Yan Pan
Youting Xu- Department of Blood Transfusion, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou, Zhejiang, China
Background: Sepsis-induced liver injury (SILI) is critical in the progression of high morbidity and mortality associated with sepsis which ends in hepatic dysfunction and multi-organ failure. Mesenchymal stem cell–derived small extracellular vesicles (MSC-sEVs) are valued for their anti-inflammatory and regenerative potential as favorable strategy. The present systematic review and meta-analysis aimed to assess the effect of MSC- sEVs in rodent models with SILI.
Methods: A comprehensive systematic search was carried out in the PubMed, Web of Science, Embase, Scopus, and the Cochrane Library through April 2025. All published studies in relation to the effect of MSC- sEVs in rodent models were included. Pooled standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for study outcomes.
Results: Ten studies were included in the present study. MSC- sEVs significantly reduced ALT (SMD = −2.49, 95% CI: 3.37, −1.62), AST (SMD = −1.97, 95% CI: 3.32, −0.62), reduced pro-inflammatory cytokines (TNF-α: SMD = −5.23, 95% CI: 7.05, −3.41; IL-6: SMD = −5.00, 95% CI: 7.36, −2.64), and increased survival (OR = 6.11, 95% CI: 2.20–16.98; P = 0.001). No significant effects were observed for IL-10 (SMD = −3.39, 95% CI: 9.47, 2.69) or NLR (SMD = −0.65, 95% CI: 1.75, 0.45). Subgroup analyses illustrated that overall efficacy of treatment may vary dependent to source of sEVs, route of administration, and induction methods.
Conclusion: MSC- sEVs is able to improve liver function, inflammation, and survival rate in rodent sepsis model. These findings suggest that MSC- sEVs could be considered as therapeutic strategy for sepsis. These findings not only quantify the effect size of MSC- sEVs but also provide methodological insights for preclinical studies and guide future translational research.
1 Introduction
Sepsis is characterized with host immune responses to infection contributing to systemic inflammation (Mehdi et al., 2025; Jacob et al., 2025). Its high morbidity and mortality worldwide pose a major challenge to global public health (Prest et al., 2022; Bauer et al., 2020). The liver serves as a key organ in the pathogenesis of sepsis (Yan et al., 2014; Beyer et al., 2022). Sepsis-associated liver injury (SILI) has been associated with liver dysfunction and increased risk of multiple organ dysfunction syndrome (MODS) (Strnad et al., 2017; Kobashi et al., 2013; Chen et al., 2024; Guo et al., 2025).
Evidence indicates that mesenchymal stem cells (MSCs) could be considered as a research hotspot in regenerative medicine. Several beneficial properties have been attributed to the MSCs such as immunomodulatory properties, regenerative functions (Via et al., 2012; Sart et al., 2014; Naji et al., 2019; Marino et al., 2019). In this context, small extracellular vesicles (sEVs) have been known as key mediators which transfer transferring bioactive molecules (Park et al., 2019; Hashemian et al., 2020). Likewise, Yue et al. and Feng et al. deomstrated that MSC-derived sEVs are potent enough to improve renal ischemia-reperfusion injury (Yue et al., 2022; Feng et al., 2024). Similarly, improve lung injury was shown by MSC-derived sEVs (Cui et al., 2024; Li et al., 2019). This favorable features are possible through several mechanisms such as inhibition of NF-κB signaling pathway (Sun et al., 2021), regulation of macrophage polarization (Liu et al., 2020), and promoted proliferation (Tan et al., 2014).
Taken together, these findings suggest that a significant gap remains in understanding the protective effects of MSC-derived sEVs in sepsis-induced liver injury models. In this regard, discrepancies in animal models, cell sources, sEV isolation methods, and dosage have led to inconsistent findings across studies. However, this systematic review and meta-analysis have been conducted based on the SYRCLE risk-of-bias tool to illustrate the efficacy of MSC-derived sEVs in treating SILI.
