Dual-Target hUCMSCs/EVs therapy for autism spectrum disorder: remodeling gut microbiota and modulating neuroimmune crosstalk in a valproic Acid-Induced C57BL/6 mice model
Open accessAbstract
INTRODUCTION: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Accumulating evidence implicates neuroimmune dysregulation and gut microbiota dysbiosis in its pathogenesis, yet effective therapies targeting these mechanisms are lacking. This study investigated the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUCMSCs) and their extracellular vesicles (EVs), both alone and in combination, in a valproic acid (VPA)-induced ASD mouse model. METHODS: VPA-exposed C57BL/6 mice were randomized into five groups: control, VPA, hUCMSCs alone, EVs alone, and hUCMSCs + EVs combination. Behavioral tests, biochemical analyses, 16 S rRNA sequencing, immunofluorescence, and transmission electron microscopy (TEM) were performed RESULTS: While both hUCMSCs and EVs alone showed some beneficial effects on certain ASD-like symptoms, each exhibited limited efficacy in achieving comprehensive remediation. In contrast, the combined hUCMSCs + EVs therapy yielded the most robust improvements across multiple domains, including social interaction and repetitive behaviors. Furthermore, the combination therapy synergistically normalized neuroinflammatory cytokine levels and oxidative stress, restored synaptic and mitochondrial ultrastructure in key brain regions, and promoted gut microbiota homeostasis by enriching beneficial bacteria such as Lactobacillus and reducing pathogens. DISCUSSION: These results highlight that although individual treatments offer partial relief, only the combined strategy fully restores neuroimmune-microbiota homeostasis, demonstrating a complementary and synergistic therapeutic effect. This study establishes a novel dual-target approach leveraging systemic hUCMSCs and CNS-targeted EVs, providing a promising translational strategy for ASD through orchestrated regulation of the neuro-immune-microbiota axis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Riordan et al. is included as a normal part of the scientific literature in articles contributing to meta-analyses and reviews or aiding interpretation of newly reported data.
“Instead, this retracted article is included as a normal part of the scientific literature in these articles, contributing to metaanalyses and reviews of the current state of stem cell science19,20 or aiding the interpretation of newly reported data.21,22”
From Why retracted articles can have an influential afterlife—and what to do about it (2026) · cites this paper as [22]
The References section (reference 40; page unavailable) lists Riordan et al. (2019) alongside other stem-cell research, supporting that Wu et al. includes it as part of the scientific literature. The passages found do not show Wu et al. using Riordan et al. to interpret its newly reported data, and this source is not itself a meta-analysis or review. The copy also does not address the article’s retraction status. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Riordan, N. H., Hincapié, M. L., Morales, I., Fernández, G., Allen, N., Leu, C., Madrigal, M., Rodríguez, J. P., & Novarro, N. (2019) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0010 · Cited by 62 · see citing works
RetractedThe ARRIVE guidelines 2.0: updated guidelines for reporting animal research
du Sert, N. P., Hurst, V., Ahluwalia, A., Alam, S., Avey, M. T., Baker, M., Browne, W. J., Clark, A., Cuthill, I. C., Dirnagl, U., et al. (2020) · The Journal of Physiology · doi:10.1113/jp280389 · Cited by 623 · see citing works
Perets, N., Hertz, S., London, M., & Offen, D. (2018) · Molecular Autism · doi:10.1186/s13229-018-0240-6 · Cited by 172 · see citing works
Kodali, M., Madhu, L. N., Reger, R. L., Milutinovic, B. S., Upadhya, R., Gonzalez, J. J., Attaluri, S., Shuai, B., Gitaí, D. L. G., Rao, S., et al. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.11.014 · Cited by 108 · see citing works
Hacohen, M., Stolar, O. E., Berkovitch, M., Elkana, O., Kohn, E., Hazan, A., Heyman, E., Sobol, Y., Waissengreen, D., Gal, E., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02104-8 · Cited by 80 · see citing works
Tiwari, A., Khera, R., Rahi, S., Mehan, S., Makeen, H. A., Khormi, Y. H., Rehman, M. U., & Khan, A. (2021) · Brain Sciences · doi:10.3390/brainsci11030288 · Cited by 73 · see citing works
Mehan, S., Rahi, S., Tiwari, A., Kapoor, T., Rajdev, K., Sharma, R., Khera, H., Kosey, S., Kukkar, U., & Dudi, R. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.270316 · Cited by 72 · see citing works
Sun, J. M., Dawson, G., Franz, L., Howard, J., McLaughlin, C. A., Kistler, B., Waters‐Pick, B., Meadows, N., Troy, J. D., & Kurtzberg, J. (2020) · Stem Cells Translational Medicine · doi:10.1002/sctm.19-0434 · Cited by 67 · see citing works
Perets, N., Oron, O., Herman, S., Elliott, E., & Offen, D. (2020) · Molecular Autism · doi:10.1186/s13229-020-00366-x · Cited by 64 · see citing works
Alteration of Gut Microbiota: New Strategy for Treating Autism Spectrum Disorder
Liu, J., Gao, Z., Chuanqi, L., Liu, T., Gao, J., Cai, Y., & Fan, X. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.792490 · Cited by 62 · see citing works
Mesenchymal Stem Cell-Derived Exosomes for Treatment of Autism Spectrum Disorder
Liang, Y., Duan, L., Xu, X. G., Li, X., Liu, M., Chen, H., Lu, J., & Xia, J. (2020) · ACS Applied Bio Materials · doi:10.1021/acsabm.0c00831 · Cited by 61 · see citing works
Self-citationYin, F., Wang, W., & Jiang, W. (2019) · World Journal of Stem Cells · doi:10.4252/wjsc.v11.i8.548 · Cited by 57 · see citing works
Morgan, K. L., Estevez, A. O., Mueller, C. L., Cacho‐Valadez, B., Miranda‐Vizuete, A., Szewczyk, N. J., & Estevez, M. (2010) · Toxicological Sciences · doi:10.1093/toxsci/kfq273 · Cited by 56 · see citing works
Sun, Z., Gu, P., Xu, H., Zhao, W., Zhou, Y., Zhou, L., Zhang, Z., Wang, W., Han, R., Chai, X.-Q., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.808905 · Cited by 55 · see citing works
Biomarker-Guided Strategy for Treatment of Autism Spectrum Disorder (ASD)
Liu, H., Talalay, P., & Fahey, J. W. (2016) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527315666160413120414 · Cited by 54 · see citing works
Kumar, A., Mehan, S., Tiwari, A., Khan, Z., Gupta, G. D., Narula, A. S., & Samant, R. (2024) · Current Pharmaceutical Design · doi:10.2174/0113816128321466240816075041 · Cited by 52 · see citing works
He, Y., Yang, X. H., Zhang, Y., Shen, X., Xu, K., Lin, C., Tao, B., Li, K., Chen, M., Hu, Y., et al. (2019) · Biomaterials Science · doi:10.1039/c9bm01158g · Cited by 38 · see citing works
Self-citationNovau-Ferré, N., Papandreou, C., Rojo-Marticella, M., Canals, J., & Bulló, M. (2025) · Research in Developmental Disabilities · doi:10.1016/j.ridd.2025.105003 · Cited by 33 · see citing works
Romano, K., Shah, A., Schumacher, A., Zasowski, C., Zhang, T., Bradley-Ridout, G., Merriman, K., Parkinson, J., Szatmári, P., Campisi, S. C., et al. (2023) · Gut Microbiome · doi:10.1017/gmb.2023.16 · Cited by 24 · see citing works
Qin, Q., Fan, L., Zeng, X., Zheng, D., Wang, H., Li, M., Jiang, Y., Wang, H., Liu, H., Liang, S., et al. (2025) · Journal of Nanobiotechnology · doi:10.1186/s12951-025-03250-z · Cited by 24 · see citing works
Self-citationAlam, M., Yadav, R. K., Minj, E., Tiwari, A., & Mehan, S. (2020) · Current Molecular Pharmacology · doi:10.2174/1566524020666200427214356 · Cited by 21 · see citing works
Zhang, Y., Xu, T., Xie, J., Wu, H. J., Hu, W., & Yuan, X. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01617-7 · Cited by 20 · see citing works
Microbiota and Autism: A Review on Oral and Gut Microbiome Analysis Through 16S rRNA Sequencing
Anaclerio, F., Minelli, M., Antonucci, I., Gatta, V., & Stuppia, L. (2024) · Biomedicines · doi:10.3390/biomedicines12122686 · Cited by 20 · see citing works
Tiwari, A., Rahi, S., & Mehan, S. (2020) · Current Drug Targets · doi:10.2174/1389450121666201020155010 · Cited by 19 · see citing works
Hrnčiarová, J., Kubelková, K., Boštíková, V., Rychlı́k, I., Karasová, D., Babák, V., Datkova, M., Simackova, K., & Macela, A. (2024) · Nutrients · doi:10.3390/nu16131988 · Cited by 18 · see citing works
Yang, R., Ma, L., Peng, H., Zhai, Y., Zhou, G., Zhang, L., Zhuo, L., Wu, W., Guo, Y., Han, J., et al. (2025) · Theranostics · doi:10.7150/thno.103737 · Cited by 18 · see citing works
Rashaid, A. H. B., Alqhazo, M. T., Nusair, S. D., Adams, J. B., Bashtawi, M. A., & Al-Fawares, O. (2022) · Nutritional Neuroscience · doi:10.1080/1028415x.2022.2101976 · Cited by 17 · see citing works
Qin, Q., Shan, Z., Xing, L., Jiang, Y., Li, M., Fan, L., Zeng, X., Ma, X., Zheng, D., Wang, H., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05257-w · Cited by 17 · see citing works
Self-citationLu, Y., Huangfu, S., Ma, C., Ding, Y., Zhang, Y., Zhou, C., Liao, L., Li, M., You, J., Chen, Y., et al. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-04028-0 · Cited by 17 · see citing works
Jayathilaka, E. H. T. T., Edirisinghe, S. L., Oh, C., Nikapitiya, C., & Zoysa, M. D. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.108777 · Cited by 15 · see citing works
Sherawat, K., Mehan, S., Khan, Z., Tiwari, A., Gupta, G. D., & Narula, A. S. (2024) · Current Molecular Pharmacology · doi:10.2174/0118761429326799241121104310 · Cited by 15 · see citing works
Pasam, T., Padhy, H. P., & Dandekar, M. P. (2024) · Neurochemical Research · doi:10.1007/s11064-024-04251-4 · Cited by 14 · see citing works
Pan, Q., Guo, F., Chen, J., Huang, Y., Huang, Y., Xiao, Z., Xiao, Z., Wang, X., You, L., Yang, L., et al. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00716-8 · Cited by 14 · see citing works
Singla, R., Mishra, A., Joshi, R., Sarma, P., Kumar, R., Kaur, G., Sharma, A. R., Jain, A., Prakash, A., Bhatia, A., et al. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.09.003 · Cited by 13 · see citing works
Cheng, X., Wang, S., Li, Z., He, D., Wu, J., & Ding, W. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e20124 · Cited by 12 · see citing works
Pasam, T., & Dandekar, M. P. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1336537 · Cited by 12 · see citing works
Kamalmaz, N., Bacha, A. G. B., Alonazi, M. A., Albasher, G. I., Khayyat, A. I. A., & El-Ansary, A. K. (2023) · PeerJ · doi:10.7717/peerj.15488 · Cited by 11 · see citing works
Extracellular Vesicles in Neurological Disorders
Mazurskyy, A., & Howitt, J. A. (2021) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-3-030-67171-6_16 · Cited by 10 · see citing works
Yang, M., Chen, X., Zhang, M., Zhang, X., Xiao, D., Xu, H., & Lu, M. (2025) · Biological Research · doi:10.1186/s40659-024-00578-y · Cited by 10 · see citing works
Li, J., Lin, W., Yuan, C., Lingling, Z., Qianqian, J., Xu, A., & Yansong, G. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122330 · Cited by 9 · see citing works
Sharma, T., Mehan, S., Tiwari, A., Khan, Z., Gupta, G. D., & Narula, A. S. (2024) · Current Neurovascular Research · doi:10.2174/0115672026336440240822063430 · Cited by 9 · see citing works
Köhli, P., Otto, E., Jahn, D., Reisener, M., Appelt, J., Rahmani, A., Taheri, N., Keller, J., Pumberger, M., & Tsitsilonis, S. (2021) · Cells · doi:10.3390/cells10112955 · Cited by 9 · see citing works
Günaydın, M., Doğan, Ö., Günay, F., Uytun, M. Ç., Buyukceran, O. C., & Öztop, D. B. (2025) · Acta Neuropsychiatrica · doi:10.1017/neu.2025.10017 · Cited by 7 · see citing works
Sharma, R., Tiwari, A., Rahi, S., & Mehan, S. (2020) · Current Psychopharmacologye · doi:10.2174/1389203721999200820165117 · Cited by 6 · see citing works
Elsherif, R., Abdel-Hafez, A. M. M., Hussein, O. A., Sabry, D., Abdelzaher, L. A., & Bayoumy, A. A. (2025) · Journal of Molecular Histology · doi:10.1007/s10735-024-10335-w · Cited by 6 · see citing works
Kabataş, S., Çivelek, E., Savrunlu, E. C., Karaaslan, U., Yıldız, Ö., & Karaöz, E. (2024) · World Journal of Methodology · doi:10.5662/wjm.v15.i1.95857 · Cited by 5 · see citing works
Longitudinal change in symptom severity in children with ASD : Results from the ELENA cohort
Dellapiazza, F., Rattaz, C., Michelon, C., Peyre, H., Picot, M., & Baghdadli, A. (2024) · Autism Research · doi:10.1002/aur.3242 · Cited by 5 · see citing works
Ávila‐Gálvez, M. Á., Romo‐Vaquero, M., Mazarío‐Gárgoles, C., Tomé‐Carneiro, J., Hazas, M. L. D. L., Dávalos, A., Selma, M. V., González‐Sarrías, A., & Espı́n, J. C. (2025) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.70104 · Cited by 5 · see citing works
A novel function for exosomes in depression
Yu, Q., Ye, S., Chen, M., Sun, P., & Weng, N. (2025) · Life Sciences · doi:10.1016/j.lfs.2025.123558 · Cited by 5 · see citing works
Tiwari, A., Khera, R., Rahi, S., Mehan, S., Makeen, H. A., Khormi, Y. H., Rehman, M. U., & Khan, A. (2024) · Brain Sciences · doi:10.3390/brainsci14100959 · Cited by 1 · see citing works
Flagged first, then by citations
Research works printed but not linked: 7
- [4]Cai XZ, Ni J, Li Z, Shen LJ, Xu KL, Gu J. [Regulation of UC-MSC on Immune Inflammatory Thrombophilia in MRL/lpr Mice]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2015;23:1697–701. 26708896
- [7]Elliott SJ, Marshall D, Morley K, Uphoff E, Kumar M, Meader N. Behavioural and cognitive behavioural therapy for obsessive compulsive disorder (OCD) in individuals with autism spectrum disorder (ASD). Cochrane Database Syst Rev. 2021;9:CD013173. 34693989 PMC8543671
- [9]Gu J, Lin CM, Gu W, Cai XZ, Li Z, Ren MM, Sun X, Ni J, Shen LJ, Wu W, et al. [Immunomodulatory effect of UC-MSC on function of immunocytes of rats with collagen type II induced arthritis]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014;22:166–70. 24598671
- [24]Liu YY, Li Y, Wang L, Zhao Y, Yuan R, Yang MM, Chen Y, Zhang H, Zhou FH, Qian ZR, et al. Mesenchymal stem cell-derived exosomes regulate microglia phenotypes: a promising treatment for acute central nervous system injury. Neural Regen Res. 2023;18:1657–65. 36751776 PMC10154505
- [42]Sharifzadeh N, Tabesh H, Kharrazi H, Tara F, Kiani F, Rasoulian Kasrineh M, et al. Play and learn for surgeons: a serious game to educate medical residents in uterine artery ligation surgery. Games Health J. 2021;10:220–7. 34264757
- [53]Yang X, Liu J, Yin Y, Yang L, Gao M, Wu Z, et al. MSC-EXs inhibits uranium nephrotoxicity by competitively binding key proteins and inhibiting ROS production. Ecotoxicol Environ Saf. 2025c;289:117654. 39793287 · DOI
- [56]Zhang J, Zhao D, Zang Z, Ruan Z, Fu Q, Zhang K. miR-200a-3p-enriched MSC-derived extracellular vesicles reverse erectile function in diabetic rats by targeting Keap1. Biomed Pharmacother. 2024a;177:116964. 38959607 · DOI
Cited by
Sorted by citations
Why retracted articles can have an influential afterlife—and what to do about it
Snyder, J., & Turner, L. (2026) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szag080
“21,22 This can be seen in Patil et al., another retracted article from this journal, as well.”
Hong, C.-E., & Lyu, S. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27198634
Salidroside regulates hippocampal neuronal autophagy in ASD mice via the SIRT2/FoxO1 pathway
Ning, X., Yu, Z., Liu, L., 谢晓普, & Guo, L. (2026) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2026.112161
- Authors
- Wu, C., Li, X., Yang, X., Wang, H., Lin, G., & Liu, Z.
- Affiliations
- Guangdong Academy of Sciences (CN)
- Guangzhou Health Science College (CN)
- Chinese Academy of Sciences (CN)
- Corresponding author
- Wu, Caixia
- Liu, Zhaoming
- Venue
- Stem Cell Research & Therapy
- Published
- 2025-12-12
- Volume
- 17
- Issue
- 1
- Pages
- 32-32
- ISSN
- 1757-6512 (ISSN-L)
- PMC
- PMC12817768
- OpenAlex
- W4417279754
- Cited by
- 3
- References
- 46
- Citations by year
- 2026: 3
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Research & Therapy (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Funders
- the GDAS Project of Science and Technology Development (2023GDASZH-2023030602)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Keywords
- autism spectrum disorder, human umbilical cord mesenchymal stem cells, extracellular vesicles, gut microbiota, neuroimmune interactions, neuroinflammation, oxidative stress, synaptic ultrastructure, mitochondrial ultrastructure, Lactobacillus, social interaction, repetitive behavior, combination therapy
- MeSH terms
- Autism Spectrum Disorder, Gastrointestinal Microbiome, Animals, Disease Models, Animal, Humans, Male, Mice, Inbred C57BL, Valproic Acid, Mesenchymal Stem Cell Transplantation, Mice, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
