; Leviton, A.; Goldstein, M.; Bax, M.; Damiano, D.; Dan, B.; Jacobsson, B. A report: The definition and classification of cerebral palsy April 2006. Dev. Med. Child Neurol. 2007, 109, 8–14, Erratum in: Dev Med Child Neurol. 2007, 49, 480. [Google Scholar] [PubMed]
  5. Zhang, J.; Huang, X.; Wang, H.; Liu, X.; Zhang, T.; Wang, Y.; Hu, D. The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res. Ther. 2015, 6, 234. [Google Scholar] [CrossRef]
  6. Yarygin, K.N.; Namestnikova, D.D.; Sukhinich, K.K.; Gubskiy, I.L.; Majouga, A.G.; Kholodenko, I.V. Cell Therapy of Stroke: Do the Intra-Arterially Transplanted Mesenchymal Stem Cells Cross the Blood-Brain Barrier? Cells 2021, 10, 2997. [Google Scholar] [CrossRef]
  7. Isaković, J.; Šerer, K.; Barišić, B.; Mitrečić, D. Mesenchymal stem cell therapy for neurological disorders: The light or the dark side of the force? Front. Bioeng. Biotechnol. 2023, 11, 1139359. [Google Scholar] [CrossRef]
  8. Schu, S.; Nosov, M.; O’Flynn, L.; Shaw, G.; Treacy, O.; Barry, F.; Murphy, M.; O’Brien, T.; Ritter, T. Immunogenicity of allogeneic mesenchymal stem cells. Cell. Mol. Med. 2012, 16, 2094–2103. [Google Scholar] [CrossRef]
  9. Li, J.; Yawno, T.; Sutherland, A.E.; Gurung, S.; Paton, M.; McDonald, C.; Tiwari, A.; Pham, Y.; Castillo-Melendez, M.; Jenkin, G.; et al. Preterm umbilical cord blood derived mesenchymal stem/stromal cells protect preterm white matter brain development against hypoxia-ischemia. Exp. Neurol. 2018, 308, 120–131. [Google Scholar] [CrossRef]
  10. Nair, S.; Rocha-Ferreira, E.; Fleiss, B.; Nijboer, C.H.; Gressens, P.; Mallard, C.; Hagberg, H. Neuroprotection offered by mesenchymal stem cells in perinatal brain injury: Role of mitochondria, inflammation, and reactive oxygen species. J. Neurochem. 2021, 158, 59–73. [Google Scholar] [CrossRef]
  11. Paton, M.C.B.; Allison, B.J.; Fahey, M.C.; Li, J.; Sutherland, A.E.; Pham, Y.; Nitsos, I.; Bischof, R.J.; Moss, T.J.; Polglase, G.R.; et al. Umbilical cord blood versus mesenchymal stem cells for inflammation-induced preterm brain injury in fetal sheep. Pediatr. Res. 2019, 86, 165–173. [Google Scholar] [CrossRef] [PubMed]
  12. Vaes, J.E.G.; Vink, M.A.; de Theije, C.G.M.; Hoebeek, F.E.; Benders, M.; Nijboer, C.H.A. The Potential of Stem Cell Therapy to Repair White Matter Injury in Preterm Infants: Lessons Learned From Experimental Models. Front. Physiol. 2019, 10, 540. [Google Scholar] [CrossRef] [PubMed]
  13. Zheng, H.; Zhang, B.; Chhatbar, P.Y.; Dong, Y.; Alawieh, A.; Lowe, F.; Hu, X.; Feng, W. Mesenchymal Stem Cell Therapy in Stroke: A Systematic Review of Literature in Pre-Clinical and Clinical Research. Cell Transplant. 2018, 27, 1723–1730. [Google Scholar] [CrossRef] [PubMed]
  14. Chiossone, L.; Conte, R.; Spaggiari, G.M.; Serra, M.; Romei, C.; Bellora, F.; Becchetti, F.; Andaloro, A.; Moretta, L.; Bottino, C. Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses. Stem. Cells 2016, 34, 1909–1921. [Google Scholar] [CrossRef]
