Published online Jul 26, 2026. doi: 10.4252/wjsc.119260
Revised: March 10, 2026
Accepted: May 7, 2026
Published online: July 26, 2026
Processing time: 183 Days and 2.6 Hours
Spinal cord injury (SCI) is a severe neurological condition characterized by limited treatment options and an unfavorable prognosis. Mesenchymal stem cell (MSC)-derived exosomes constitute a novel cell-free therapeutic modality; however, the underlying mechanisms, particularly the role of microRNAs (miRNAs), remain to be fully elucidated.
To determine whether MSC-derived exosomes facilitate functional recovery following SCI by regulating microglial polarization through the delivery of miR-181d-5p.
In vitro, primary microglia stimulated with lipopolysaccharide were treated with characterized MSC-derived exosomes. Microglial polarization was assessed using quantitative real-time polymerase chain reaction and enzyme-linked immunosor
MSC-derived exosomes displayed characteristic morphological features and surface markers. In lipopolysaccharide-activated microglia, exosome treatment resulted in a significant reduction in pro-inflammatory cytokines and an increase in anti-inflammatory factors, reflecting a shift from the M1 to the M2 microglial phenotype. Notably, miR-181d-5p was upregulated in microglia following exosome treatment. Downregulation of miR-181d-5p abolished the exo
MSC-derived exosomes attenuate neuroinflammation and promote functional recovery after SCI by delivering miR-181d-5p, which induces a beneficial microglial M2 polarization through targeting HMGA2 and HMGB2. These findings underscore the therapeutic promise of exosomal miR-181d-5p for SCI repair.
Core Tip: Our work demonstrates that mesenchymal stem cell-exosomes promote recovery after spinal cord injury by delivering miR-181d-5p to microglia, thereby repolarizing them from an M1 to an M2 state. This proposed mechanism provides fresh insight into the therapeutic action of mesenchymal stem cell-exosomes and underscores the translational potential of miR-181d-5p in spinal cord injury treatment strategies.
- Citation: Wang W, Wang B, Yin H. Exosomal miR-181d-5p promotes spinal cord injury repair by driving microglial polarization from M1 to M2 phenotype. World J Stem Cells 2026; 18(7): 119260
- URL: https://www.wjgnet.com/1948-0210/full/v18/i7/119260.htm
- DOI: https://dx.doi.org/10.4252/wjsc.119260
Spinal cord injury (SCI) is a devastating neurological disorder caused by traumatic events - including traffic accidents, falls, or sports-related impacts - that results in severe motor, sensory, and autonomic impairments[1]. Globally, approximately 27 million individuals are affected by SCI, with nearly one million new cases reported annually. The in-hospital mortality rate for patients with acute SCI ranges from 4.4% to 16.7%[2,3]. The initial mechanical insult is followed by a complex secondary injury phase in SCI, marked by inflammation, neuronal apoptosis, and oxidative stress[4]. Of these pathological features, neuroinflammation emerges as a central mediator that impedes functional recovery.
Microglia, the primary immune cells of the central nervous system, become rapidly activated following SCI. Upon activation, they can polarize into two distinct phenotypes: The pro-inflammatory M1 phenotype, which releases cytotoxic factors and exacerbates neuronal damage, and the anti-inflammatory M2 phenotype, which facilitates tissue repair and inflammation resolution[5,6]. Maintaining a balanced M1/M2 microglial polarization is essential for recovery after SCI. Therefore, therapeutic strategies aimed at shifting microglial polarization toward the beneficial M2 phenotype hold significant promise for SCI treatment[7].
Exosomes derived from mesenchymal stem cells (MSCs) have recently been recognized as a promising cell-free the
Herein, we hypothesized that distinct exosomal miRNAs play an essential role in regulating microglial polarization. By performing miRNA expression profiling, we identified miR-181d-5p as a potential mediator accounting for exosome-induced effects. We therefore designed this study to examine whether MSC-derived exosomes attenuate neuroinflammation and enhance functional recovery following SCI by shuttling miR-181d-5p to modulate microglial phenotypic conversion.
The animal study was approved by the Ethics Committee of Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University. All animal experiments complied with the ARRIVE guidelines and were performed in accordance with relevant guidelines and regulations.
