Knee osteoarthritis (OA) causes significant chronic pain and disability. Current non-operative treatments are largely symptom-modifying. While intra-articular mesenchymal stem cell (MSC) therapies are promising, randomized controlled trials (RCTs) report inconsistent results due to heterogeneity in cell sources, preparations, and techniques. We searched PubMed, Scopus, Cochrane Library, and Google Scholar through December 10, 2025. Peer-reviewed RCTs evaluating intra-articular stem cell-based therapies for knee OA were included. Primary analyses compared MSCs versus controls across pain, function, structure, and safety. Subgroup and sensitivity analyses explored heterogeneity by preparation, source, comparator, follow-up, age, and injection guidance. Twenty-eight RCTs were included. MSC therapies significantly improved pain: ΔVAS (MD -1.67; p = 0.007), post-treatment VAS (MD -3.55; p = 0.01), and KOOS pain (MD 15.37; p = 0.03). Functional gains occurred in KOOS ADL (MD 12.84; p = 0.04), KOOS sports (MD 11.76; p < 0.001), and KOOS symptoms (MD 15.16; p = 0.02). WOMAC, KOOS quality of life, and Lequesne Index showed no significant differences. Benefits were more consistent with culture-expanded preparations, bone marrow sources, saline controls, and ultrasound guidance. ΔVAS remained significant after excluding short follow-up studies; ΔVAS and KOOS pain remained significant in older cohorts. MRI-based WORMS scores were non-significant, indicating no consistent structural benefit. Safety analyses revealed higher rates of injection-site pain (RR 2.04; p = 0.0005), joint swelling (RR 3.39; p = 0.0003), and other adverse events (RR 1.26; p = 0.01). Serious complications (e.g., infection) were uncommon and non-significant. Current evidence suggests stem cell-based therapies serve a primarily symptom-modifying rather than structure-modifying role. Higher frequencies of local reactions must be weighed against symptomatic benefits. Larger, standardized trials are needed to identify optimal preparations and patient profiles for consistent clinical benefit. • Intra-articular stem cell-based therapies demonstrate modest improvements in pain outcomes in knee osteoarthritis compared with control injections across randomized controlled trials, although results vary across cell preparations, comparators, and study conditions. • Symptomatic and functional improvements were observed in several KOOS domains, particularly activities of daily living, sports, and symptoms, with benefits appearing more consistent in selected subgroups rather than uniformly across all stem cell interventions. • Structural changes on MRI (WORMS) were not significantly improved, suggesting that current evidence supports symptomatic relief rather than consistent disease-modifying effects on joint structure. • Stem cell injections were associated with increased local reactions such as injection-site pain and joint swelling, while serious complications remained uncommon, indicating a generally manageable but non-negligible safety profile.

Safety and efficacy of allogeneic umbilical cord-derived mesenchymal stem cell infusion for frailty: a phase 2, single-centre, randomised, open-label controlled trial.

Berberine pretreatment enhances the homing and anti-inflammatory efficacy of dental pulp mesenchymal stem cells in TNBS-induced inflammatory bowel disease via activating the CXCR4/SDF-1 signaling pathway.

Feline panleukopenia is an acute and highly contagious disease caused by feline panleukopenia virus (FPV). Conventional therapeutic approaches often yield suboptimal outcomes in managing leukopenia, which consequently contributes to its high mortality rate. Mesenchymal stem cells (MSCs) are a type of multipotent stem cell characterized by their multidirectional differentiation potential and immunomodulatory capabilities. Studies have shown that MSCs possess the potential to treat inflammatory and immune-mediated diseases, support and promote hematopoiesis, and facilitate tissue repair. Therefore, this study was to investigate the clinical efficacy of combining MSCs with feline panleukopenia monoclonal antibody to propose a potential treatment for FPV. MSCs were extracted from a newborn kitten's umbilical cord tissue. Fifteen healthy unimmunized kittens aged 2 to 4 months were divided evenly into three groups: control group, conventional treatment group, and MSCs group (conventional treatment combined with MSCs therapy, involving daily intravenous administration of 1 × 107 MSCs for 3 consecutive days). Treatments were commenced once evident clinical symptoms manifested and white blood cell counts declined below the normal range. The subject cats were assessed for clinical signs, complete blood count (CBC), blood biochemistry, serum amyloid A (SAA), pathology and viral load in major organs. The results revealed that in the control group and conventional treatment group, cats exhibited a rapid decline in white blood cell count following disease onset, ultimately resulting in mortality. Conversely, in the MSCs group, four cats demonstrated an increase in white blood cell count post-treatment, subsequently returning to normal levels. However, one cat did not exhibit a significant increase and died on the third day of treatment. These findings highlight the therapeutic potential of MSCs in elevating leukocyte counts, improving clinical symptoms, and ultimately leading to a significant enhancement of survival rates among FPV-affected cats.

