Mesenchymal stem cells (MSCs) are multipotent stromal cells with dual regenerative and immunomodulatory properties that have attracted growing attention in cancer therapy. Their inherent tumor-homing ability enables localized delivery of therapeutic agents, while their capacity to regulate both innate and adaptive immunity positions MSCs at the interface of stromal biology and cancer immunotherapy. However, MSC functions are highly context-dependent and vary across tumor types. This review summarizes preclinical and clinical evidence on the immunomodulatory roles of MSCs in cancer. Experimental studies and early-phase clinical trials involving unmodified, preconditioned, and genetically engineered MSCs, as well as MSC-derived extracellular vesicles, were evaluated. Unmodified MSCs often promote immune evasion by expanding regulatory T cells, expressing checkpoint ligands, and secreting immunosuppressive and metabolic mediators, such as IDO, nitric oxide, and PGE2. In contrast, engineered or primed MSCs can redirect immune responses toward activation, enhancing NK- and T-cell cytotoxicity and enabling targeted delivery of cytokines, oncolytic viruses, and pro-apoptotic ligands. Early clinical trials generally demonstrate safety and feasibility; however, efficacy remains variable due to heterogeneity of MSC sources, manufacturing challenges, and lack of standardized potency assays. Notably, tumor-promoting effects have been reported under specific conditions. MSCs Represent a highly plastic and programmable platform for immune modulation in cancer. Advances in genetic engineering and extracellular vesicle-based strategies may improve therapeutic efficacy while reducing oncogenic risk.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by relapsing and remitting colonic mucosal inflammation. Rodent dextran sodium sulfate (DSS) induced colitis models are widely used but have limited translational relevance due to anatomical and physiological differences. As a pilot feasibility study, this work aimed to explore whether graded DSS administration could induce reproducible colitis-like features in minipigs. We developed a pilot large-animal UC model using Sus scrofa minipigs. Eight male Micropigs® were divided into four groups, with three groups receiving DSS at 0.2, 0.4, or 0.8 g/kg/day for 7 days. Clinical signs, body weight, colon length, endoscopic evaluation, and histopathology were assessed. DSS administration induced dose-dependent UC features. Group 4 minipigs (0.8 g/kg/day) showed the most severe clinical manifestations, including diarrhea, anorexia, and lethargy. Colon length was reduced by 34
Mesenchymal stem cells (MSCs) are multipotent mesoderm-derived cells with high proliferation capacity, self-renewal, paracrine activity, and multilineage differentiation potential. Autologous MSCs from the same patients are particularly valuable for regenerative therapies, including those targeting degenerative intervertebral disc disorder (DIVDD). In this study, we directly compared autologous MSC sources obtained from the same patients, thereby reducing biological variability and strengthening translational relevance. We compared MSCs isolated from bone marrow (BM–MSCs), adipose tissue (AD–MSCs), and nucleus pulposus (NP–MSCs) obtained from the same DIVDD patient donor (N = 10 donors). We assessed their morphologies, proliferation abilities, immunophenotype, multilineage differentiation capacity, and chondrogenic differentiation–related gene and protein expression. All three MSC populations displayed similar fibroblast-like morphology and consistent immunophenotypic profiles. However, their functional properties differed: AD–MSCs exhibited significantly higher proliferative activity and greater adipogenic differentiation potential (p < 0.01 and p < 0.001), while osteogenic and chondrogenic differentiation capacities were comparable across BM-MSCs, AD-MSCs, and NP-MSCs at both gene and protein levels (SOX9 and COMP). These findings suggest that AD-MSCs offer practical advantages in terms of proliferation capacity and accessibility. However, chondrogenic differentiation capacity was largely comparable across MSC sources. Further mechanistic studies and in vivo validation are required to determine their relative therapeutic efficacy for intervertebral disc regeneration.