Bone marrow-derived MSCs were acquired from the Chinese Academy of Sciences (Shanghai, China) and cultured in DMEM supplemented with 10% foetal bovine serum (FBS) and 1% penicillin/streptomycin under standard conditions
An miR-181d-5p-specific inhibitor (anti-miR-181d-5p) and its corresponding negative control (anti-miR-NC) were purchased from Shanghai GenePharma Co., Ltd. (Shanghai, China). To knock down miR-181d-5p expression, primary microglia were transfected with anti-miR-181d-5p or anti-miR-NC using Lipofectamine 3000 reagent (Invitrogen, Carlsbad, CA, United States).
Bone marrow-derived MSCs at roughly 80% confluence were maintained in medium with exosome-depleted FBS for 48 hours to produce conditioned medium for exosome preparation. Sequential centrifugation at 300 × g and 2000 × g for 10 minutes each at 4 °C was applied to remove cellular debris. After filtration through a 0.22-μm filter, the supernatant was concentrated using an Amicon Ultra-15 centrifugal filter at 4000 × g. Exosomes were pelleted by ultracentrifugation at 100000 × g for 60 minutes at 4 °C over a 30% sucrose/D2O cushion. The pellet was resuspended in phosphate buffered saline (PBS) and concentrated to approximately 200 μL. Morphological features, size distribution, and exosomal marker expression [tumor susceptibility gene 101 (TSG101), CD9, CD63] of the isolated vesicles were evaluated by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting, respectively.
Exosomes were prefixed with 2.5% glutaraldehyde at 4 °C for 2 hours and then adsorbed onto carbon-coated copper grids over a 10 minutes incubation. Excess liquid was removed, after which the grids were negatively stained using 2% phosphotungstic acid (pH = 6.8) for 1 minute. Following air-drying, samples were examined under a Hitachi HT7800 transmission electron microscope (Tokyo, Japan).
Exosome preparations were diluted in sterile 1 × PBS to obtain particle concentrations falling within the optimal detection range (107-109 particles/mL). A ZetaView PMX-120 system (Particle Metrix, Inning am Ammersee, Germany) was employed for measurements. The integrated ZetaView software was used to capture and analyze three independent 60-second videos for determination of mean particle size and concentration.
RIPA buffer (Beyotime, Shanghai, China) was used to lyse exosomal proteins, and protein concentrations were de
Cells were harvested for total RNA extraction using TRIzol reagent (Invitrogen, Carlsbad, CA, United States). Reverse transcription and quantitative polymerase chain reaction (qPCR) for mRNA detection were carried out with the PrimeScript RT Kit and TB Green Premix Ex Taq II (both from Takara Bio, Shiga, Japan), whereas those for miR-181d-5p were performed using the miScript II RT Kit and miScript SYBR Green PCR Kit (Qiagen, Hilden, Germany). All qPCR reactions were run on a QuantStudio 5 system (Applied Biosystems, Foster City, CA, United States). Gene expression levels were normalized to GAPDH (for mRNAs) or U6 snRNA (for miR-181d-5p) and quantified using the 2-∆∆Ct method. The primer sequences used were as follows: Tumor necrosis factor-alpha (TNF-α): FP: 5’-CCCTCCTGGCCAACGGCATG-3’, RP: 5’-TCGGGGCAGCCTTGTCCCTT-3’; interleukin-1β (IL-1β): FP: 5’-GCCTCGTGCTGTCGGACCCATAT-3’, RP: 5’-TCCTTTGAGGCCCAAGGCCACA-3’; inducible nitric oxide synthase (iNOS): FP: 5’-GCTCGCTTTGCCACGGACGA-3’, RP: 5’-AAGGCAGCGGGCACATGCAA-3’; arginase1 (Arg1): FP: 5’-CTATGTGTCATTTGGGTGGA-3’, RP: 5’-TCTGG
The levels of inflammatory cytokines in cell culture supernatants [TNF-α, DTA00D; IL-1β, DLB50; IL-6, D6050B; trans
Synthesized wild-type (WT) 3’ untranslated regions (UTRs) of HMGA2 and HMGB2 harboring the predicted miR-181d-5p binding sites, together with their mutant (MUT) counterparts containing disrupted seed region sequences, were cloned into the pmirGLO dual-luciferase miRNA target expression vector (Promega, Madison, WI, United States). Cells were co-transfected with Lipofectamine 3000 (Invitrogen, Carlsbad, CA, United States) using either the WT or MUT 3’UTR reporter construct along with anti-miR-181d-5p or anti-miR-NC. After 48 hours, firefly and Renilla luciferase activities were assessed sequentially using the Dual-Luciferase Reporter Assay System (Promega, Madison, WI, United States), and firefly luciferase activity was normalized to Renilla luciferase activity.