  15. Pang, S.H.M.; D’Rozario, J.; Mendonca, S.; Bhuvan, T.; Payne, N.L.; Zheng, D.; Hisana, A.; Wallis, G.; Barugahare, A.; Powell, D.; et al. Mesenchymal stromal cell apoptosis is required for their therapeutic function. Nat. Commun. 2021, 12, 6495. [Google Scholar] [CrossRef]
  16. Paton, M.C.B.; Finch-Edmondson, M.; Dale, R.C.; Fahey, M.C.; Nold-Petry, C.A.; Nold, M.F.; Griffin, A.R.; Novak, I. Persistent Inflammation in Cerebral Palsy: Pathogenic Mediator or Comorbidity? A Scoping Review. J. Clin. Med. 2022, 11, 7368. [Google Scholar] [CrossRef]
  17. Pittenger, M.F.; Discher, D.E.; Péault, B.M.; Phinney, D.G.; Hare, J.M.; Caplan, A.I. Mesenchymal stem cell perspective: Cell biology to clinical progress. NPJ Regen. Med. 2019, 4, 22. [Google Scholar] [CrossRef]
  18. Lalu, M.M.; McIntyre, L.; Pugliese, C.; Fergusson, D.; Winston, B.W.; Marshall, J.C.; Granton, J.; Stewart, D.J. Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLoS ONE 2012, 7, e47559. [Google Scholar] [CrossRef]
  19. Eggenberger, S.; Boucard, C.; Schoeberlein, A.; Guzman, R.; Limacher, A.; Surbek, D.; Mueller, M. Stem cell treatment and cerebral palsy: Systemic review and meta-analysis. World J. Stem Cells 2019, 11, 891–903. [Google Scholar] [CrossRef]
  20. Xie, B.; Chen, M.; Hu, R.; Han, W.; Ding, S. Therapeutic Evidence of Human Mesenchymal Stem Cell Transplantation for Cerebral Palsy: A Meta-Analysis of Randomized Controlled Trials. Stem Cells Int. 2020, 2020, 5701920. [Google Scholar] [CrossRef]
  21. Sun, J.M.; Case, L.E.; McLaughlin, C.; Burgess, A.; Skergan, N.; Crane, S.; Jasien, J.M.; Mikati, M.A.; Troy, J.; Kurtzberg, J. Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial. Dev. Med. Child Neurol. 2022, 64, 1477–1486. [Google Scholar] [CrossRef] [PubMed]
  22. Peters, M.D.J.; Marnie, C.; Tricco, A.C.; Pollock, D.; Munn, Z.; Alexander, L.; McInerney, P.; Godfrey, C.M.; Khalil, H. Updated methodological guidance for the conduct of scoping reviews. JBI Evid. Synth. 2020, 18, 2119–2126. [Google Scholar] [CrossRef] [PubMed]
  23. Tricco, A.C.; Lillie, E.; Zarin, W.; O’Brien, K.K.; Colquhoun, H.; Levac, D.; Moher, D.; Peters, M.D.J.; Horsley, T.; Weeks, L.; et al. PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation. Ann. Intern. Med. 2018, 169, 467–473. [Google Scholar] [CrossRef] [PubMed]
  24. Couto, P.S.; Bersenev, A.; Verter, F. The first decade of advanced cell therapy clinical trials using perinatal cells (2005–2015). Regen. Med. 2017, 12, 953–968. [Google Scholar] [CrossRef]
  25. Paton, M.C.B.; Finch-Edmondson, M.; Fahey, M.C.; London, J.; Badawi, N.; Novak, I. Fifteen years of human research using stem cells for cerebral palsy: A review of the research landscape. J. Paediatr. Child Health 2021, 57, 295–296. [Google Scholar] [CrossRef]
  26. Abo Elkheir, W.; Gabr, H. Neuro-regenerative effect of autologous mesenchymal stem cell therapy in cerebral palsy patients: Pilot clinical trial. Cytotherapy 2014, 16, S15. [Google Scholar] [CrossRef]
  27. Amanat, M.; Majmaa, A.; Zarrabi, M.; Nouri, M.; Akbari, M.G.; Moaiedi, A.R.; Ghaemi, O.; Zamani, F.; Najafi, S.; Badv, R.S.; et al. Clinical and imaging outcomes after intrathecal injection of umbilical cord tissue mesenchymal stem cells in cerebral palsy: A randomized double-blind sham-controlled clinical trial. Stem Cell Res. Ther. 2021, 12, 439. [Google Scholar] [CrossRef]