The involvement of circRNAs in tumors, such as non-small cell lung cancer (NSCLC), has been established. The objective of this research was to examine the function and regulatory mechanism of hsa_circ_0008758 (circ_0008758) in NSCLC. The expression of circ_0008758 in NSCLC tissues and cell lines was evaluated by RT-qPCR. Cell proliferation was assessed using the CCK-8 assay and colony formation assay. Apoptosis was evaluated through flow cytometry. Cell migration was measured using the scratch test, while cell invasion was determined using the transwell assay. The Warburg effect was assessed by measuring glucose uptake and lactic acid production using commercially available kits. The targeting relationship between miR-361-3p and circ_0008758 or SPIN1 was confirmed through a bioinformatics website analysis and a dual-luciferase reporter assay. The MDM2/FOXO3a/PGK1 pathway was examined by Western blot analysis. circ_0008758 expression was augmented in NSCLC. Inhibiting circ_0008758 or elevating miR-361-3p resulted in decreased proliferation, migration, invasion, and Warburg effect in NSCLC cells, while promoting cell apoptosis. The opposite effect could be obtained by up-regulating circ_0008758 or down-regulating miR-361-3p. Furthermore, circ_0008758 was found to enhance SPIN1 expression by acting as a sponge for miR-361-3p. Up-regulating SPIN1 counteracted the effects of circ_0008758 down-regulation on NSCLC cells. Additionally, circ_0008758 was found to activate the MDM2/FOXO3a/PGK1 pathway by the miR-361-3p/SPIN1 axis. circ_0008758 promotes the Warburg effect in NSCLC through the miR-361-3p/SPIN1 axis and by activating the MDM2/FOXO3a/PGK1 pathway.
To evaluate whether the application of cell-free adipose liquid extract (ALE) synergistically enhances the therapeutic efficacy of vascularized lymph node transfer (VLNT) by reconstructing the lymphatic-vascular network and restoring the lymph node immune niche in a rat lymphedema model. A rat hindlimb lymphedema model was established involving popliteal lymph node excision. Animals were randomized into four groups: Control, ALE only, VLNT only, and VLNT combined with ALE (VLNT + ALE). ALE was prepared using a mechanical emulsification and filtration protocol. Edema resolution was monitored by limb circumference. Lymphatic drainage function was visualized via indocyanine green (ICG) lymphography. Histological assessments included Masson’s trichrome and immunofluorescence for LYVE-1 (lymphangiogenesis), CD31 (angiogenesis), and MECA-79 (high endothelial venules, HEVs) to evaluate structural and functional regeneration. The VLNT + ALE group achieved the most rapid and significant edema regression compared to VLNT or ALE alone. ICG lymphography revealed that the combined therapy orchestrated the formation of continuous, linear lymphatic channels, effectively eliminating dermal backflow. Histologically, ALE treatment significantly increased the density of both LYVE-1+ lymphatic vessels and CD31+ blood vessels, suggesting a dual-regenerative effect on the microenvironment. ALE directly promoted tube formation in human lymphatic endothelial cells (HLECs), confirming its pro-lymphangiogenic activity in vitro. Crucially, within the transplanted lymph nodes, ALE treatment restored the expression of MECA-79+ HEVs to levels comparable to healthy young nodes. This indicates that ALE not only supports graft survival but also preserves the essential lymphoid microarchitecture required for immune surveillance. Cell-free ALE synergistically enhances the therapeutic efficacy of VLNT by promoting vascular-lymphatic coupling and restoring the functional immune niche of transplanted nodes. As a readily available, safe, and cell-free biologic adjuvant, ALE represents a promising translational strategy to optimize surgical outcomes in secondary lymphedema.