Female Sprague-Dawley rats (six-week-old) weighing 180-200 g were obtained from Charles River Laboratories (Beijing, China). Animals were randomly divided into three groups (n = 5 per group): Sham, SCI, and SCI + Exo. Rats were acclimated for one week prior to surgery, then anesthetized with 3% isoflurane (Sigma-Aldrich, St. Louis, MO, United States). A dorsal midline incision was centered at T10, and the paravertebral muscles were retracted to expose the T9-T11 spinous processes and laminae. After laminectomy at T10, a moderate contusion injury was produced using a 10 g weight dropped from a height of 2.5 cm onto the exposed dura mater. Successful injury was verified by the immediate appearance of hindlimb twitching and tail flicking[16]. Rats in the Sham group underwent T10 laminectomy only, without impact. In the SCI + Exo group, animals received daily tail vein injections of MSC-derived exosomes (100 μg in 0.5 mL PBS) for five consecutive days post-injury, whereas the SCI group was administered an equal volume of PBS[17]. At 28 days post-surgery, all rats were euthanized by an overdose of 5% isoflurane, and spinal cord tissues containing the lesion epicenter were collected for subsequent analyses.
Tissue blocks containing the lesion site were fixed and embedded in paraffin. Sections were cut at 4 μm thickness, then deparaffinized and stained with hematoxylin and eosin for morphological analysis. Following dehydration and clearing, the sections were mounted and examined with an Olympus light microscope.
Hindlimb motor function was evaluated on days 1, 3, 7, 14, 21, and 28 post-SCI using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. The BBB scale assigns scores from 0 (complete absence of hindlimb movement) to 21 (normal locomotion). Elevated scores indicate progressive recovery of motor function. Scoring was performed by two blinded observers according to standardized criteria.
Double immunofluorescence staining was performed on spinal cord sections harvested 28 days after surgery. Following blocking with 5% normal goat serum, sections were incubated overnight at 4 °C with primary antibodies against Iba-1 (Wako, Richmond, VA, United States), CD86 (Abcam, United Kingdom), and CD206 (Abcam, United Kingdom), then with Alexa Fluor-conjugated secondary antibodies for 1 hour. Nuclei were counterstained with DAPI, and images were captured using an Olympus fluorescence microscope (Center Valley, PA, United States).
Data are shown as mean ± SD from ≥ 3 independent experiments. Statistical analyses were performed using GraphPad Prism 9.0. Two-group comparisons were analyzed by Student’s t-test, and multiple-group comparisons were assessed via one-way or two-way ANOVA followed by Tukey’s or Bonferroni’s post hoc tests. P < 0.05 was considered statistically significant.
We first systematically characterized exosomes isolated from MSCs. TEM showed that isolated exosomes exhibited classical cup-shaped or spherical morphology (Figure 1A). NTA identified a main particle size range of 50-200 nm (Figure 1B). Western blot analysis confirmed the expression of exosomal markers TSG101, CD9 and CD63, demonstrating effective isolation of MSC-derived exosomes (Figure 1C).
To determine the role of exosomes in the context of SCI, primary microglia were stimulated with LPS for 24 hours to establish an in vitro inflammatory model, and then exposed to MSC-derived exosomes. Exosome treatment significantly downregulated pro-inflammatory cytokine levels (TNF-α, IL-1β, IL-6; Figure 2A-C) and upregulated the release of anti-inflammatory cytokines (TGF-β, IL-4, IL-10; Figure 2D-F). To evaluate microglial phenotypic switching, we measured the expression of phenotype-specific markers. Exosome treatment significantly reduced M1-related gene expression (TNF-α, IL-1β, iNOS; Figure 2G-I) and increased M2-related gene levels (Arg1, CD163, CD206; Figure 2J-L).