  28. Boyali, O.; Kabatas, S.; Civelek, E.; Ozdemir, O.; Bahar-Ozdemir, Y.; Kaplan, N.; Savrunlu, E.C.; Karaoz, E. Allogeneic mesenchymal stem cells may be a viable treatment modality in cerebral palsy. World J. Clin. Cases 2024, 12, 1585–1596. [Google Scholar] [CrossRef]
  29. Chen, W.m.; Hu, Y.x.; Yin, J.y.; Lu, J.j.; Wang, J.; Zou, Q.y. Effect of autologous bone marrow mesenchymal stem cell transplantation on motor development of cerebral palsy children. J. Clin. Rehabil. Tissue Eng. Res. 2011, 15, 7589–7592. [Google Scholar] [CrossRef]
  30. Chroscinska-Kawczyk, M.; Zdolinska-Malinowska, I.; Boruczkowski, D. The Impact of Umbilical Cord Mesenchymal Stem Cells on Motor Function in Children with Cerebral Palsy: Results of a Real-world, Compassionate use Study. Stem Cell Rev. Rep. 2024, 20, 1636–1649. [Google Scholar] [CrossRef]
  31. Dong, H.; Li, G.; Shang, C.; Yin, H.; Luo, Y.; Meng, H.; Li, X.; Wang, Y.; Lin, L.; Zhao, M. Umbilical cord mesenchymal stem cell (UC-MSC) transplantations for cerebral palsy. Am. J. Transl. Res. 2018, 10, 901–906. [Google Scholar] [PubMed]
  32. Du, K.; Luan, Z.; Qu, S.-q.; Liu, W.-p.; Wang, Z.-y.; Yang, Y.-x.; Yang, H. Clinical outcome of bone marrow mesenchymal stem cells transplantation in children with severe cerebral palsy. J. Clin. Pediatr. 2011, 29, 55–58. [Google Scholar] [CrossRef]
  33. Fu, X.; Hua, R.; Wang, X.; Wang, P.; Yi, L.; Yu, A.; Yang, J.; Li, Y.; An, Y. Synergistic Improvement in Children with Cerebral Palsy Who Underwent Double-Course Human Wharton’s Jelly Stem Cell Transplantation. Stem Cells Int. 2019, 2019, 7481069. [Google Scholar] [CrossRef] [PubMed]
  34. Gabr, H. Intrathecal Autologous Bone Marrow Derived MSC Therapy in Cerebral Palsy: Safety and Short Term Efficacy. Am. J. Biosci. Bioeng. 2015, 3, 24. [Google Scholar] [CrossRef]
  35. Gu, J.; Huang, L.; Zhang, C.; Wang, Y.; Zhang, R.; Tu, Z.; Wang, H.; Zhou, X.; Xiao, Z.; Liu, Z.; et al. Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: A randomized, controlled trial. Stem Cell Res. Ther. 2020, 11, 43. [Google Scholar] [CrossRef]
  36. Hastuti, S.; Sartika, C.R.; Haifa, R.; Naura, N.; Hasibuan, A.; Devi, D.; Pertiwi, V. Mesenchymal Stem/Stromal Cells: Therapeutic Potential of Umbilical Cord Mesenchymal Stem Cell in Patient With Cerebral Palsy: A Case Report. Cytotherapy 2023, 25, S58. [Google Scholar] [CrossRef]
  37. Hirano, A.; Sano, M.; Urushihata, N.; Tanemura, H.; Oki, K.; Suzaki, E. Assessment of safety and feasibility of human allogeneic adipose-derived mesenchymal stem cells in a pediatric patient. Pediatr. Res. 2018, 84, 575–577. [Google Scholar] [CrossRef]
  38. Huang, L.; Zhang, C.; Gu, J.; Wu, W.; Shen, Z.; Zhou, X.; Lu, H. A Randomized, Placebo-Controlled Trial of Human Umbilical Cord Blood Mesenchymal Stem Cell Infusion for Children With Cerebral Palsy. Cell Transpl. 2018, 27, 325–334. [Google Scholar] [CrossRef]