2 Methods
2.1 Ethic statement
The study protocol has been registered (CRD420251184561) in the International Prospective Register of Systematic Reviews (PROSPERO) database. Also, this study is conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and adheres to the Meta-analysis of Observational Studies in Epidemiology (MOOSE).
2.2 Eligibility criteria
All inclusion criteria of the study is performed based on the PICOS as follow: (P: population) rodent models of sepsis; (I: intervention) sEVs from various types of mesenchymal stem cells (C: comparison) studies with comparison groups, (O: outcomes) such as: liver function tests (ALT, AST), inflammatory markers (TNF-α, IL-6, IL-10), survival, and the neutrophil-to-lymphocyte ratio (NLR) and (S: study design) randomized control study and MSC-sEVs treated group vs. sepsis control group.
2.3 Search strategy
A comprehensive systematic search was performed in PubMed, Web of Science, Embase, Scopus, and Cochrane Library to identify studies that met our predefined criteria up to April 2025. There was no limitation in the publication date or language. Search strategy and study selection process have been provided in Supplementary Table S1 and Figure 1, respectively.
Figure 1. Flowchart of study selection process.
2.4 Data extraction
Screening process and data extraction have been done by two investigators independently. Any discrepancies were resolved through discussion, and when consensus could not be achieved, a third researcher was consulted to make the final decision. Basic characteristics of included studies such as study design, sample size, animal model, exosome characteristics, administration route and treatment duration, and mean and SD for included outcomes.
2.5 Statistical analysis
The data analysis of this study was conducted using RevMan 5.4 and STATA 18.0 software. Subgroup analyses were based on the MSC-Exos source (human umbilical cord mesenchymal stem cells (hUC-MSCs), human umbilical cord Wharton’s gel mesenchymal stem cells (WJ-MSCs), others (MSC-derived sEVs obtained from alternative tissue sources, such as bone marrow, adipose tissue)), administration route (tail vein injection and intraperitoneal injection), and induction method (CLP, LPS). All outcomes are presented with pooled SMD and 95% confidence interval (CI). The degree of heterogeneity was evaluated using the I2 statistic. Publication bias was evaluated using the Egger regression model and visualized using a funnel plot.
2.6 Risk of bias and quality assessment
Two independent reviewers evaluated the risk of bias using Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool and the National Institutes of Health (NIH) guidelines.
3 Result
3.1 Study characteristics
A total of 927 articles were identified through the literature search, of which 10 met the inclusion criteria1 (Chang et al., 2021; Eshghi et al., 2022; Cai et al., 2023; Rahnama et al., 2023; Ahangari et al., 2024; Pei et al., 2024; Shahi et al., 2024; Yuan et al., 2023; Chang et al., 2018, Song et al., 2017). Basic characteristics of included studies are provided in the Table 1.
Table 1. Characteristics of the included studies.
3.2 Bias and quality assessment
Table 2 presents the bias risk assessment for each study across various domains. The following domains including: sequence generation, baseline characteristics, allocation concealment, randomization of interventions, and blinding of outcome assessment were scored as lower risk of bias. However, incomplete outcome data, selective reporting, and other potential sources of bias domains were rated as unclear risk of bias.
Table 2. Risk assessment of bias in mesenchymal stem cell exosome therapy in animal models of sepsis.
3.3 Effects of MSC-Exos on septic related injury model
ALT and AST biomarkers have been known as a key indicator in the sepsis-induced hepatocellular injuries. Pooled effect of eight studies involving 73 mice demonstrated that MSC-sEVs significantly decreased ALT level (SMD: −2.49, 95% CI: −3.37, −1.62, P < 0.001; I2 = 40.2%; P = 0.111) (Figure 2A) and AST (SMD: −1.97, 95% CI: −3.32, −0.62, P = 0.004; I2 = 78.3%; P < 0.001) level (Figure 2B). These findings indicate that MSC-sEVs treatment may alleviate hepatocellular damage in rodent model. Subgroup analyses demonstrated both sources of MSC-sEVs (hUC-MSCs, or WJ-MSCs), both administration route (tail vein injection and intraperitoneal injection), and induction method (CLP, LPS) are able to decrease ALT level in mice model (P < 0.05). While, just hUC, LPS, and caudal vein were accompanied with significant decrease in the AST level (Table 3).