Musculoskeletal disorders are one of the most common causes that lead to disability throughout the world and routinely present with only limited or short-term symptom relief following traditional treatments. Recent developments, such as platelet-rich plasma (PRP) and mesenchymal stem/stromal cell (MSC) interventions, are being used as regenerative biologic adjuncts in musculoskeletal medicine, yet significant variability exists in preparation strategies, activation methods, and dosing protocols. In addition, clinical interpretation remains limited by inconsistent biologic characterization and protocol variability. A comprehensive review of current clinical evidence regarding dosing parameters, activation methods, and functional outcomes of PRP and MSC therapies for musculoskeletal recovery, focusing on protocol variability and clinical reproducibility. A structured literature search was conducted using predefined search terms in PubMed, BMJ Journals, and SpringerLink to identify human clinical studies evaluating platelet-rich plasma and mesenchymal stem cell therapies for musculoskeletal conditions. Studies published between January 2016 and December 2025 were screened. An updated search extending through December 31, 2025 identified additional records published after February 2025; however, none met the predefined inclusion criteria. Five controlled trials featuring PRP or MSC techniques met inclusion criteria. Significant heterogeneity was observed across studies in biologic preparation techniques, leukocyte content, activation methods, cell expansion protocols, dosing regimens, and follow-up duration. While improvements in pain and functional scores were reported across both types of interventions, dose-response relationships were inconsistently evaluated and direct protocol comparisons were limited. Although regenerative biologic therapies such as PRP and MSC are associated with improvements in musculoskeletal rehabilitation, significant variability and inconsistent reporting in dosing, activation, and preparation limit generalizability and reproducibility. Prospective clinical trials featuring standardized biologic characterization and uniform reporting frameworks are necessary to begin defining evidence-informed dosing recommendations and rehabilitation delivery.

Purpose Cutaneous radiation syndrome (CRS) arises from high dose-ionizing radiation exposure and remains a major clinical challenge owing to limited effective therapies. This study investigated the time-dependent therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) for treating radiation-induced soft tissue injury in a Göttingen minipig model. Materials and methods Six minipigs were locally irradiated with 100 Gy gamma radiation on each thigh. Two animals served as irradiated group (IR group), whereas four received local intradermal hUCB-MSC injections five times, initiated at week 1 (early treatment; Group I) or week 7 (delayed treatment; Group II) post-irradiation. Serial ultrasonographic and color Doppler imaging were used to monitor changes in skin thickness, vascularity, and edema. Gross morphological and histopathological evaluations were conducted to assess wound progression and tissue repair. Results All irradiated minipigs developed severe radiation-induced skin burns. Ultrasonography detected skin thickening and vascular abnormalities at early time points, prior to the appearance of gross morphological changes, suggesting that vascular damage precedes visible lesions. Compared with IR group, both MSC-treated groups exhibited reduced ulcer formation, edema, and skin thickness, as confirmed by ultrasound and gross inspection. Early hUCB-MSC administration (Group I) markedly improved wound healing, reduced scab formation, and preserved tissue structure, whereas delayed treatment (Group II) showed limited recovery with persistent necrosis and thick scabbing. Conclusions Early administration of hUCB-MSCs combined with noninvasive ultrasonographic diagnosis effectively mitigates radiation-induced skin injury and promotes wound repair. Ultrasound-based monitoring combined with time-dependent MSC therapy may represent a promising strategy for the clinical management of severe CRS.

Pathological mechanisms of hepatic ischemia-reperfusion injury and stem cell-based therapeutic strategies: Mechanistic insights and translational perspectives.

Traumatic brain injury (TBI) remains a major global health challenge with limited effective treatments. This systematic review documents the significant evolution of mesenchymal stem cell (MSC) therapies from traditional cell transplants to advanced cell-free products and engineered delivery systems. A systematic search was conducted across Web of Science, Embase, and PubMed/Medline for studies published from January 2015 to June 2025, resulting in the inclusion of 80 studies for qualitative synthesis. The review identifies four primary therapeutic mechanisms: reducing inflammation, protecting brain cells, maintaining the blood-brain barrier, and supporting tissue repair/regrowth. This PROSPERO-registered systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Methodological quality and risk-of-bias were rigorously assessed using a multi-tool approach tailored to study design (Cochrane RoB, SYRCLE, NOS/JBI). Recent clinical evidence (e.g. STEMTRA trial) suggests these treatments are safe and can improve function in chronic TBI patients. Despite this, critical research gaps persist in establishing standardized protocols, optimal dosing, and long-term safety data. Emerging trends include (1) shifting toward enhanced exosomes/secretomes, (2) integrating MSCs/derivatives with advanced biomaterials for controlled delivery, (3) exploring alternative MSC sources, and (4) developing combination therapies. With a deepening mechanistic understanding and positive early clinical results, future research must prioritize standardization and personalized treatment plans to accelerate clinical translation.

Chimeric antigen receptor (CAR) is a receptor engineered to engraft defined specificity onto immune effector cells, usually T cells, and enhance cellular function. Currently, the anticancer effects of CAR-engineered T cells, macrophages, and NK cells are being intensively explored. Pre-eclampsia (PE) is a pregnancy-specific disease with complex pathogenesis, and no effective treatment exists other than delivery. Placental dysfunction is a major contributing factor; the abnormal placenta releases factors into the maternal bloodstream, leading to systemic inflammation and widespread endothelial dysfunction. This review comprehensively assesses the therapeutic prospects of CAR-engineered mesenchymal stem cell (CAR-MSC) therapies in addressing the pathophysiological mechanisms of PE, while outlining future directions for CAR-MSC integrated treatment strategies. Although non-tumor research based on CAR technology is still in its early stages, in-depth investigation into CAR-MSCs may offer novel insights and perspectives for the treatment of PE by modulating placental immune function and enhancing placental repair. Given that pregnant women constitute a special population, safety considerations must be fully prioritized in future research.

Senkyunolide H potentiates bone marrow-derived mesenchymal stem cells therapy for liver cirrhosis by targeting MAEA to enhance ERK-driven HGF secretion.

Mesenchymal stem cells therapy for Ischaemic stroke: Mechanism and progress.

Cell and gene therapies (CGT) have been increasingly translated into clinical practice over the past three decades; however, their development has been uneven across modalities and regions. Through a bibliometric analysis indexed in PubMed from 1989 to 2023, supplemented by citation and affiliation data from OpenAlex, we examined modality-specific progression under different regional and collaborative configurations and how transitions from basic to clinical research have emerged. Hematopoietic stem cell therapies have shown sustained growth in both clinical and high-impact publications, reflecting a mature field that remains scientifically relevant. In contrast, mesenchymal stem cell therapies experienced a rise in high-impact papers in the mid-2000s, but clinical publications stagnated, indicating a gap between academic interest and clinical applications. In gene therapy, the number of in vivo approaches increased in the 1990s. However, this was followed by a plateau in high-impact publications and a decline in clinical output, whereas ex vivo strategies have sharply increased since the mid-2010s, marking a transition toward tangible clinical translation. To further evaluate the global research landscape, we analyzed research activity and co-authorship patterns across countries and institutions in CGT. Our findings reveal distinct patterns of international collaboration. The United States and, more recently, China accounted for a large and growing share of CGT publications and high-impact papers, whereas Europe maintained steady contributions, and Japan's presence stagnated. Higher-impact output is generally associated with broader cross-border co-authorship, especially collaborations linking the United States and Europe, whereas collaborations involving China and Japan remain comparatively narrow. These results provide a data-driven foundation for guiding research policies and strategic cooperation in this evolving field.

Osteoarthritis is fundamentally a whole-joint disease, and a critical pathological feature is the limited capacity of articular cartilage for self-regeneration, leading to accelerated joint degeneration once breakdown begins. Current therapeutic strategies are primarily palliative, and conventional marrow stimulation procedures such as microfracture often yield suboptimal, short-lived outcomes. Stem cell-based biologic augmentation using mesenchymal stem cells has emerged as a promising approach through direct chondrocyte differentiation, paracrine stimulation, and immunomodulation. Umbilical cord-derived mesenchymal stem cells offer robust proliferative capacity, enhanced biological potency, and lower immunogenicity than adult mesenchymal stem cells, and can be obtained with minimal ethical concerns. Clinical trials of human umbilical cord blood-derived mesenchymal stem cells combined with hyaluronic acid hydrogel (CARTISTEM®) have demonstrated excellent safety, improved patient-reported outcomes, and durable hyaline-like cartilage regeneration. Emerging evidence further suggests that combining high tibial osteotomy with human umbilical cord blood-derived mesenchymal stem cells-based cartilage regeneration for medial compartment osteoarthritis with varus malalignment creates a synergistic biological and mechanical environment that promotes structural cartilage repair. In conclusion, surgically transplanted human umbilical cord blood-derived mesenchymal stem cells show therapeutic potential in arthritic knees, although the role of intra-articular injections and the optimal indications for combined high tibial osteotomy remain to be clarified.

Mesenchymal stem cells (MSCs) show therapeutic effects for acute liver failure (ALF), as demonstrated in small animal models of ALF, which showed improved survival and liver function. Nevertheless, small animal models are limited by their simplified immune systems and lower pathophysiological complexity, which prevent them from fully capturing the key features of human ALF. Large animal models offer better physiological similarity; however, the effectiveness of MSC therapy on large animal models of ALF, such as pigs and monkeys, remains unclear. In this study, we performed a meta-analysis to comprehensively evaluate the therapeutic effect and safety of MSC therapy in large animal models of ALF. A comprehensive search was conducted across PubMed/Medline, Web of Science, Embase, and the Cochrane Library for studies published prior to 3 March 2025. Of the 609 identified studies, 13 were included, with the majority showing a low or unclear risk of bias. The results of the meta-analysis indicated that MSC therapy was associated with a higher survival rate and lower levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in large animal models with ALF, compared with the control groups. Subgroup analyses showed efficacy in both pig and monkey models. Furthermore, they showed that bone marrow-derived mesenchymal stem cells and the deep vein transplantation route were each linked to a significantly higher survival rate and to lower ALT and AST levels after treatment in pigs with ALF. Additionally, a dose of (3.0-3.3) × 106/kg was associated with a significantly higher survival rate, as well as a lower AST level after treatment. In summary, the findings suggest MSC therapy is a safe and potential therapeutic option for large animals with ALF, although randomized controlled trials (RCTs) are needed for further validation.

Diabetic retinopathy (DR) is a microvascular and retinal neurologic disorder that occurs in patients with long-term diabetes. Umbilical cord blood-derived mesenchymal stem cell (UCB-MSC) therapy has emerged as a promising treatment because of its regenerative potential; however, its effectiveness is limited under hyperglycemic conditions, which results in the overproduction of mitochondrial reactive oxygen species (mtROS), leading to cellular senescence. In this study, we examined the potential of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, to enhance the efficacy of MSCs in a high glucose environment, which is typical of DR. Increased glucose levels enhanced glucose uptake, primarily through glucose transporter 3 (GLUT3) overexpression, which resulted in the excess generation of mtROS and ultimately induced cell death. Everolimus inhibited intracellular glucose levels and mtROS production, and increased the survival of MSCs under high glucose conditions. Everolimus also inhibited mTORC1, which resulted in reduced actin stabilization and decreased membrane translocation of GLUT3. This effect was associated with the down-regulation of cofilin phosphorylation, a key factor in actin dynamics, which further suppressed high glucose-induced glucose influx and mtROS generation. Furthermore, the results of the streptozotocin (STZ)-induced DR rat model indicated that the groups receiving a subconjunctival injection of GLUT3 knockdown or everolimus-pretreated UCB-MSCs in STZ rats showed improved retinal function compared with the untreated DR groups. Taken together, the results suggest that everolimus enhances the viability and function of UCB-MSCs under hyperglycemic conditions by modulating glucose homeostasis and reducing oxidative stress. This represents a novel therapeutic strategy for the treatment of DR.

Acute and chronic kidney diseases are major clinical challenges in companion animals, yet therapeutic options for reversing established injury remain limited. Mesenchymal stem cells (MSCs) have emerged as a promising therapy due to their immunomodulatory and tissue-repair properties. This review synthesizes current evidence on MSC therapy for kidney disease in cats and dogs, with a focus on mechanisms, preconditioning strategies, delivery routes, and clinical outcomes. Key findings indicate that MSCs exert renoprotective effects primarily through paracrine-mediated immunomodulation rather than direct differentiation. Intravenous administration, while simple, results in >80% pulmonary entrapment and renal homing below 5%; arterial or local injection increases homing to 15-20% but carries procedural risks and lacks standardized dosing. Preconditioning strategies (hypoxia, melatonin, ATRA) enhance MSC survival and homing in rodent models, but feline- and canine-specific validation remains limited. Clinical data from 19 studies in cats/dogs demonstrate that MSC therapy is generally safe, with most adverse events being infusion-related and transient. In feline CKD, consistent trends toward improved glomerular filtration rate and quality of life are reported, although statistical significance is rarely achieved. In canine AKI, MSC therapy improves survival and renal function, but results are heterogeneous and predominantly derived from experimentally induced models. Major evidence gaps include lack of dose standardization, variable MSC characterization, short follow-up durations, and limited long-term safety data. Moving forward, establishing consensus on weight-based dosing, MSC characterization standards, and multicenter randomized controlled trials in naturally occurring disease is essential to translate preclinical promise into clinical practice.

Fracture healing represents one of the most fundamental challenges in veterinary orthopaedic practice, encompassing the management of a diverse range of species, body sizes, fracture configurations, and clinical contexts. Achieving optimal fracture repair requires not only appropriate mechanical fixation but also the creation of a favourable biological environment conducive to bone regeneration. This review critically evaluates the evolving landscape of strategies employed to enhance fracture healing in veterinary patients, drawing on evidence from peer-reviewed literature published between 1996 and 2026. The mechanistic underpinnings of bone fracture healing are reviewed, followed by a systematic discussion of established and emerging interventions. These include conventional and advanced internal fixation techniques—notably locking compression plates and minimally invasive plate osteosynthesis (MIPO)—as well as biological adjuncts such as platelet-rich plasma (PRP), bone morphogenetic proteins (BMPs), and mesenchymal stem cell (MSC) therapy. Physical modalities including photobiomodulation therapy (PBMT) and extracorporeal shockwave therapy (ESWT) are evaluated in the context of their proposed mechanisms and clinical evidence in veterinary species. The role of three-dimensional (3D) printing and bone tissue engineering scaffolds in addressing critical-sized bone defects is also examined. The management of delayed union and non-union fractures, which represent the most clinically demanding complication of fracture treatment, is discussed in detail. Species-specific considerations for small animals, equines, and large ruminants are addressed throughout. The review identifies significant gaps in comparative evidence across veterinary species and calls for more rigorously designed clinical trials. A multimodal, biologically informed approach appears to offer the greatest potential for optimising fracture healing outcomes in diverse veterinary patients. The rapid pace of development in regenerative medicine, biomaterials science, and additive manufacturing means that some of the most recent advances may not yet have been fully evaluated at the time of this review, and practitioners are encouraged to monitor emerging literature critically and with appropriate methodological scrutiny.

Mesenchymal stem cell-derived exosomes (MSC-exo), natural functional nanovesicles, are considered a potent alternative for MSC therapy for the treatment of systemic lupus erythematosus (SLE); however, the molecular mechanisms underlying their therapeutic effects remain elusive. Here, we report that cytidine/uridine monophosphate kinase 2 (CMPK2) is markedly upregulated in monocytes/macrophages from both SLE patients and murine lupus models. CMPK2 overexpression promoted M1 macrophage polarization and induced mitochondrial dysfunction, leading to activation of the cGAS-STING pathway. Conversely, CMPK2 knockdown potently suppressed cytoplasmic mtDNA release and abrogated the induction of cGAS, STING, and IFN-β in macrophages stimulated with LPS/IFN-γ. Treatment with MSC-exo markedly ameliorated disease progression in lupus-prone mice and reprogrammed macrophage phenotypes in splenic and renal microenvironments. Mechanistically, MSC-exo downregulated CMPK2 expression and attenuated cGAS-STING activation, thereby restoring mitochondrial integrity as evidenced by increased mitochondrial mass, reduced mitochondrial ROS generation, and recovery of mitochondrial membrane potential. Our findings uncover a key mechanism through which MSC-exo modulate immune and inflammatory responses in SLE, providing a mechanistic foundation for their therapeutic application and highlighting CMPK2 as a potential target for future biomarker-driven and bioengineering-enhanced treatment strategies.

Pulmonary fibrosis is a debilitating lung disease for which effective therapies remain limited. In this study, we developed a mesenchymal stem cell (MSC)-based delivery system incorporating PDA@Au/CeO2 nanoparticles (MSCs-PDA@Au/CeO2/NT) for targeted antifibrotic therapy and imaging guidance. PDA@Au/CeO2 nanoparticles showed excellent biocompatibility, efficient MSC uptake, and superior CT imaging performance. In TGF-β1-induced fibroblast models, the composite system markedly inhibited myofibroblast differentiation, suppressed ROS accumulation, and selectively induced apoptosis of aberrantly activated fibroblasts while preserving MSC viability. In bleomycin-induced pulmonary fibrosis mice, MSCs-PDA@Au/CeO2/NT significantly improved lung architecture and function, decreased collagen deposition, and modulated the immune microenvironment by downregulating fibrosis-related signaling pathways. Biosafety assessments confirmed no significant systemic toxicity. This study demonstrates a safe and effective nanomaterial-assisted stem cell strategy for pulmonary fibrosis treatment and potential clinical translation.

Acute lung injury (ALI) is characterized by uncontrolled inflammation, oxidative stress, and fibrotic remodeling, yet mesenchymal stem cell (MSC) therapies remain limited by poor retention and insufficient microenvironmental adaptation. Here, we engineered a composite system, GelMA@hMSCs-Alg-RGD (hereafter referred to as the sandwich composite), in which RGD (Arg-Gly-Asp) -functionalized alginate microbeads support human MSCs and are encapsulated within an adhesive, stress-relaxing dopamine-modified GelMA (GelMA-DA) hydrogel. This design provided a 3-dimensional low-tension niche that preserved MSC identity while enhancing paracrine potency, antioxidative capacity, and resistance to apoptosis. Conditioned media from hMSCs-Alg-RGD promoted endothelial proliferation, migration, invasion, and tube formation, while attenuating oxidative stress in a partially cytoskeleton-dependent manner. In fibroblasts, treatment suppressed alpha-smooth muscle actin stress fiber formation, focal adhesion maturation, and Yes-associated protein nuclear translocation, thereby preventing myofibroblast differentiation and restoring isotropic morphology. GelMA@hMSCs-Alg-RGD enabled rapid gelation, robust wet adhesion, stress-relaxing mechanics, and controlled degradation, resulting in prolonged pulmonary retention confirmed by in vivo and ex vivo imaging. In murine ALI, this strategy alleviated edema, reduced inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and interleukin-1β), myeloperoxidase activity, and lipid peroxidation (malondialdehyde), while enhancing superoxide dismutase activity, improving survival, and reshaping the immune microenvironment through reduced neutrophil infiltration and enhanced macrophage M1 → M2 polarization. Together, these results establish GelMA@hMSCs-Alg-RGD as a bioengineered therapeutic that integrates localized retention with paracrine amplification to reprogram immune and mechanical microenvironments, offering a broadly applicable platform for MSC-based regenerative medicine.