  39. Li, M.; Yu, A.; Zhang, F.; Dai, G.; Cheng, H.; Wang, X.; An, Y. Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells. J. Transl. Med. 2012, 10, 100. [Google Scholar] [CrossRef]
  40. Liu, X.; Fu, X.; Dai, G.; Wang, X.; Zhang, Z.; Cheng, H.; Zheng, P.; An, Y. Comparative analysis of curative effect of bone marrow mesenchymal stem cell and bone marrow mononuclear cell transplantation for spastic cerebral palsy. J. Transl. Med. 2017, 15, 48. [Google Scholar] [CrossRef]
  41. Liu, Y.s.; Wang, X.d.; Yang, J.; Hua, R.r.; Cheng, H.b.; Liu, Y.f.; An, Y.h. Effect evaluation of autologous bone marrow mesenchymal stem cell transplantation on motor function in children with cerebral palsy. Chin. J. Tissue Eng. Res. 2012, 16, 4290–4295. [Google Scholar] [CrossRef]
  42. Miao, X.; Wu, X.; Shi, W. Umbilical cord mesenchymal stem cells in neurological disorders: A clinical study. Indian J. Biochem. Biophys. 2015, 52, 140–146. [Google Scholar] [PubMed]
  43. Okur, S.C.; Erdogan, S.; Demir, C.S.; Gunel, G.; Karaoz, E. The Effect of Umbilical Cord-derived Mesenchymal Stem Cell Transplantation in a Patient with Cerebral Palsy: A Case Report. Int. J. Stem Cells 2018, 11, 141–147. [Google Scholar] [CrossRef]
  44. Rojek, M.; Piatek, M.; Zdolinska-Malinowska, I.; Boruczkowski, D. (Eds.) The Polish Experience of Wharton’s Jelly-derived Mesenchymal Stem Cell Treatment of Paediatric Patients. In Bone Marrow Transplantation; Springernature Campus: London, UK, 2020. [Google Scholar]
  45. Venkataramana, N.; Pal, R.; Rao, S.; Naik, A. A Pilot Study on Safety and Efficacy of Mesenchymal Stem Cells for Children with Cerebral Palsy. In Proceedings of the 39th Annual Meeting of the International Society for Pediatric Neurosurgery, Goa, India, 16–20 October 2011. Childs Nerv Syst 2011, 27, 1751–1850. [Google Scholar] [CrossRef]
  46. Vij, R.; Kim, H.; Park, H.; Cheng, T.; Lotfi, D.; Chang, D. Multi-Dose Hope Biosciences-Adipose-Derived Mesenchymal Stem Cell (HB-adMSC) Therapy for a Patient with Cerebral Palsy: A Case Report. Int. J. Stem Cell Res. Ther. 2023, 10, 78. [Google Scholar] [CrossRef]
  47. Wang, J.-G.; Yin, Z.-M.; Wen, H.; Wang, L.-Z.; Chen, Z. Application of Umbilical Cord Mesenchumal Stem Cells in Cerebral Palsy Treatment: Report of 51 Cases. Chin. Gen. Pract. 2011, 14, 2446–2447. [Google Scholar]
  48. Wang, L.; Ji, H.; Zhou, J.; Xie, J.; Zhong, Z.; Li, M.; Bai, W.; Li, N.; Zhang, Z.; Wang, X.; et al. Therapeutic potential of umbilical cord mesenchymal stromal cells transplantation for cerebral palsy: A case report. Case Rep. Transpl. 2013, 2013, 146347. [Google Scholar] [CrossRef] [PubMed]
  49. Wang, X.; Cheng, H.; Hua, R.; Yang, J.; Dai, G.; Zhang, Z.; Wang, R.; Qin, C.; An, Y. Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: A preliminary clinical study. Cytotherapy 2013, 15, 1549–1562. [Google Scholar] [CrossRef]
  50. Wang, X.; Hu, H.; Hua, R.; Yang, J.; Zheng, P.; Niu, X.; Cheng, H.; Dai, G.; Liu, X.; Zhang, Z.; et al. Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: Pilot study on the correlation of efficacy and hereditary factors. Cytotherapy 2015, 17, 224–231. [Google Scholar] [CrossRef]