Figure 2. (A) Forest plot for the impact of MSC-sEVs on ALT in sepsis models. (B) Forest plot for the impact of MSC-sEVs on AST in sepsis models.
Table 3. Subgroup analyses for the comparison between outcomes.
Moreover, sepsis is characterized by elevated inflammatory responses. Likewise, TNF-α and IL-6 are pro-inflammatory cytokines are involved in the systemic inflammation in SILIs. Combined effect of eleven studies (111 animal) investigating the effect of MSC-sEVs on TNF-α showed that MSC-sEVs are potent to reduce the TNF-α level compared to sepsis induced animals with no interventions (SMD: −5.23, 95% CI: −7.05, −3.41, P < 0.001; I2 = 78.7%; P < 0.001) (Figure 3A). Subgroup analysis was performed based on the source of sEVs, administration route and induction method for inflammatory markers. Likewise, all subgroups of both administration route (tail vein injection and intraperitoneal injection), and induction method (CLP, LPS) showed significant reduction in the TNF-α level. A significant reduction was also observed in the hUC subgroup (Table 3). Similarly, it had beneficial effect on the IL-6 in the pooled five studies (SMD: −5.00, 95% CI: −7.36, −2.64, P < 0.001; I2 = 69.0%; P = 0.012) (Figure 3B.). Subgroup analysis revealed that all subgroups, regardless of the sEV source, administration route, or induction method, were associated with a significant decrease in IL-6 levels (Table 3). While, MSC-sEVs failed to exert favorable effects on the IL-10 (SMD: −3.39, 95% CI: −9.47, 2.69, P = 0.274; I2 = 93.7%; P < 0.001) (Figure 3C.) and NLR (SMD: −0.65, 95% CI: −1.75, 0.45, P = 0.248; I2 = 51.9%; P = 0.110) value significantly (Figure 3D).
Figure 3. (A) Forest plot for the impact of MSC-Exos on TNF-α in sepsis models. (B) Forest plot for the impact of MSC-Exos on IL-6 in sepsis models. (C) Forest plot for the impact of MSC-Exos on IL-10 in sepsis models. (D) Forest plot for the impact of MSC-Exos on NLR in sepsis models.
Furthermore, survival rate serves as a comprehensive indicator of treatment efficacy in SILIs, as, it is accompanied with improved diseases condition including functional efficacy and inflammatory state. Elevated survival rate could be translated to multiorgan failure and hepatocellular dysfunction which has been triggered by sepsis ten studies encompassing 220 animals with sepsis and treated with MSC- sEVs illustrated that MSC- sEVs could increase survival rate significantly (OR: 6.11, 95% CI: 2.20, 16.98, P = 0.001; I2 = 44.9%; P = 0.060) (Figure 4). In this regard, subgroup analysis revealed that, hUC was no associated with increased OR of survival rate in the rodent model, while alternative tissue sources, such as bone marrow, adipose tissue were associated with elevated OR (Table 3). Also, both intraperitoneal and caudal vein route and both induction methods such as CLP or LPS showed increased OR in pooled studies (Table 3).
Figure 4. Forest plot for the impact of MSC-Exos on survival rate in sepsis models.
3.4 Sensitivity analysis and publication bias
The sensitivity analyses demonstrated that leave-one-out approach did not affect the overall pooled results for all study outcomes including ALT, AST, TNF-α, IL-6, IL-10, and survival rate. Exclusion of Eshghi et al.’s study resulted in a significant change in the pooled effect on NLR (Supplementary Figures S2–S7).
