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Article Open Access

Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis

  • Authors:
    • Dirga Rachmad Aprianto
    • Agung Putra
    • Chodidjah
    • Titiek Sumarawati
  • View Affiliations / Copyright

    Affiliations: Department of Doctoral Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Central Java 50183, Indonesia, Department of Anatomy, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Central Java 50183, Indonesia
    Copyright: © Aprianto et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 60
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    Published online on: May 14, 2026
       https://doi.org/10.3892/wasj.2026.475
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Abstract

The present systematic review and meta‑analysis aimed to evaluate the efficacy of mesenchymal stromal cells (MSCs) and MSC‑derived exosomes administered in the acute phase after traumatic brain injury (TBI), comparing neurological, histopathological and biochemical outcomes in pre‑clinical models. For this purpose, pre‑clinical studies involving MSCs or MSC‑derived exosomes administered to animal models of TBI were reviewed. The present study analyzed functional outcomes, lesion volume and cognitive recovery. Meta‑analytic techniques (RevMan Web) were used to calculate effect sizes for each outcome. A total of 46 studies were included with 1,558 animals for analysis. Both MSC‑based therapies and MSC‑derived exosomes significantly improved neurological function [pooled mean difference (MD), ‑2.09; 95% confidence interval (CI), ‑3.06 to ‑1.13; P<0.0001], cognitive performance (pooled MD, ‑16.72; 95% CI, ‑22.87 to ‑10.58; P<0.00001) and reduced lesion volume (pooled MD, ‑0.15; 95% CI, ‑0.16 to ‑0.14; P<0.00001). Subgroup analyses revealed that MSC‑derived exosomes, particularly intravenously administered, had the largest effects on cognitive recovery and lesion volume reduction. High heterogeneity (I²=100%) was observed due to variations in study designs, intervention types and delivery routes. On the whole, as demonstrated herein, MSC‑based therapies and MSC‑derived exosomes demonstrate significant neuroprotective effects in TBI, with intravenous MSC‑derived exosomes exhibiting the most promising results. These findings highlight the role of paracrine mechanisms in MSC‑mediated neuroprotection and support further investigations into cell‑free therapies for the treatment of TBI.
View Figures

Figure 1

Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of the
study selection process for the present systematic review.

Figure 2

Characteristics of the 46 preclinical
studies, with (A) MSC therapy vs. cell-free therapy; and (B)
injection route from all studies. MCS, mesenchymal stem cell; IN,
intranasally; IR, intra-retrobulbar; IP, intraperitoneal; IA,
intra-arterial; IV, intravenous; ICV, intracerebroventricular.

Figure 3

Risk of bias assessment with SYRCLE
of (A) from all MSC and MSC-derived cell-free therapy studies; (B)
percentage of high risk (red), unclear risk (yellow), low risk
(green). MCS, mesenchymal stem cell.

Figure 4

Funnel plots for all groups for (A)
the modified neurological severity score, (B) Morris water maze
test, and (C) lesion volume. MD, mean difference.

Figure 5

Forest plots demonstrating mean
effect size and 95% CI values of mNSS for (A) all routes from MSC
and cell-free groups; (B) MSC groups; (C) MSC ICV route groups, (D)
MSC IV route groups, (E) cell-free groups, (F) cell-free ICV route
groups, and (G) cell-free IV route groups. CI, confidence interval;
mNSS, modified neurological severity score; MCS, mesenchymal stem
cell; ICV, intracerebroventricular; IV, intravenous.

Figure 6

Forest plots demonstrating mean
effect size and 95% CI values of MWM for (A) all routes from MSC
and cell-free groups; (B) MSC groups; (C) MSC ICV route groups, (D)
MSC IV route groups, (E) cell-free groups, and (F) cell-free IV
route groups. CI, confidence interval; MWM, Morris water maze test;
MCS, mesenchymal stem cell; ICV, intracerebroventricular; IV,
intravenous.

Figure 7

Forest plots demonstrating mean
effect size and 95% CI values of lesion volume for (A) all routes
from MSC and cell-free groups; (B) MSC groups, (C) MSC ICV route
groups, (D) MSC IV route groups, (E) cell-free groups, and (F)
cell-free IV route groups. CI, confidence interval; MCS,
mesenchymal stem cell; ICV, intracerebroventricular; IV,
intravenous.

Figure 8

Illustration of the key findings of
the present study demonstrating different administration routes of
MSCs and exosomes, which affect: (A) Functional outcomes (mNSS),
(B) cognitive outcomes, and (C) structural outcomes (lesion volume)
in rodent models of traumatic brain injury. MCS, mesenchymal stem
cell; mNSS, modified neurological severity score; MWM, Morris water
maze test.
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Copy and paste a formatted citation
Spandidos Publications style
Aprianto DR, Putra A, Chodidjah and Sumarawati T: Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis. World Acad Sci J 8: 60, 2026.
APA
Aprianto, D.R., Putra, A., Chodidjah, , & Sumarawati, T. (2026). Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis. World Academy of Sciences Journal, 8, 60. https://doi.org/10.3892/wasj.2026.475
MLA
Aprianto, D. R., Putra, A., Chodidjah, , Sumarawati, T."Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis". World Academy of Sciences Journal 8.4 (2026): 60.
Chicago
Aprianto, D. R., Putra, A., Chodidjah, , Sumarawati, T."Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis". World Academy of Sciences Journal 8, no. 4 (2026): 60. https://doi.org/10.3892/wasj.2026.475
Copy and paste a formatted citation
x
Spandidos Publications style
Aprianto DR, Putra A, Chodidjah and Sumarawati T: Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis. World Acad Sci J 8: 60, 2026.
APA
Aprianto, D.R., Putra, A., Chodidjah, , & Sumarawati, T. (2026). Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis. World Academy of Sciences Journal, 8, 60. https://doi.org/10.3892/wasj.2026.475
MLA
Aprianto, D. R., Putra, A., Chodidjah, , Sumarawati, T."Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis". World Academy of Sciences Journal 8.4 (2026): 60.
Chicago
Aprianto, D. R., Putra, A., Chodidjah, , Sumarawati, T."Mesenchymal stromal cells and their exosomes as acute therapeutic interventions for traumatic brain injury in pre‑clinical studies: A systematic review and meta‑analysis". World Academy of Sciences Journal 8, no. 4 (2026): 60. https://doi.org/10.3892/wasj.2026.475
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