  51. Wang, X.-d.; Yang, J.; Li, M. Effects of bone marrow mesenchymal stem cell graft on gross motor function in children withcerebral palsy. J China-Jpn. Friendsh. Hosp. 2010, 24, 337–342. [Google Scholar]
  52. Wu, F.; Yang, J.-y.; Zhang, M.; Chen, C.-h.; Yang, Z.-g.; Sheng, Y.-x.; Liang, H.-w.; Chi, Q.; Yu-ting, W.; Yang, W.-z. Effect of umbilical cord blood mesenchymal stem cell transplantation on nervous system function in 20 cerebral palsy children. J. Clin. Rehabil. Tissue Eng. Res. 2008, 12, 3198–3200. [Google Scholar]
  53. Yang, H.; Zhang, R.; Du, L.; Li, D. Effect of Umbilical Cord Mesenchymal Stem Cell Transplantation Therapy for Cerebral Palsy on Motor Function. Prog. Mod. Biomed. 2012, 12, 91–98. [Google Scholar]
  54. NCT01929434, Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Children With Cerebral Paralysis. National Library of Medicine (US). Available online: https://clinicaltrials.gov/study/NCT01929434 (accessed on 11 February 2025).
  55. IRCT20110628006907N18, A Triple Blinded, Parallel Randomized Clinical Trial Phase II&III of 3 Times Intrathecal Injections of an Umbilical Cord-Derived Mesenchymal Stromal Cell Product “WhartoCell” in Children with Cerebral Palsy. Iranian Registry of Clinical Trials (IR). Available online: https://irct.behdasht.gov.ir/trial/68950 (accessed on 10 February 2025).
  56. Tanaka, M.; Miyazawa, H.; Terashima, R.; Ikuma, M. Conditional early approval for new drug applications in Japan: Current and emerging issues. Clin. Transl. Sci. 2023, 16, 1289–1293. [Google Scholar] [CrossRef]
  57. Cyranoski, D.; Sipp, D.; Mallik, S.; Rasko, J.E.J. Too little, too soon: Japan’s experiment in regenerative medicine deregulation. Cell Stem Cell 2023, 30, 913–916. [Google Scholar] [CrossRef]
  58. Oeffinger, D.; Bagley, A.; Rogers, S.; Gorton, G.; Kryscio, R.; Abel, M.; Damiano, D.; Barnes, D.; Tylkowski, C. Outcome tools used for ambulatory children with cerebral palsy: Responsiveness and minimum clinically important differences. Dev. Med. Child Neurol. 2008, 50, 918–925. [Google Scholar] [CrossRef] [PubMed]
  59. Finch-Edmondson, M.; Paton, M.C.B.; Honan, I.; Karlsson, P.; Stephenson, C.; Chiu, D.; Reedman, S.; Griffin, A.R.; Morgan, C.; Novak, I. Are We Getting It Right? A Scoping Review of Outcomes Reported in Cell Therapy Clinical Studies for Cerebral Palsy. J. Clin. Med. 2022, 11, 7319. [Google Scholar] [CrossRef]
  60. Nouri, M.; Zarrabi, M.; Masoumi, S.; Khodadoust, E.; Majmae, A.; Amanat, M.; Ashrafi, M.R.; Vosough, M. Cell-Based Therapy for Cerebral Palsy: A Puzzle in Progress. Cell J. 2025, 26, 569–574. [Google Scholar] [CrossRef]
  61. Musiał-Wysocka, A.; Kot, M.; Majka, M. The Pros and Cons of Mesenchymal Stem Cell-Based Therapies. Cell Transpl. 2019, 28, 801–812. [Google Scholar] [CrossRef]
  62. NCT03414697, Transplantation of Umbilical Cord-Derived Mesenchymal Stem Cells Via Different Routes. National Library of Medicine (US). Available online: https://clinicaltrials.gov/study/NCT03414697?id=NCT03414697&rank=1 (accessed on 11 February 2025).
