Mesenchymal stem cell therapy in perinatal arterial ischemic stroke: systematic review of preclinical studies

Background Perinatal arterial ischemic stroke (PAIS) is a neurologic disorder leading to long-term complications. Mesenchymal stem cells (MSCs) have emerged as a novel therapeutic agent. This systematic review aims to determine the effects of stem cell-based interventions for the treatment of PAIS in preclinical studies. Methods We included all controlled studies on MSCs in neonatal animals with PAIS. Functional outcome was the primary outcome. The literature search was performed in February 2021. Results In the 20 included studies, MSCs were most frequently delivered via intracerebral injection (n = 9), 3 days after the induction of PAIS (n = 8), at a dose ranging from 5 × 104 to 5 × 106 cells. The meta-analysis showed an improvement on the cylinder rearing test (MD: −10.62; 95% CI: −14.38 to −6.86) and on the water maze test (MD: 1.31 MD; 95% CI: 0.80 to 1.81) in animals treated with MSCs compared to the control group animals. Conclusion MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured animals; however, the certainty of the evidence is low. Registration of the protocol of preclinical studies, appropriate sample size calculation, rigorous randomization, and reporting of the data on animal sex and survival are warranted. PROSPERO registration number: CRD42021239642. Impact This is the first systematic review and meta-analysis of preclinical studies investigating the effects of MSCs in an experimental model of PAIS. MSCs appear to improve sensorimotor and cognitive performance in PAIS-injured neonatal animals. The certainty of the evidence is low due to high or unclear risk of bias in most domains.


Information sources
6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.
p.6, l77-82 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.p.6, Suppl.
Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Data collection process
9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
p.7, 95-107 Data items 10a List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).
p.8, l 126f Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.p.7

Study selection 16a
Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.
p.9, l 139-148; Figure 1 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.p.9, l 142-146

Study characteristics
17 Cite each included study and present its characteristics.p.9, l 147-161; Table 1 Risk of bias in studies 18 Present assessments of risk of bias for each included study.p. 11, Table 3 Results of individual studies 19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g.confidence/credible interval), ideally using structured tables or plots.
synthesis, briefly summarise the characteristics and risk of bias among contributing studies.p.11 20b Present results of all statistical syntheses conducted.If meta-analysis was done, present for each the summary estimate and its precision (e.g.confidence/credible interval) and measures of statistical heterogeneity.If comparing groups, describe the direction of the effect. of all investigations of possible causes of heterogeneity among study results./ 20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results./ Reporting biases 21 Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed./ Certainty of evidence 22 Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.p.12 DISCUSSION Discussion 23a Provide a general interpretation of the results in the context of other evidence.p.16ff 23b Discuss any limitations of the evidence included in the review.p.19, l 185-395 23c Discuss any limitations of the review processes used.p.20, l 396-403 23d Discuss implications of the results for practice, policy, and future research.p.21