Publication bias using Egger’s tests along with funnel plots was assessed. There was evidence of publication bias regarding ALT (egger’s test = 0.001), AST (egger’s test = <0.001), TNF-α (egger’s test = <0.001), survival rate (egger’s test = 0.012). However, the trim-and-fill analysis indicated no significant adjustments. In contrast, for IL-10 (egger’s test = 0.060), and NLR (egger’s test = 0.625) the funnel plots were symmetrical (Supplementary Figures S8–S11).
4 Discussion
The present systematic review and meta-analysis provide a comprehensive effect of MSC-sEVs in rodent models of sepsis-induced liver injury. The findings demonstrated that MSC- sEVs treatment is able to promote liver function (ALT, AST), alleviate the systemic inflammation (TNF-α, IL-6) and increase survival rates in rodent model.
It has been revealed that MSC-sEVs treatment is potent enough to improved liver function, as evidenced by the reduction in ALT and AST levels. Promoted sepsis-induced inflammation in hepatocellulars represent liver injury. Likewise, it seems that MSC-sEV administration may have protective effects against the liver function. Evidence suggests that protective effects of may be triggered by suppressed NF-κB and TLR4 signaling pathways (Peng et al., 2023).
Moreover, it is able to alleviate inflammatory state by decreasing TNF-α and IL-6, and In addition, subgroup analyses provided insightful effects of MSC-sEVs across source of sEVs, adminstration route and induction methods. It sems that MSC- sEVs may have therapeutic effects to modulate inflammation and promote tissue repair. These anti-inflammatory properties may be mediated through the following mechanisms: the modulation of inflammatory signaling pathways (suppression of NF-κB and TLR4 signaling) and attenuation of liver injury (Jin et al., 2025), the promotion of tissue repair via bioactive molecules that enhance hepatocyte proliferation and differentiation (Aguiar Koga et al., 2023), and the activation of protective intracellular signaling cascades that support cell survival and functional recovery (Li et al., 2024).
A moderate to high degree of heterogeneity was observed among the included studies for all study outcomes. Accordingly, subgroup analysis was performed to investigate the impact of factors such as modeling methods, administration routes, and exosome sources on therapeutic efficacy. The results indicated that various source of sEVs (hUC or WJ or other), different modeling methods (CLP or. LPS) and administration routes (intraperitoneal injection or tail vein injection) had distinct effects on specific indicators.
ALT was decreased irrespective of MSC-sEVs source, injection route, or induction method. While, significant improvement in AST was observed in the hUC, caudal vein, and LPS method. Additionally, hUC MSC-derived sEVs (hUC-MSCs) appeared more effective than other sources with both injection route in modulation of inflammatory markers.
Although this study provides a comprehensive evaluation of MSC-sEVs therapy in sepsis-induced liver injury models, several limitations remain. First, smaller sample size affects statistical power and limits the generalizability of the findings. Second, there is a major gap in relation to long-term studies. Third, it is better to interpret the results with caution regarding publication bias in term of ALT, AST, TNF-α, I_6, and survival rate. Taken together, these findings warrant further studies with larger sample sizes and investigations of dose–response relationships.
5 Conclusion
This study highlights the significant therapeutic potential of MSCs-derived sEVs in the sepsis-induced liver injury in rodent model. Moreover, it has been shown that MSCs-derived sEVs is able to improve liver function, attenuate inflammatory responses, and enhance survival rates. Furthermore, attention should be given to the source of sEVs, administration routes, and induction methods, as these factors may influence therapeutic efficacy.
Data availability statement
The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.
Author contributions
YP: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. YX: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. TS: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. JH: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing. XL: Conceptualization, Investigation, Methodology, Software, Validation, Writing – original draft, Writing – review and editing. HC: Project administration, Software, Supervision, Writing – original draft, Writing – review and editing.
Funding
The authors declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Generative AI was used in the creation of this manuscript.
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Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2025.1707784/full#supplementary-material
References
Aguiar Koga, B. A., Fernandes, L. A., Fratini, P., Sogayar, M. C., and Carreira, A. C. O. (2023). Role of MSC-derived small extracellular vesicles in tissue repair and regeneration. Front. Cell Developmental Biology 10, 1047094. doi:10.3389/fcell.2022.1047094
Ahangari, F., Soudi, S., Khaligh, S. G., Mirsanei, Z., Soufihasanabad, S., Asl, P. E., et al. (2024). Combinational therapy of mesenchymal stem cell-derived extracellular vesicles and azithromycin improves clinical and histopathological recovery in CLP sepsis model. Int. Immunopharmacol. 139, 112732. doi:10.1016/j.intimp.2024.112732
Bauer, M., Gerlach, H., Vogelmann, T., Preissing, F., Stiefel, J., and AdAM, D. (2020). Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019—results from a systematic review and meta-analysis. Crit. Care 24, 239. doi:10.1186/s13054-020-02950-2
Beyer, D., Hoff, J., Sommerfeld, O., Zipprich, A., Gaßler, N., and Press, A. T. (2022). The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation. Mol. Med. 28, 84. doi:10.1186/s10020-022-00510-8
Cai, J., Tang, D., Hao, X., Liu, E., Li, W., and Shi, J. (2023). Mesenchymal stem cell-derived exosome alleviates sepsis-associated acute liver injury by suppressing MALAT1 through microRNA-26a-5p: an innovative immunopharmacological intervention and therapeutic approach for sepsis. Front. Immunol. 14, 1157793. doi:10.3389/fimmu.2023.1157793
Chang, C.-L., Sung, P.-H., Chen, K.-H., Shao, P.-L., Yang, C.-C., Cheng, B.-C., et al. (2018). Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am. Journal Translational Research 10, 1053–1070.
Chang, C. Y., Chen, K. Y., Shih, H. J., Chiang, M., Huang, I. T., Huang, Y. H., et al. (2021). Let-7i-5p mediates the therapeutic effects of exosomes from human placenta choriodecidual membrane-derived mesenchymal stem cells on mitigating endotoxin-induced mortality and liver injury in high-fat diet-induced Obese mice. Pharm. (Basel) 15, 36. doi:10.3390/ph15010036
Chen, J.-W., Liu, C.-Y., Li, S., Wu, S.-W., Cai, C., and Lu, M.-Q. (2024). Sepsis-associated liver injury: mechanisms and potential therapeutic targets. World J. Gastroenterology 30, 4518–4522. doi:10.3748/wjg.v30.i42.4518
Cui, E., Lv, L., Wang, B., Li, L., Lu, H., Hua, F., et al. (2024). Umbilical cord MSC-derived exosomes improve alveolar macrophage function and reduce LPS-induced acute lung injury. J. Cell. Biochem. 125, e30519. doi:10.1002/jcb.30519
Eshghi, F., Tahmasebi, S., Alimohammadi, M., Soudi, S., Khaligh, S. G., Khosrojerdi, A., et al. (2022). Study of immunomodulatory effects of mesenchymal stem cell-derived exosomes in a mouse model of LPS induced systemic inflammation. Life Sci. 310, 120938. doi:10.1016/j.lfs.2022.120938
Feng, Y., Bao, X., Zhao, J., Kang, L., Sun, X., and Xu, B. (2024). MSC-derived exosomes mitigate myocardial ischemia/reperfusion injury by reducing neutrophil infiltration and the formation of neutrophil extracellular traps. Int. J. Nanomedicine 19, 2071–2090. doi:10.2147/IJN.S436925