  63. Conrado, D.J.; Karlsson, M.O.; Romero, K.; Sarr, C.; Wilkins, J.J. Open innovation: Towards sharing of data, models and workflows. Eur. J. Pharm. Sci. 2017, 109, S65–S71. [Google Scholar] [CrossRef]
  64. van Wijk, R.C.; Imperial, M.Z.; Savic, R.M.; Solans, B.P. Pharmacokinetic analysis across studies to drive knowledge-integration: A tutorial on individual patient data meta-analysis (IPDMA). CPT Pharmacomet. Syst. Pharmacol. 2023, 12, 1187–1200. [Google Scholar] [CrossRef]
  65. Finch-Edmondson, M.; Paton, M.C.B.; Webb, A.; Ashrafi, M.R.; Blatch-Williams, R.K.; Cox, C.S., Jr.; Crompton, K.; Griffin, A.; Kim, M.; Kosmach, S.; et al. Cord blood treatment for children with cerebral palsy: Individual participant data meta-analysis. Pediatrics 2025, e2024068999. [Google Scholar] [CrossRef] [PubMed]
  66. Jantzie, L.L.; Scafidi, J.; Robinson, S. Stem cells and cell-based therapies for cerebral palsy: A call for rigor. Pediatr. Res. 2018, 83, 345–355. [Google Scholar] [CrossRef] [PubMed]
  67. Viswanathan, S.; Blanc, K.L.; Ciccocioppo, R.; Dagher, G.; Filiano, A.J.; Galipeau, J.; Krampera, M.; Krieger, L.; Lalu, M.M.; Nolta, J.; et al. An International Society for Cell and Gene Therapy Mesenchymal Stromal Cells (MSC) Committee perspectives on International Standards Organization/Technical Committee 276 Biobanking Standards for bone marrow-MSCs and umbilical cord tissue-derived MSCs for research purposes. Cytotherapy 2023, 25, 803–807. [Google Scholar] [CrossRef] [PubMed]
  68. Moll, G.; Ankrum, J.A.; Olson, S.D.; Nolta, J.A. Improved MSC Minimal Criteria to Maximize Patient Safety: A Call to Embrace Tissue Factor and Hemocompatibility Assessment of MSC Products. Stem Cells Transl. Med. 2022, 11, 2–13. [Google Scholar] [CrossRef]
  69. Webbe, J.W.H.; Duffy, J.M.N.; Afonso, E.; Al-Muzaffar, I.; Brunton, G.; Greenough, A.; Hall, N.J.; Knight, M.; Latour, J.M.; Lee-Davey, C.; et al. Core outcomes in neonatology: Development of a core outcome set for neonatal research. Arch. Dis. Child. -Fetal Neonatal Ed. 2020, 105, 425–431. [Google Scholar] [CrossRef]
  70. Quirke, F.A.; Ariff, S.; Battin, M.R.; Bernard, C.; Biesty, L.; Bloomfield, F.H.; Daly, M.; Finucane, E.; Healy, P.; Haas, D.M.; et al. COHESION: A core outcome set for the treatment of neonatal encephalopathy. Pediatr. Res. 2024, 95, 922–930. [Google Scholar] [CrossRef]
  71. Walker, M.F.; Hoffmann, T.C.; Brady, M.C.; Dean, C.M.; Eng, J.J.; Farrin, A.J.; Felix, C.; Forster, A.; Langhorne, P.; Lynch, E.A.; et al. Improving the development, monitoring and reporting of stroke rehabilitation research: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable. Int. J. Stroke 2017, 12, 472–479. [Google Scholar] [CrossRef]
  72. Paton, M.C.B.; Benders, M.; Blatch-Williams, R.; Dallimore, E.; Edwards, A.; Elwood, N.; Facer, K.; Finch-Edmondson, M.; Garrity, N.; Gordon, A.; et al. Updates on neonatal cell and novel therapeutics: Proceedings of the Second Neonatal Cell Therapies Symposium (2024). Pediatr. Res. 2025. [Google Scholar] [CrossRef]
  73. Robb, K.P.; Galipeau, J.; Shi, Y.; Schuster, M.; Martin, I.; Viswanathan, S. Failure to launch commercially-approved mesenchymal stromal cell therapies: What’s the path forward? Proceedings of the International Society for Cell & Gene Therapy (ISCT) Annual Meeting Roundtable held in May 2023, Palais des Congrès de Paris, Organized by the ISCT MSC Scientific Committee. Cytotherapy 2024, 26, 413–417. [Google Scholar] [CrossRef]
Cells 14 00700 g001
Figure 1. PRISMA Flow Diagram.