miRNAs are key exosomal components that facilitate intercellular communication and regulate fundamental biological activities. To identify key miRNAs involved in exosome-mediated microglial modulation, we analyzed miRNA ex
To clarify the specific involvement of exosomal miR-181d-5p in microglial phenotype switching, we silenced miR-181d-5p in primary microglia and confirmed the silencing efficiency using qPCR (Figure 4A). Under LPS-induced inflammatory conditions, exosome treatment inhibited the release of TNF-α, IL-1β, and IL-6 (Figure 4B-D) and promoted the secretion of TGF-β, IL-4, and IL-10 (Figure 4E-G). However, these regulatory effects were abrogated upon miR-181d-5p knockdown. Furthermore, qPCR analysis of microglial polarization markers revealed that exosomes reduced the expression of TNF-α, IL-1β, and iNOS (Figure 4H-J) and enhanced the expression of Arg1, CD163, and CD206 (Figure 4K-M) following LPS stimulation. Notably, these effects were also reversed by miR-181d-5p knockdown.
To determine functional target genes of miR-181d-5p, we selected five candidate genes (CCNG1, DDX3X, HMGA2, HMGB2, and HSPA5) based on bioinformatics predictions and literature reports. miR-181d-5p knockdown significantly elevated HMGA2 and HMGB2 mRNA expression, while CCNG1, DDX3X, and HSPA5 showed no significant alterations (Figure 5A). The WT 3’UTR sequences of HMGA2 and HMGB2 contained predicted complementary binding sites for miR-181d-5p, which were disrupted in the MUT constructs (Figure 5B). Co-transfection of anti-miR-181d-5p with the WT reporter constructs significantly increased luciferase activity (Figure 5C and D), whereas no significant differences were observed with the MUT reporter constructs. These data demonstrate that miR-181d-5p directly targets HMGA2 and HMGB2 by binding to their 3’UTRs and suppressing their expression.
Finally, the therapeutic potential of MSC-derived exosomes was evaluated in a rat SCI model. Hematoxylin and eosin staining revealed marked histopathological damage in the SCI group, characterized by disrupted tissue architecture, disorganized cellular arrangement, and extensive inflammatory cell infiltration. In contrast, exosome treatment markedly improved tissue structure and reduced inflammatory cell infiltration (Figure 6A). BBB locomotor rating scale showed that hindlimb motor function was severely impaired in the SCI group, whereas exosome administration significantly improved locomotor recovery over the 28-day observation period (Figure 6B). On day 28 post-surgery, exosome treatment significantly reduced the levels of TNF-α, IL-1β, and IL-6 in spinal cord tissues (Figure 6C-E). Double immunofluorescence staining revealed that SCI induced a prominent M1 polarization (increased Iba-1+CD86+ cells), whereas exosome treatment shifted microglial/macrophage polarization toward the reparative M2 phenotype, as evidenced by decreased Iba-1+CD86+ cells and increased Iba-1+CD206+ cells at the lesion site (Figure 6F and G).
SCI remains a formidable clinical challenge with limited effective therapeutic interventions[18]. Cell-free therapies, particularly exosome-based approaches, have emerged as promising strategies for neural repair. For instance, Schwann cell-derived exosomes mitigate post-SCI inflammation by modulating microglial polarization[19]. Exosomes from other sources also mediate functional recovery after SCI: MiR-709 derived from regulatory T cell exosomes suppresses microglial pyroptosis and enhances motor function[20], while platelet-rich plasma-derived exosomes aid recovery by restoring the blood-spinal cord barrier and reducing neuroinflammation[21]. Among these, MSC-derived exosomes have garnered considerable attention owing to their immunomodulatory properties and ability to traverse biological barriers. For example, adipose-derived MSC exosomes alleviate SCI by triggering the nuclear factor erythroid 2-related factor 2 pathway and modulating microglial polarization[22]. Conversely, exosomes from umbilical cord MSCs promote functional recovery through the regulation of nerve growth factor signaling by miR-199a-3p and miR-145-5p[23]. Furthermore, bone marrow MSC-derived exosomes confer protection, with exosomal miR-455-5p alleviating SCI and miR-497-5p promoting repair by targeting the TXNIP/NLRP3 axis[24,25].
In the present study, vesicles purified from MSC-conditioned medium were comprehensively characterized and shown to have typical exosomal properties, including cup-shaped morphology, predominant size distribution of 50-200 nm, and positive expression of exosomal markers TSG101, CD9, and CD63. This comprehensive characterization confirms that the observed biological effects are attributable specifically to exosomes, rather than to other extracellular vesicles or non-vesicular components. Building upon this foundation, we first explored the direct effects of MSC-derived exosomes on microglial polarization under inflammatory conditions. Exosome treatment effectively reversed LPS-induced M1 polarization of microglia toward a protective M2 phenotype in vitro. This repolarization was reflected at both functional and transcriptional levels: A switch from a pro-inflammatory to an anti-inflammatory cytokine profile, accompanied by downregulation of M1-associated genes and upregulation of M2-associated genes.
Recognizing that exosomes function as natural carriers of bioactive molecules, particularly miRNAs, we sought to identify specific miRNAs responsible for mediating these polarization effects. Through comprehensive miRNA profiling and subsequent validation, we identified miR-181d-5p as the most significantly upregulated miRNA in exosome-treated microglia under inflammatory conditions. Emerging evidence highlights the multifaceted role of exosomal miR-181d-5p in modulating disease processes across different biological contexts. For instance, miR-181d-5p transferred via cancer-associated fibroblast-derived exosomes functions as a multifunctional oncogenic driver, promoting cancer progression and inducing epithelial-mesenchymal transition in breast cancer by modulating the CDX2/HOXA5 signaling pathway[26]. Beyond oncology, this miRNA also contributes to inflammatory and regenerative processes: It modulates NLRP3/caspase-1/GSDMD-mediated pyroptosis in human mesangial cells via M0 macrophage-derived exosomes[27], promotes osteogenic differentiation through the miR-181d-5p/TNF signaling axis in periodontal ligament cells under cyclic stretch[28], and alleviates allograft rejection via exosomal transfer from rapamycin-primed myeloid-derived suppressor cells by targeting Kruppel-like factor 6[29]. Additionally, miR-181d-5p promoted neurite outgrowth in PC12 cells by activating the phosphatidylinositol 3-kinase/protein kinase B signaling pathway[30]. Herein, LPS stimulation significantly suppressed endogenous miR-181d-5p levels in microglia, an effect that was reversed and enhanced by treatment with MSC-derived exosomes, confirming their role as efficient delivery vehicles. To establish a causal link, we employed a specific knockdown strategy. Ablation of miR-181d-5p in microglia completely abolished the ability of MSC-derived exosomes to modulate microglial polarization. While our findings establish miR-181d-5p as a necessary mediator, the therapeutic efficacy of MSC-derived exosomes likely stems from the synergistic action of multiple bioactive molecules. Other co-delivered miRNAs, proteins, and lipids may cooperate with miR-181d-5p to fine-tune the microglial response or modulate additional pathways involved in repair, such as angiogenesis or axonal growth. Furthermore, the inherent heterogeneity of exosome preparations - influenced by factors such as MSC donor variability, culture conditions, and isolation methods - remains a critical consideration for clinical translation[31-33]. Batch-to-batch variations in the relative abundance of miR-181d-5p or other key effectors could significantly impact the consistency and potency of therapeutic outcomes. Moving forward, establishing robust quality control metrics, including quantification of specific active cargo molecules such as miR-181d-5p, will be essential to minimize variability and ensure reproducible therapeutic effects.
The identification of miR-181d-5p as a key functional mediator prompted us to investigate its direct downstream targets. HMGA2 and HMGB2 were identified as direct targets of miR-181d-5p. Functional assays verified that miR-181d-5p directly targets the 3’UTRs of both genes, and silencing miR-181d-5p markedly elevated their mRNA levels in microglia. Both HMGA2 and HMGB2 are known to play significant roles in inflammation and immune regulation. HMGB2, a member of the high-mobility group box family, has recently been characterized as a damage-associated molecular pattern molecule. Upon cellular stress - such as radiation-induced damage - HMGB2 undergoes nuclear-to-cytoplasmic translocation, and its extracellular release functions as an intercellular communication signal between injured cells and immune cells, activating immune response pathways[34]. In the context of SCI, HMGB2 released from damaged neural cells or activated microglia could propagate neuroinflammation by engaging pattern recognition receptors on surrounding immune cells, thereby amplifying the M1 pro-inflammatory response and hindering recovery[35]. Similarly, HMGA2 is involved in diverse cellular processes, including inflammatory responses. Recent studies in ischemic stroke models have revealed that HMGA2 serves as a downstream mediator in neuroinflammatory cascades, where its re
Consistent with our in vitro observations, exosome treatment significantly improved functional recovery as assessed by the BBB locomotor scale, with treated animals showing progressively better coordination and weight-bearing capacity over the 28-day observation period. Histological analysis further revealed that exosome administration preserved tissue architecture and reduced inflammatory cell infiltration at the lesion site. Corroborating our in vitro findings, exosome treatment significantly suppressed pro-inflammatory cytokine levels in spinal cord tissue. This anti-inflammatory effect was further supported by immunofluorescence staining of the injured spinal cord. Exosome treatment not only decreased the overall number of Iba-1-positive microglia/macrophages at the lesion site but, more importantly, fundamentally altered their polarization state. While SCI induced a predominant M1 phenotype (Iba-1+CD86+ cells), exosome administration shifted the balance toward a protective M2 phenotype. These in vivo findings demonstrate that the immunomodulatory effects observed in our in vitro experiments translate effectively to the complex pathological environment of SCI, where exosomal miR-181d-5p promotes a pro-reparative microenvironment by reprogramming microglial polarization.
Several elements in our study merit further exploration. First, while our in vitro knockdown experiments established the functional necessity of miR-181d-5p in exosome-mediated microglial polarization, whether this specific miRNA is sufficient to drive therapeutic effects in vivo remains to be determined. Loss-of-function studies utilizing miR-181d-5p inhibitors or knockout models in the context of SCI are needed to definitively establish the causal role of this miRNA in the observed functional recovery. Second, the potential synergistic effects of miR-181d-5p with other exosomal components deserve consideration, as exosomes contain numerous miRNAs, proteins, and lipids that may work in concert to produce the observed therapeutic effects. Third, successful traversal of the blood-spinal cord barrier and homing of exosomes to the injury site remain to be verified. Although we demonstrated therapeutic efficacy following systemic administration, direct visualization of exosome biodistribution is imperative. Beyond biodistribution, a more comprehensive understanding of exosome pharmacokinetics is required. The optimal therapeutic window - including initiation, frequency, and duration of treatment - remains to be defined, as the dynamic nature of secondary injury may necessitate tailored dosing regimens. Future studies should incorporate in vivo imaging or tissue section fluorescence microscopy using dye-labeled exosomes (e.g., PKH26 or DiR) to verify their accumulation within the injured spinal cord and confirm their uptake by microglia. Furthermore, the kinetics of exosomal miRNA transfer and the duration of their effects in the complex SCI microenvironment require further characterization to optimize treatment timing and dosage.
Although our study focused on microglial polarization, the functional recovery observed likely involves a broader spectrum of repair mechanisms. MSC-derived exosomes are known to exert pleiotropic effects, and miR-181d-5p itself has been implicated in promoting neurite outgrowth[30]. It is plausible that exosomal miR-181d-5p directly contributes to neuroprotection and axonal regeneration by targeting, for example, HMGA2 or HMGB2 in neurons. Additionally, these exosomes could modulate astrocyte reactivity, reducing glial scar formation and creating a more permissive environment for regeneration. Future studies employing in vivo cell-type-specific tracking of exosome uptake and functional assays on neurons and astrocytes will be crucial to fully elucidate the multifaceted mechanisms by which MSC-derived exosomes and miR-181d-5p orchestrate repair after SCI.
Collectively, our findings demonstrate that MSC-derived exosomes exert neuroprotective effects and enhance functional recovery post-SCI by shuttling miR-181d-5p to microglia, thus promoting their phenotypic transition from M1 to M2 through direct inhibition of HMGA2 and HMGB2. These results advance the understanding of the therapeutic mechanism underlying MSC-derived exosomes and highlight exosomal miR-181d-5p as a viable candidate with translational promise for SCI therapy.
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