Guo, Y., Guo, W., Chen, H., Sun, J., and Yin, Y. (2025). Mechanisms of sepsis-induced acute liver injury: a comprehensive review. Front. Cell. Infect. Microbiol. 15, 1504223. doi:10.3389/fcimb.2025.1504223
Hashemian, S. M., Pourhanifeh, M. H., Fadaei, S., Velayati, A. A., Mirzaei, H., and Hamblin, M. R. (2020). Non-coding RNAs and exosomes: their role in the pathogenesis of sepsis. Mol. Therapy Nucleic Acids 21, 51–74. doi:10.1016/j.omtn.2020.05.012
Jacob, S., Jacob, S. A., and ThoppiL, J. (2025). Targeting sepsis through inflammation and oxidative metabolism. World J. Crit. Care Med. 14, 101499. doi:10.5492/wjccm.v14.i1.101499
Jin, C., Wu, P., Wu, W., Chen, W., Liu, W., Zhu, Y., et al. (2025). Therapeutic role of hucMSC-sEV-enriched miR-13896 in cisplatin-induced acute kidney injury through M2 macrophage polarization. Cell Biol. Toxicol. 41, 50. doi:10.1007/s10565-025-09998-2
Kobashi, H., Toshimori, J., and Yamamoto, K. (2013). Sepsis-associated liver injury: incidence, classification and the clinical significance. Hepatology Res. 43, 255–266. doi:10.1111/j.1872-034X.2012.01069.x
Li, Q.-C., Liang, Y., and Su, Z.-B. (2019). Prophylactic treatment with MSC-derived exosomes attenuates traumatic acute lung injury in rats. Am. J. Physiology-Lung Cell. Mol. Physiology 316, L1107–L1117. doi:10.1152/ajplung.00391.2018
Li, D., Li, D., Wang, Z., Li, J., Shahzad, K. A., Wang, Y., et al. (2024). Signaling pathways activated and regulated by stem cell-derived exosome therapy. Cell & Biosci. 14, 105. doi:10.1186/s13578-024-01277-7
Liu, W., Yu, M., Xie, D., Wang, L., Ye, C., Zhu, Q., et al. (2020). Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway. Stem Cell Research & Therapy 11, 259. doi:10.1186/s13287-020-01756-x
Marino, L., Castaldi, M. A., Rosamilio, R., Ragni, E., Vitolo, R., Fulgione, C., et al. (2019). Mesenchymal stem cells from the Wharton’s jelly of the human umbilical cord: biological properties and therapeutic potential. Int. J. Stem Cells 12, 218–226. doi:10.15283/ijsc18034
Mehdi, S. F., Qureshi, M. H., Pervaiz, S., Kumari, K., Saji, E., Shah, M., et al. (2025). Endocrine and metabolic alterations in response to systemic inflammation and sepsis: a review article. Mol. Med. 31, 16. doi:10.1186/s10020-025-01074-z
Naji, A., Eitoku, M., Favier, B., Deschaseaux, F., Rouas-Freiss, N., and Suganuma, N. (2019). Biological functions of mesenchymal stem cells and clinical implications. Cell. Molecular Life Sciences 76, 3323–3348. doi:10.1007/s00018-019-03125-1
Park, E. J., Appiah, M. G., Myint, P. K., Gaowa, A., KawamotO, E., and Shimaoka, M. (2019). Exosomes in sepsis and inflammatory tissue injury. Curr. Pharm. Des. 25, 4486–4495. doi:10.2174/1381612825666191116125525
Pei, L., Li, R., Wang, X., Xu, D., Gong, F., Chen, W., et al. (2024). MSCs-derived extracellular vesicles alleviate sepsis-associated liver dysfunction by inhibiting macrophage glycolysis-mediated inflammatory response. Int. Immunopharmacol. 128, 111575. doi:10.1016/j.intimp.2024.111575
Peng, Y. Q., Deng, X. H., Xu, Z. B., Wu, Z. C., and Fu, Q. L. (2023). Mesenchymal stromal cells and their small extracellular vesicles in allergic diseases: from immunomodulation to therapy. Eur. J. Immunol. 53, 2149510. doi:10.1002/eji.202149510