Autogenous tooth bone graft (AutoBT), derived from extracted teeth, has emerged as a promising alternative for bone regeneration due to its osteoinductive and osteoconductive properties. Its structural and compositional similarity to bone supports physiologic bone regeneration, and it has been successfully applied in various clinical procedures. However, despite its increasing clinical application, evidence regarding the long-term outcomes of AutoBT in large cystic defects remains limited. A 22-year-old woman presented with a 4-cm multilobular radiolucent lesion in the left mandible that was diagnosed as an odontogenic keratocyst (OKC). Following a period of decompression, cyst enucleation and bone grafting were performed using AutoBT combined with recombinant human bone morphogenetic protein-2 (rhBMP-2). Radiographic follow-up at 1.5 months, 1 year, and 3 years postoperatively demonstrated stable bone remodeling, reestablishment of the cortico-cancellous architecture, and no evidence of recurrence. The postoperative clinical course was uneventful. This case demonstrates successful long-term bone regeneration using AutoBT combined with rhBMP-2 in a large mandibular OKC defect. Although limited to a single case, these findings support the potential of AutoBT combined with rhBMP-2 as a reliable graft material for extensive jawbone lesions. Further studies are needed to validate its long-term efficacy and safety.
Essential oils (EOs) derived from plants have been utilized for the development of various approaches in biomedical applications due to their superior properties. In particular, their antimicrobial, anti-inflammatory, antioxidant, and wound-healing effects, alongside their biocompatibility and biodegradability, have made EOs a significant complementary agent in tissue regeneration-focused applications. Initial uses of EOs focused primarily on direct application and evaluation of their therapeutic efficacy; however, these approaches have been limited by issues such as volatility, instability, and potential for irritation. This review focuses on current perspectives in tissue engineering strategies, based on the biological functions of EO, such as biocompatibility, antimicrobial, anticancer, and antioxidant properties. Based on this comprehensive background of biological functions, current studies addressing nanoparticle systems, smart delivery systems, and wound dressings and coatings have been analyzed to identify existing issues and strategies to tackle these challenges. In skin tissue engineering applications, innovative strategies such as nanoparticle encapsulation, integration into smart delivery systems, and the development of wound dressings containing EO have been developed. These advanced approaches offer advantages such as improved EO stability, controlled release, and enhanced efficacy, while also enriching the biofunctionality of the platform. While advanced delivery systems improve the stability of EOs, long-term stability under physiological and clinical conditions remains challenging. However, compared to conventional methods, these advancements strengthen the potential of EOs to drive tissue repair processes in a more controlled and functional manner. The integration of EO-based tissue engineering with nanotechnology offers a promising approach to optimizing the biological effects of these systems and enhancing the success of their application. Although challenges such as safety, biomaterial interactions, and scalability persist, recent advancements are rapidly overcoming these obstacles. EO-based strategies hold significant potential for overcoming current limitations and advancing the field, particularly in skin tissue engineering.
Exosomes derived from mesenchymal stem cells (MSCs) have garnered significant research interest for their roles in promoting wound healing and preventing scar formation. Studies have shown that MSC-derived exosomes (MSC-Exos) accelerate the repair of cutaneous and corneal wounds through multiple mechanisms, including modulation of cell migration, anti-inflammatory responses, inhibition of apoptosis, collagen remodeling, and promotion of angiogenesis. Notably, exosomal miRNAs play a pivotal role in inhibiting fibroblast-to-myofibroblast transformation and modulating the TGF-β signaling pathway, thereby effectively reducing scar formation. Promising outcomes of exosomes derived from adipose tissue- and umbilical cord blood-derived MSCs in various wound models underscore their clinical potential. This review systematically elaborates on the specific mechanisms by which MSC-Exos promote wound healing and inhibit scar formation, and summarizes their application outcomes in different wound models. Additionally, it explores current advanced biomaterial delivery systems designed to optimize exosome delivery, aiming to provide insights and future directions for the clinical translation of MSC-Exos. MSC-Exos effectively promote tissue repair and reduce scarring through multi-target and multi-pathway mechanisms, demonstrating significant clinical application prospects. Delivery systems incorporating biomaterials hold promise for further enhancing their therapeutic efficacy and stability. Future research should focus on elucidating the molecular mechanisms of exosome action, developing scalable preparation protocols, and conducting preclinical and clinical evaluations to advance their translation into clinical therapeutic applications.
Tonsil-derived mesenchymal stem cells (TMSCs) are widely used in regenerative medicine due to their high proliferative capacity and differentiation potential. However, their origin from immunological gateways exposes them to pathogens, raising concern about viral contamination during cell preparation. Understanding how these pathogens affect the biological and immunological properties of TMSCs is crucial for ensuring the safety and consistency of cell-based therapies. This study evaluated TMSC susceptibility and molecular responses to mammalian orthoreovirus (MRV). MRV infectivity in TMSCs and the innate immune responses were investigated using RNA-seq. Viral replication was confirmed by viral titration, L1 segment RT-PCR, and transcriptome mapping. Cellular impact was assessed using Live/Dead assays and protein–protein interaction network analysis. TMSCs were infected with MRV strains to evaluate their susceptibility. Although no significant cytopathic effects were observed, the cells exhibited high viral permissivity to MRV, with stable viral titers of 3.9–5.5 log TCID50/ml and positive L1 gene segment RT-PCR. RNA-seq confirmed active replication, with reads successfully mapped to the MRV genome. Transcriptomic profiling showed robust induction of antiviral and stress response genes, including HSPA6, PEG10, OASL, and IFIT2. Gene set enrichment and protein network analyses highlighted enrichment of viral defense pathways and identified IL1B, ISG15, and RSAD2 as key hub genes driving the host inflammatory immune response. MRV establishes a permissive but non-cytopathic infection in TMSCs, triggering innate immune activation through upregulation of IL1B, ISG15, and RSAD2. This virus-induced shift from a quiescent to an immunomodulatory phenotype may compromise therapeutic consistency. Because visual quality control fails to detect latent infections, rigorous viral monitoring during TMSC preparation is essential to ensure safety in clinical applications.
Small extracellular vesicles (sEVs) are nanoscale, membrane-bound vesicles mediating intercellular communication by transferring bioactive molecules, including nucleic acids, proteins, lipids, and metabolites. Electrical stimulation (ES) has emerged as a bioengineering strategy for modulating cellular electrophysiology, calcium signaling, and vesicle secretion. Although ES is increasingly recognized as a regulator of sEV biology, its effects on sEV biogenesis, cargo composition, and regenerative function have not been systematically defined. Therefore, this review aims to synthesize current evidence to clarify the influence of ES on sEV biogenesis, release, cargo remodeling, and functional outcomes in regenerative contexts. Relevant published literature was reviewed to summarize current evidence on the effects of electrical stimulation on sEV biogenesis, secretion, cargo composition, and regenerative function. Articles were selected based on their relevance to ES-mediated sEV regulation, electrically responsive tissues, and regenerative medicine applications. The reviewed studies indicate that ES can regulate sEV secretion and alter molecular cargo profiles in a context-dependent manner. Evidence from diverse electroresponsive tissue-related systems suggests that ES-modulated sEVs may contribute to regenerative and tissue-protective responses. This review summarizes current evidence on ES–mediated sEV modulation across electroresponsive tissues. Given remaining challenges in standardization and in vivo mechanistic validation, we propose future directions including advanced EV tracking and cell-type-specific analyses. Overall, ES-enabled sEV modulation represents a promising strategy for next-generation regenerative therapies.
Pelvic organ prolapse (POP) occurs due to the weakening of the pelvic floor connective tissues and their decreased collagen content, leading to the descent of pelvic organs into or through vagina. Therefore, biodegradable materials designed to enhance collagen production could be a future option for POP treatment. Here, we studied novel L-ascorbic acid 2-phosphate (A2P)-releasing biodegradable poly(trimethylene carbonate) (PTMC) materials. The effects of varying A2P concentrations (0, 5 or 10 wt
BACKGROUND:This study aimed to explore the dental applications of AG73, a laminin-derived adhesive peptide, by examining its effects on human dental pulp cells (hDPCs), particularly in cell adhesion and mineralization. It also sought to identify the key functional residue of AG73 and the signaling pathways involved in its pro-mineralization activity. METHODS:We compared AG73's pro-mineralization activity with peptides derived from LAMA5 using alizarin red staining. Immunofluorescence staining assessed its cell adhesion properties. Alanine-scanning mutagenesis was performed to identify key residues for AG73's adhesion activity. Finally, we used p38 and JNK MAPK inhibitors to determine which signaling pathways were involved in AG73-induced mineralization. RESULTS:AG73 exhibited superior pro-mineralization activity compared to other peptides derived from LAMA5 in hDPCs. Immunofluorescence staining confirmed AG73's strong cell adhesive ability within 20 minutes. Alanine-scanning identified isoleucine at the tenth position as crucial for adhesion. AG73 was the most effective peptide in inducing mineralization, with no mutated versions outperforming it. p38 signaling was found to play a positive role in AG73-induced mineralization, while JNK inhibition enhanced mineralization, suggesting JNK inhibitors as potential inducers. CONCLUSION:AG73 has strong pro-mineralization activity and significant cell adhesive properties in hDPCs. The isoleucine at the tenth amino acid position was identified as a critical residue for AG73's adhesive ability. Additionally, p38 was found to be involved in AG73-regulated mineralization, while JNK inhibition promoted the process. This is the first study to explore AG73's effects in hDPCs and provides a foundation for its potential use as a dental-pulp regenerative material.
BACKGROUND:Ventral midbrain dopaminergic (vmDA) neurons derived from human pluripotent stem cells provide a powerful platform for modeling Parkinson's disease (PD) and developing therapeutic strategies. Although robust protocols exist for generating vmDA progenitors, maturation into functionally competent neurons typically requires prolonged culture periods and occurs with substantial heterogeneity in maturity, representing major bottlenecks. METHODS:Building on established protocols for vmDA progenitor differentiation, we introduce a sequential strategy that specifically targets the subsequent phases of neuronal conversion and postmitotic maturation. Transient overexpression of the proneural transcription factor achaete-scute family bHLH transcription factor 1 (ASCL1) was applied to human embryonic stem cell-derived vmDA progenitors to induce neuronal commitment, followed by accelerated postmitotic maturation using the small-molecule cocktail GENtoniK. This approach was evaluated in CRISPR/Cas9-engineered human induced pluripotent stem cell (hiPSC) lines lacking either PINK1 or PRKN and their isogenic control hiPSCs. RESULTS:Transient ASCL1 overexpression promoted rapid cell cycle exit and neuronal conversion of vmDA progenitors while preserving ventral midbrain identity and dopaminergic fate. Subsequent GENtoniK treatment enhanced postmitotic dopaminergic maturation and increased neurite complexity, synaptic organization, and dopaminergic neurotransmission without altering lineage specification. Consequently, within two weeks, our protocol yielded high-purity vmDA neurons with enhanced functional maturation from vmDA progenitors. Importantly, PINK1- and PRKN-deficient neurons generated from CRISPR/Cas9-engineered hiPSC lines using this strategy recapitulated key PD-associated mitochondrial phenotypes, including impaired mitophagy, mitochondrial dysfunction, and elevated oxidative stress. CONCLUSION:Taken together, these findings address the central limitations of current dopaminergic differentiation paradigms by enabling the rapid and uniform acquisition of advanced functional maturity, thereby providing a robust platform for disease modeling and translational research in PD.
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by β-cell dysfunction and insulin resistance with limited treatment options. The targeting of pancreatic β-cell apoptosis and dedifferentiation represents a promising approach for T2DM therapy. Recently, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have demonstrated repair potential for metabolic diseases. However, the effects of MSC-EVs on β-cell apoptosis and dedifferentiation in T2DM remain largely unclear. We established db/db mouse model and high glucose-stimulated MIN6 cell model to evaluate the therapeutic efficacy of MSC-EVs in vivo and in vitro. Transcriptome sequencing, proteomic analysis, and microRNA (miRNA) sequencing were applied to explore the molecular mechanism underlying MSC-EV-induced β-cell protection. MSC-EVs significantly mitigated hyperglycemia, improved glucose tolerance, and restored β-cell function by preventing β-cell loss and reducing dedifferentiated β-cell populations in db/db mice. Mechanistically, MSC-EV treatment reversed hyperglycemia-induced ecotropic virus integration site 1 (EVI1) upregulation in β cells, and EVI1 knockdown significantly suppressed β-cell apoptosis and dedifferentiation by promoting forkhead box protein O1 (FOXO1) expression. MiRNA sequencing revealed that miR-4436 enriched in MSC-EVs inhibited EVI1 expression by directly binding to EVI1 mRNA. MiR-4436 knockdown abolished the therapeutic effects of MSC-EVs in T2DM MSC-EVs inhibit pancreatic β-cell loss and dedifferentiation by miR-4436-mediated EVI1/FOXO1 regulation. Therefore, MSC-EV administration may represent a promising therapeutic strategy for T2DM
Gemcitabine (GE) is a widely used chemotherapeutic agent for solid tumors; however, its therapeutic efficacy is often compromised by rapid diffusion from the tumor site and insufficient intratumoral retention following local administration. Injectable hydrogel-based drug depots offer a promising strategy to prolong local drug availability and enhance antitumor efficacy while minimizing systemic toxicity. An intratumoral injectable, gemcitabine-loaded, click-crosslinked hyaluronic acid hydrogel (GE + Cx-HA) was developed using a bioorthogonal click reaction to enable rapid in situ gelation. Physicochemical properties, gelation behavior, viscoelasticity, and injectability through a fine-gauge needle were characterized. In vitro gemcitabine release profiles and anticancer activity against B16F10 melanoma cells were evaluated. Antitumor efficacy, angiogenesis inhibition, and systemic toxicity were assessed in a murine melanoma model following a single intratumoral injection. GE + Cx-HA remained in a low-viscosity solution state prior to injection and rapidly formed a stable hydrogel depot upon click crosslinking without needle clogging. The crosslinked network significantly suppressed burst release and enabled sustained gemcitabine release in vitro. Compared with free gemcitabine, GE + Cx-HA exhibited prolonged anticancer activity against B16F10 melanoma cells. In vivo, a single intratumoral administration of GE + Cx-HA markedly inhibited tumor growth and angiogenesis for up to 18 days, without observable systemic toxicity. These results demonstrate that GE + Cx-HA functions as an effective intratumoral drug depot, providing sustained local chemotherapy and enhanced antitumor efficacy, highlighting its potential as a localized therapeutic platform for solid tumor treatment.