Figure 1. PRISMA Flow Diagram.
Cells 14 00700 g001
Cells 14 00700 g002
Figure 2. Overview of participants treated by publication status and study type. Total number of participants treated, with breakdown of published/unpublished reports as well as number treated across report type (case series, Phase 1–3 and compassionate/Expanded access). Abbreviations: n, number of participants. # Two reports with compiled sample (n) from personal correspondence with authors.
Figure 2. Overview of participants treated by publication status and study type. Total number of participants treated, with breakdown of published/unpublished reports as well as number treated across report type (case series, Phase 1–3 and compassionate/Expanded access). Abbreviations: n, number of participants. # Two reports with compiled sample (n) from personal correspondence with authors.
Cells 14 00700 g002
Cells 14 00700 g003
Figure 3. Overview of MSC characteristics and treatment regimens used in included studies. (A) Source of MSCs and (B) number of treatments with participant numbers reported and proportion of all participants treated (%). (C) Report of how dose calculations were determined, either by standard dosing across participants or by participant body weight. (D) Total number of participants receiving treatment across the most frequent routes of administration. Abbreviations: IT, intrathecal; IV, intravenous.
Figure 3. Overview of MSC characteristics and treatment regimens used in included studies. (A) Source of MSCs and (B) number of treatments with participant numbers reported and proportion of all participants treated (%). (C) Report of how dose calculations were determined, either by standard dosing across participants or by participant body weight. (D) Total number of participants receiving treatment across the most frequent routes of administration. Abbreviations: IT, intrathecal; IV, intravenous.
Cells 14 00700 g003
Cells 14 00700 g004
Figure 4. Forest Plots for GMFM at 1-, 3-, 6- and 12- After MSC Treatment [21,27,29,35,38,40].
Figure 4. Forest Plots for GMFM at 1-, 3-, 6- and 12- After MSC Treatment [21,27,29,35,38,40].
Cells 14 00700 g004
Cells 14 00700 g005
Figure 5. Forest Plots for Subgroup Analyses of GMFM [21,27,29,35,38,40].
Figure 5. Forest Plots for Subgroup Analyses of GMFM [21,27,29,35,38,40].
Cells 14 00700 g005
Cells 14 00700 g006
Figure 6. Risk of Bias-2 for controlled studies included in the meta-analysis [21,27,29,35,38,40].
Figure 6. Risk of Bias-2 for controlled studies included in the meta-analysis [21,27,29,35,38,40].
Cells 14 00700 g006
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Paton, M.C.B.; Griffin, A.R.; Blatch-Williams, R.; Webb, A.; Verter, F.; Couto, P.S.; Bersenev, A.; Dale, R.C.; Popat, H.; Novak, I.; et al. Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes. Cells 2025, 14, 700. https://doi.org/10.3390/cells14100700

AMA Style

Paton MCB, Griffin AR, Blatch-Williams R, Webb A, Verter F, Couto PS, Bersenev A, Dale RC, Popat H, Novak I, et al. Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes. Cells. 2025; 14(10):700. https://doi.org/10.3390/cells14100700

Chicago/Turabian Style

Paton, Madison C. B., Alexandra R. Griffin, Remy Blatch-Williams, Annabel Webb, Frances Verter, Pedro S. Couto, Alexey Bersenev, Russell C. Dale, Himanshu Popat, Iona Novak, and et al. 2025. "Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes" Cells 14, no. 10: 700. https://doi.org/10.3390/cells14100700

APA Style

Paton, M. C. B., Griffin, A. R., Blatch-Williams, R., Webb, A., Verter, F., Couto, P. S., Bersenev, A., Dale, R. C., Popat, H., Novak, I., & Finch-Edmondson, M. (2025). Clinical Evidence of Mesenchymal Stromal Cells for Cerebral Palsy: Scoping Review with Meta-Analysis of Efficacy in Gross Motor Outcomes. Cells, 14(10), 700. https://doi.org/10.3390/cells14100700

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop