Search Results (188)

Background/Objectives: Modern approaches for post-stroke rehabilitation cover mechanistically different ways—from physiotherapy to digital technologies. Among these approaches, stem cell-based therapy represents probably the most complex but promising strategy. Methods: We discuss the current state-of-the-art of using mesenchymal stem cells (MSCs) in post-stroke regenerative therapy. Despite relatively wide use of bone marrow and adipose tissue MSCs, these cells represent a more mature (“adult”) state, which limits their proliferative and regenerative potentials. Compared to the “adult” MSCs, less “mature” MSCs obtained from umbilical cord, specifically Wharton’s jelly MSCs (WJ-MSCs), demonstrate unique functional capabilities and are free from certain technical and ethical issues. Results: The molecular and cellular mechanisms of action of WJ-MSCs are thoroughly discussed in comparison with abundantly used “adult” types of MSCs. We also comparatively evaluate their preclinical and clinical application for treating post-stroke patients. Recent findings indicate that not only MSCs but also their secretome/exosomes (cell-free product) represent a therapeutically beneficial cellular drug in post-stroke recovery. Specially designed and carefully evaluated protocols, which preserve the bioactivity of the cell-free product intact, are mentioned. Neuroprotective and neuroreparative properties of cell-free products—secretome and exosomes—derived from Wharton’s jelly MSCs are summarized. Conclusions: Cell-free products obtained from WJ-MSCs are an innovative adjunct therapy for post-stroke disorders, despite certain challenges and limitations of this type of therapy still present. By further investigation of the molecular composition and biological mechanisms of the WJ-MSC secretome and exosomes, their clinical applicability in neuroinflammatory and neurodegenerative pathologies will be promoted. Full article

Objective: In a lipopolysaccharide (LPS)-induced acute lung injury (ALI) mouse model, the present study sought to assess the therapeutic efficacy of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and characterize their anti-inflammatory mechanistic basis. Methods: Forty mice were randomly divided into four groups: control, LPS model, LPS + DEX (positive control), and LPS + hUC-MSCs. Except for the control group, mice received intratracheal instillation of LPS to establish ALI. One hour after LPS administration, animals in the hUC-MSC group were intravenously infused with hUC-MSCs. The positive control group was given an intraperitoneal injection of DEX for 3 consecutive days, starting at 24 h after modeling. On day 4 after cell transplantation or at 24 h after the completion of DEX injection, lung function indicators were detected. Bronchoalveolar lavage fluid (BALF), serum, and lung tissues were subsequently obtained for evaluation of inflammatory cell infiltration, histopathological injury, lung wet-to-dry (W/D) ratio, and cytokine levels. Additionally, the localization of transplanted hUC-MSCs in lungs was examined, and the mRNA and protein expression levels of TLR4, MyD88, and NF-κB p65 were quantified. Results: LPS exposure markedly impaired pulmonary function and induced robust inflammatory responses, evidenced by elevated levels of pro-inflammatory cytokines, increased inflammatory cell counts in BALF and serum, and extensive histological lung damage. Moreover, hUC-MSC injection improved lung function, decreased inflammatory cytokine production and alleviated pulmonary edema, while inhibiting the TLR4/MyD88/NF-κB pathway at transcriptional and protein levels. Conclusions: Intravenous hUC-MSC administration alleviates LPS-induced ALI in mice, an effect associated with suppression of the TLR4/MyD88/NF-κB cascade. These results indicate that this signaling cascade partially mediates the observed anti-inflammatory effects. Full article

Osteoarthritis (OA) is a prevalent degenerative joint disorder characterized by cartilage degradation, synovial inflammation, and osteophyte formation, yet effective therapies that alter disease progression remain absent. Mesenchymal stem cell-derived exosomes (MSC-EXOs), as a cell-free regenerative medicine strategy, have shown great potential in the treatment of osteoarthritis. In this study, we successfully isolated and purified exosomes derived from human umbilical cord mesenchymal stem cells using a scalable tangential flow filtration (TFF)–chromatography platform and evaluated their therapeutic effects on OA model induced by anterior cruciate ligament transection (ACLT). OARSI scores were significantly reduced compared with the ACLT group (p < 0.01). Exosomes administration markedly reduced osteophyte formation, preserved cartilage structure, enhanced collagen II expression (p < 0.01), and suppressed MMP13-mediated matrix degradation (p < 0.05) compared with the ACLT group. The treatment also significantly decreased pro-inflammatory cytokines, indicating alleviation of the inflammatory microenvironment. Transcriptomic profiling further revealed genes and pathways potentially associated with exosome treatment. These findings suggest that hUC-MSC-EXOs isolated and purified using TFF–chromatography exert robust chondroprotective and immunomodulatory effects, supporting their potential as an effective cell-free therapeutic candidate for OA. Full article

Critical-sized bone defects lack spontaneous healing capacity. While mesenchymal stem cell-derived exosomes (sEVs) are promising osteoinductive agents, their rapid in vivo clearance limits their free-form efficacy. Here, we fabricated a nano-hydroxyapatite/chitosan (nHA/CTS) composite scaffold as a protective, sustained-delivery platform for human umbilical cord blood-derived mesenchymal stem cell exosomes (HUCB-MSCs-exos) to accelerate bone repair. The 3D porous CTS/10% nHA scaffold exhibited excellent cytocompatibility and a degradation rate commensurate with new bone ingrowth. Critically, it enabled a biphasic exosome release profile—an initial burst followed by a 14-day sustained release (89.73% cumulative release). In vitro, HUCB-MSCs-exos significantly promoted the proliferation, migration, and osteogenic differentiation of bone marrow-derived MSCs, as demonstrated by enhanced alkaline phosphatase activity and matrix mineralization. In a rabbit condylar defect model (5 mm diameter), the CTS/10% nHA-exo scaffold achieved a 57.44 ± 8.42% healing rate at two months, nearly two-fold greater than the scaffold-only group (29.33 ± 6.94%). Histological and immunohistochemical analyses at two months confirmed the formation of mature, well-vascularized trabecular bone, accompanied by robust expression of late-stage osteogenic markers (OCN and OPN). These findings demonstrate that the CTS/10% nHA scaffold synergistically integrates osteoconductive structural guidance with exosome-mediated osteoinductive paracrine signaling, providing a compelling and translatable strategy for critical-sized bone-defect management. Full article

The study aimed to investigate the individual therapeutic effects of melatonin and umbilical cord-derived mesenchymal stem cell exosomes (UC-MSC-Exo) separately on BE(2)-C neuroblastoma cells. Melatonin is recognized for its anti-cancer, antioxidant, and apoptosis-inducing properties, and its ability to cross the blood–brain barrier. UC-MSC-Exos are nanovesicles from mesenchymal stem cells that can also cross the blood–brain barrier and transport biologically active molecules. The potential therapeutic benefits of each independent agent in treating BE(2)-C neuroblastoma cells were investigated. Melatonin and UC-MSC-Exos were examined on BE(2)-C neuroblastoma cells at varying concentrations and time intervals to evaluate cell viability and apoptosis. Both melatonin and UC-MSC-Exo independently reduced cell viability and induced apoptosis in a manner that depended on the dosage and duration of exposure. Melatonin had an IC₅₀ of 2.68 mM after 24 h, while UC-MSC-Exo showed an IC₅₀ of 25.3 μg/mL after 48 h, with no cytotoxic effects observed at 24 h. Specifically, individual concentrations of 2.5 mM and 5 mM of melatonin, as well as 50 µg/mL and 100 µg/mL of UC-MSC-Exo, led to significant levels of apoptotic and necrotic cells at 48 and 72 h (p < 0.001). Our findings suggest that the individual administration of melatonin and UC-MSC-Exo may hold therapeutic potential for neuroblastoma cells, particularly given their ability to cross the blood–brain barrier. Further in vivo research is required to evaluate their clinical utility. Full article

Background: Exosomes (Exos) derived from immune cells are emerging as potent drug delivery vectors. However, their biodistribution in clinically relevant lung cancer models remains underexplored. This study aimed to evaluate the lung-homing ability of NK cell Exos (NK-Exos) compared to mesenchymal stem cell Exos (MSC-Exos) in an orthotopic lung cancer model. Methods: Male SCID mice were orthotopically injected with luciferase-tagged A549 cells into the left lung to establish the tumor model. Mice were randomized into four groups: G1 (Healthy Control), G2 (Tumor Control + PBS), G3 (Tumor + DiR-labeled NK-Exos; 5 µM DiR + 5–7 × 10⁹ Exo particles/100 μL/mouse), and G4 (Tumor + DiR-labeled MSC-Exos; 5 µM DiR + 5–7 × 10⁹ Exo particles/100 μL/mouse). Six hours (15 min, 1 h, 2 h, 4 h, 6 h) post-intravenous injection, ex vivo biodistribution was assessed using the MILabs Spectrum imaging system. Results: Umbilical cord blood-NK-Exos (UCB-NK-Exos; G3) exhibited superior accumulation in lung tissues compared to UCB-MSC-Exos (G4), suggesting enhanced pulmonary retention. Intra-pulmonary analysis revealed an asymmetric distribution, with significantly higher radiant efficiency in the right lung (non-tumor bearing) compared to the left lung (tumor injection site) across Exo-treated groups. Conclusions: UCB-NK-Exos demonstrate distinct lung-targeting properties superior to MSC-Exos, supporting their potential as therapeutic carriers. Full article

Background/Objectives: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. Methods: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O₂) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. Results: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. Conclusions: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation. Full article

Extracellular vesicles (EVs) mediate intercellular communication by delivering proteins and RNAs, with their molecular cargo often reflecting the biological context of their source. Perinatal tissues are promising sources of EV-related biomaterials with potential dermatologic applications. In this study, we compared EV-related molecular cargo from two umbilical cord-associated sources, umbilical cord mesenchymal stem cell (UCMSC)-derived EVs and cord blood plasma (CBP), to investigate whether these materials exhibit distinct functional effects on melanogenesis. UCMSC-derived EVs were isolated from conditioned culture medium and characterized using nanoparticle tracking analysis (NTA), cryo-electron microscopy (cryo-EM), and canonical EV marker detection, while cord blood samples were processed to obtain plasma following centrifugation and filtration, containing EVs together with soluble plasma components. Functional assays in the murine melanocyte cell line B16F10 demonstrated that UCMSC-derived EVs suppressed melanin production, whereas CBP treatment enhanced melanogenesis. Integrative omics analyses combining microRNAs (miRNAs) microarray profiling and proteomic characterization revealed distinct molecular signatures between UCMSC-derived EVs and CBP samples. Functional validation using miRNA mimic assays showed that selected miRNAs, including miR-6862-5p, miR-3622b-5p, miR-7847-3p, miR-6774-5p, and miR-4685-5p, reduced melanin production, whereas others, including miR-203a-3p, miR-126-3p, miR-139-5p, and miR-15b-5p, increased melanin levels. Pathway analysis using Ingenuity Pathway Analysis (IPA) (QIAGEN Inc.) associated these miRNA subsets with signaling pathways involved in melanogenesis. Together, these findings indicate that UCMSC-derived EVs and CBP exhibit opposite functional effects on melanogenesis and possess distinct miRNA and protein cargo profiles, providing potential molecular targets for modulating pigmentation and supporting the development of EV-related therapeutic strategies for pigmentation disorders. Full article

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are emerging as potent acellular therapeutics; however, their rapid clearance hinders their clinical translation. To address this issue, 3D-bioprinted genipin-crosslinked gelatin (GECL) was engineered for human health. GECL hydrogels were functionalised with human umbilical cord MSC-derived sEVs (hUCMSC-sEVs) to create a bioactive wound-healing platform. These hydrogels demonstrated favourable physicochemical, mechanical, and biodegradable properties while providing an extracellular matrix (ECM)-mimetic environment conducive to tissue regeneration. MSCs were isolated from the umbilical cords, and their small extracellular vesicles (sEVs) were extracted and incorporated into gelatin-based hydrogels via 3D bioprinting. These sEV-loaded scaffolds were embedded in full-thickness wounds in mice, and healing was evaluated through macroscopic observation, histological analysis, collagen deposition, and angiogenesis assessment. Compared with the untreated controls, both the hydrogel-only (B) and sEV-loaded hydrogel (BE) groups significantly accelerated in vivo wound healing. Notably, the BE group achieved complete wound closure within 14 days, restoring the skin architecture, which closely resembled the native tissue with well-organised epidermal and dermal layers, optimal thickness, and skin appendages. Histological and ultrastructural assessments revealed an increased collagen type I deposition, a reduced α-smooth muscle actin (α-SMA) expression, and a robust neovascularisation. The TEM revealed tight junctions and active cellular infiltration, indicating scaffold integration and functional remodelling. Immunohistochemistry further revealed an upregulated CD31 expression with a balanced α-smooth muscle actin (α-SMA) expression, reflecting coordinated angiogenesis and myofibroblast regulation. These results highlight sEV-functionalised GECL hydrogels as robust and clinically translatable acellular therapeutic green products for accelerated wound closure and functional skin regeneration, advancing the fields of regenerative medicine and life expectancy. Full article

Background: Cutaneous radiation injury arises when ionizing radiation disrupts epidermal barrier integrity, triggering persistent DNA damage, oxidative stress, and senescence-associated inflammatory signaling that drive extracellular matrix degradation and impaired regeneration. Clinical burden is rising due to dose-intensified radiotherapy, but also due to an increased use of energy-based aesthetic procedures that elicit radiation-like dermal injury. Dermal fibroblasts exhibit marked sensitivity to ionizing radiation and rapidly acquire senescence-associated secretory phenotypes that suppress collagen biosynthesis and promote chronic inflammation, underpinning the need for regenerative treatments that restore tissue homeostasis and regenerative competence. Mesenchymal stem cell–derived exosomes have emerged as a promising therapeutic strategy in this setting, with increasing preclinical evidence demonstrating their capacity to attenuate oxidative stress, enhance DNA damage-repair pathways, and normalize fibroblast metabolic function. Methods: In this study, we examine the expression profiles for 14 radiation response–associated genes of irradiated human dermal fibroblasts that were treated with bone marrow and umbilical cord MSC-derived exosomes at different timepoints using quantitative RT-PCR analysis. We also explore functional relationships among these genes through interaction network analysis, and outline a framework to organize pathway-level transcriptional responses to irradiation and exosome treatment. Results: MSC-derived exosome treatment was associated with attenuated early damage response signaling at 24 h, followed by increased expression of genes associated with DNA repair and oxidative stress recovery at intermediate timepoints. Exosome-treated cells also exhibited transcriptional changes consistent with modulation of cell-cycle regulatory pathways and reduced expression of pro-inflammatory markers by 5 d. These findings suggest that MSC-derived exosomes influence the temporal organization of the fibroblast transcriptional response to ionizing radiation and may contribute to molecular programs associated with tissue recovery following ionizing radiation exposure. Full article

Cartilage is an important yet vulnerable tissue with limited self-healing capacity, where damage often progresses to joint degeneration, which eventually leads to severe osteoarthritis (OA). Current tissue engineering strategies focus on biocompatible scaffolds for cartilage regeneration, particularly amnion (or amniotic membrane), emerging as a promising biomaterial due to its wide availability, low immunogenicity, and naturally derived microenvironment that is advantageous for cartilage regeneration. This systematic review aims to evaluate the existing evidence on the efficacy of amnion as a tissue scaffolding material for cartilage regeneration in both preclinical and clinical studies. Using terms such as “cartilage damage”, “cartilage injuries”, “amnion” and “amniotic membrane”, 19 relevant studies were identified across three major databases (PubMed, Scopus and Web of Science) until 25 December 2025. All preclinical and clinical studies that utilized amnion for cartilage repair or as cartilage tissue engineering scaffolding materials were included. Evidence quality was assessed using the OHAT and MINORS risk of bias tool. This study is prospectively registered in the PROSPERO database under the ID 1178444. The findings consistently indicate that amniotic scaffolds, regardless of processing methods or cell seeding, yield favorable outcomes without adverse effects across different species. In vitro analysis revealed that treatment groups with amnion show better cell attachment, viability, and proliferation, and higher content of cartilage-related markers expressed by the seeded cells, either chondrocyte, bone marrow-derived mesenchymal stem cells (MSCs), adipose tissue-derived MSCs, placenta-derived MSCs, umbilical cord-derived MSCs, amniotic MSCs or amniotic epithelial cells. In in vivo and ex vivo studies, amnion-treated groups demonstrated improved quality of the treated cartilage, with better integration, as indicated by higher histological scores and the presence of type II collagen (COL-II). There was an inconsistency in the reporting of cartilage defect dimensions in the in vivo models across the different studies. Nevertheless, the outcome measurements were consistently reported with histological analysis, with or without International Cartilage Repair Society (ICRS) scoring and immunohistochemistry (IHC) analysis, across the studies. Clinically, most subjects show improvement in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Sports and Recreation score and KOOS Quality of Life score, as well as reduced Visual Analogue Scale (VAS) average and maximum pain scores. In conclusion, preclinical and clinical studies support amnion as an ideal scaffold material for cartilage tissue engineering and regeneration. Future research should focus on optimizing and standardizing amnion scaffold preparation at a production scale to facilitate the translation of these positive outcomes into clinical applications. This study is funded by the Ministry of Higher Education Malaysia via Prototype Research Grant Scheme (PRGS/1/2021/SKK01/UM/02/1) and UM International Collaboration Grant—2023 SATU Joint Research Scheme Program: ST007-2024. Full article

Background: Chronic liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition and architectural remodeling, which may ultimately lead to cirrhosis and liver failure. Although mesenchymal stem cells (MSCs) exhibit antifibrotic and immunomodulatory properties, their therapeutic effects in established chronic liver fibrosis remain incompletely defined. This study aimed to evaluate the biochemical, hematological, and histopathological effects of MSC therapy in a chronic thioacetamide-induced liver fibrosis model. Methods: A controlled preclinical experimental study was conducted using rats with liver fibrosis induced by intraperitoneal thioacetamide administration for 24 weeks. Animals were allocated into three groups: control, untreated fibrosis, and fibrosis treated with MSCs derived from human umbilical cord tissue after fibrosis establishment. Serum biochemical markers, hematological parameters, and liver histopathology were assessed. Fibrosis severity was evaluated using hematoxylin–eosin and Masson’s trichrome staining and graded according to the METAVIR scoring system. Results: Thioacetamide exposure induced chronic liver injury characterized by marked elevations in serum transaminases, reduced albumin and total protein levels, hematological alterations, and early-to-intermediate fibrosis stages (METAVIR F1–F2). MSC-treated animals exhibited approximately 40–45% reductions in transaminase levels, partial recovery of hepatic synthetic function, and attenuation of hematological alterations. Histopathological analysis demonstrated a reduction in fibrotic burden and limitation of fibrogenic progression within METAVIR F1–F2 stages. Conclusions: MSC therapy partially mitigates biochemical, hematological, and histopathological alterations associated with chronic thioacetamide-induced liver fibrosis, supporting its potential as a modulatory strategy to attenuate fibrogenic progression and stabilize liver function rather than as a curative intervention. Full article

Is it reasonable to use allogeneic mesenchymal stem cells (MSCs) therapy for thin endometrium and recurrent implantation failure? Thin endometrium (TE) and recurrent implantation failure (RIF) are associated with poor reproductive outcomes. Single-cell RNA sequencing (scRNA-seq) shows that such pathologies involve functional impairment of endometrial stromal, vascular, immune cells rather than reductions in cell numbers. MSCs exert regenerative and immunomodulatory effects and are proposed as candidates for endometrial repair. scRNA-seq studies indicate that TE and RIF are characterized by stromal progenitor dysfunction, impaired angiogenesis, immune dysregulation, and cellular senescence, providing a biological rationale for investigating allogeneic MSC-based therapies. scRNA-seq studies of human endometrium in patients with TE and RIF are reviewed alongside experimental and clinical studies evaluating autologous and allogeneic MSCs, with particular emphasis on umbilical cord-derived MSCs. Transcriptomic analyses consistently demonstrate reduced proliferation and decidualization of endometrial stromal cells, suppression of angiogenesis, immune dysregulation, and activation of senescence-associated genes. Preclinical studies show that MSC administration restores endometrial structure, vascularization, and receptivity markers. Early clinical studies suggest potential benefit, although data remain limited and heterogeneous due to non-randomized studies. Allogeneic MSCs are promising as therapy, but further studies on mechanisms and clinical validation are needed. Full article

Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine–metabolic disorder with chronic low-grade inflammation and insulin resistance (IR). Elevated C-peptide, a marker of compensatory hyperinsulinemia and reduced adiponectin, an insulin-sensitizing adipokine, contribute to the metabolic dysregulation observed in PCOS. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) and their secretome have immunomodulatory properties via paracrine and epigenetic mechanisms, yet longitudinal evidence in PCOS is limited. Methods: This randomized controlled trial (RCT) involved 40 women with PCOS (Rotterdam criteria) who were randomly assigned to four treatment groups: (1) metformin 750 mg/day, (2) UC-MSC infusion (0.3 million cells/kg body weight), (3) secretome (nasal drops, 2 mL), and (4) a combination of UC-MSC (0.3 million cells/kg body weight) and secretome (nasal drops, 2 mL). Parameters measured included fasting glucose, fasting insulin, HOMA-IR, C-peptide, and adiponectin at baseline and at months 1, 3, and 6. Analysis was performed using repeated-measures ANOVA or Friedman test, and ROC curves were used to evaluate the predictive value of biomarkers on therapy response. Results: All participants completed the 6-months of follow-up. The secretome group demonstrated a significant increase in fasting glucose (month 1: p = 0.013; month 3: p = 0.007; month 6: p = 0.032), as well as an increase in adiponectin in the UC-MSC group (month 6: p = 0.016). The combination of UC-MSC and secretome induced early metabolic modulation, characterized by transient reductions in adiponectin at months 1 and 3 (p = 0.022 and p = 0.013, respectively) and early increases in insulin-related parameters; however, these effects were not sustained at month 6. ROC analysis showed that glucose, insulin, and C-peptide variables had low discriminatory ability (AUC < 0.5), while adiponectin showed a trend of increasing predictive value for improving insulin sensitivity. Conclusions: Combination therapy with UC-MSCs and secretome may have potential to improve metabolic profiles through increasing adiponectin and improving insulin sensitivity in PCOS patients, especially in the group with insulin resistance. MSC-based approaches are not only symptomatic but also have the potential to restore ovarian function through immunomodulatory and epigenetic mechanisms. Full article