Prest, J., Nguyen, T., Rajah, T., Prest, A. B., Sathananthan, M., and Jeganathan, N. (2022). Sepsis-related mortality rates and trends based on site of infection. Crit. Care Explor. 4, e0775. doi:10.1097/CCE.0000000000000775
Rahnama, M. A., Zomorrod, M. S., Abroun, S., and Atashi, A. (2023). The effect of exosomes derived from unrestricted somatic stem cells on Murine model of sepsis. Cells Tissues Organs 212, 164–175. doi:10.1159/000520639
Sart, S., Tsai, A.-C., Li, Y., and Ma, T. (2014). Three-dimensional aggregates of mesenchymal stem cells: cellular mechanisms, biological properties, and applications. Tissue Eng. Part B Rev. 20, 365–380. doi:10.1089/ten.TEB.2013.0537
Shahi, E., Khosrojerdi, A., Soudi, S., and Hosseini, A. Z. (2024). Mesenchymal stem cell-conditioned medium prevents inflammation-induced liver and lung damage in septic mice. Int. Immunopharmacol. 137, 112407. doi:10.1016/j.intimp.2024.112407
Song, Y., Dou, H., Li, X., Zhao, X., Li, Y., and Hou, Y. (2017). Exosomal miR-146a contributes to the En-hanced therapeutic efficacy of IL-1β-Primed mesenchymal stem cells against sepsis.
Strnad, P., Tacke, F., Koch, A., and Trautwein, C. (2017). Liver - guardian, modifier and target of sepsis. Nat. Rev. Gastroenterol. Hepatol. 14, 55–66. doi:10.1038/nrgastro.2016.168
Sun, J., Sun, X., Chen, J., Liao, X., He, Y., Wang, J., et al. (2021). microRNA-27b shuttled by mesenchymal stem cell-derived exosomes prevents sepsis by targeting JMJD3 and downregulating NF-κB signaling pathway. Stem Cell Res. & Ther. 12, 14. doi:10.1186/s13287-020-02068-w
Tan, C. Y., Lai, R. C., Wong, W., Dan, Y. Y., Lim, S.-K., and Ho, H. K. (2014). Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Research & Therapy 5, 76. doi:10.1186/scrt465
Via, A. G., Frizziero, A., and Oliva, F. (2012). Biological properties of mesenchymal stem cells from different sources. Muscles, Ligaments Tendons Journal 2, 154–162.
Yan, J., Li, S., and Li, S. (2014). The role of the liver in sepsis. Int. Reviews Immunology 33, 498–510. doi:10.3109/08830185.2014.889129
Yuan, H., Yu, J., Liu, C., Zhao, H., Xue, J., Liu, J., et al. (2023). LncRNA KCNQ10T1 shuttled by bone marrow mesenchymal stem cell-derived exosome inhibits sepsis via regulation of miR-154-3p/RNF19A axis. Cell Tissue Res. 393, 507–521. doi:10.1007/s00441-023-03784-4
Keywords: mesenchymal stem cell-derived small extracellular vesicles, sepsis, liver injury, animal models, meta-analysis
Citation: Pan Y, Xu Y, Shui T, Hong J, Lu X and Chen H (2025) Mesenchymal stem cell–derived small extracellular vesicles (sEVs) as a therapy for sepsis-related liver injury: evidence from a systematic review and meta-analysis. Front. Pharmacol. 16:1707784. doi: 10.3389/fphar.2025.1707784
Received: 17 September 2025; Accepted: 17 November 2025;
Published: 27 November 2025.
Edited by:
Lara Campana, Resolution Therapeutics Ltd, United KingdomReviewed by:
Joana Paiva Miranda, University of Lisbon, PortugalNico Lachmann, Hannover Medical School, Germany
Copyright © 2025 Pan, Xu, Shui, Hong, Lu and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yan Pan, MTg3NTg5OTUxMDZAMTYzLmNvbQ==