It was found that pressure can promote the regeneration and repair of cartilage defects based on bone marrow mesenchymal stem cells (BMSCs). Since the compressive microenvironment of the cartilage in vivo may change with different movement, the mechanobiological effects of different compressive condition on BMSCs, especially the impact for its chondrogenic differentiation and influence on the cartilage microenvironment, is what we concerned about. Rat BMSCs were cultured and subjected to various types of pressure stimulation for 1 h. The Cell Counting Kit-8 (CCK-8) assay was used to analyze cell proliferation, flow cytometry was employed to assess the cell cycle and apoptosis, confocal microscopy was used to observe the cytoskeleton, and transmission electron microscopy was performed to examine the cellular ultrastructure. RT-PCR was used to identify chondrogenic differentiation markers. Apoptotic vesicles derived from BMSCs were isolated by ultracentrifugation, and differentially expressed microRNAs in these vesicles under − 40 kPa compression were identified by transcriptome sequencing. Specific pressure conditions promoted the proliferation of BMSCs, with dynamic pressure showing a stronger proliferative effect than static pressure. Higher static negative pressure (− 40 kPa) significantly increased the spreading area of BMSCs. Dynamic pressure is stronger than static pressure in promoting cytoskeletal rearrangement, stress fiber formation, and cartilage marker expression in BMSCs. Flow cytometry and transmission electron microscopy results show that both − 40 kPa static and 90 kPa dynamic pressures promote BMSCs apoptosis to some extent. Under − 40 kPa static negative pressure, the differentially expressed microRNAs in BMSCs-derived apoptotic vesicles are involved in stem cell maintenance and chondrogenic proliferation processes. Static negative pressure (− 40 kPa) induces apoptosis in bone marrow mesenchymal stem cells (BMSCs). Notably, compared to chemical induction with staurosporine (STS), BMSCs subjected to − 40 kPa mechanical stimulation display distinct microRNA expression profiles within apoptotic vesicles, specifically enriched in microRNAs implicated in stem cell fate determination and cartilage regeneration. These findings offer valuable insights into biomechanical strategies for optimizing tissue-engineered cartilage repair.
The biological characteristics of mesenchymal stromal cells (MSCs) and their exosomes can vary depending on the tissue layer of origin, potentially influencing their regenerative capacity. This study aimed to determine whether exosomes derived from epithelial (TE-MSCs) and parenchymal (TP-MSCs) layers of human tonsils exhibit distinct therapeutic effects in oral mucositis (OM). MSCs Were isolated from the epithelial (TE-MSCs) and parenchymal (TP-MSCs) layers of human tonsils. Exosomes were characterized and tested for regenerative and anti-inflammatory effects in vitro and in a 5-FU-induced OM hamster model Both TP-MSCs and TE-MSCs exhibited typical MSC phenotypes and multipotency comparable to BMSCs. Transcriptomic profiling revealed distinct layer-specific features, with TE-MSCs enriched in developmental and morphogenetic pathways. TE-MSC-derived exosomes (TE-MSC-Exo) showed enhanced wound closure, downregulation of IL-1β and TNF-α, and selective induction of HGF and ICAM-1 expression. In vivo, TE-MSC-Exo treatment resulted in the smallest mean wound size and most complete re-epithelialization among experimental groups. Exosomes derived from tonsil MSCs effectively promote epithelial regeneration in OM, with TE-MSC-Exo exhibiting enhanced therapeutic potential. These findings highlight the importance of MSC layer origin in defining exosome function and suggest that TE-MSC-Exo may serve as a promising platform for exosome-based mucosal repair therapies.
Flap transplantation plays a vital role in wound reconstruction. However, the mechanisms by which remote ischemic preconditioning (RIPC) may improve flap survival remain incompletely understood. Rats were randomly assigned to three groups: sham, ischemia/reperfusion (I/R), and RIPC + I/R. The I/R model was established by ligating the iliopsoas and thoracodorsal arteries to induce flap ischemia, followed by reperfusion. RIPC was performed via limb clamping. A combination of high-throughput sequencing, functional cellular assays, and live imaging was used to assess gene expression, cellular functions, and flap viability. RIPC upregulated the expression of ZNF667. This protein acted as a transcriptional repressor of VHL by binding to its promoter region, where it competitively inhibited the recruitment of histone-modifying enzymes, including MLL3/4, SETD1A, and EP300. Consequently, histone methylation and acetylation were reduced, leading to suppressed VHL transcription. The downregulation of VHL diminished the ubiquitination-mediated degradation of hypoxia-inducible factor-1α (HIF-1α), which in turn enhanced the expression of stromal cell-derived factor 1 (SDF1). This signaling cascade promoted the proliferation, migration, differentiation, and tube-forming capacity of endothelial progenitor cells (EPCs). Live imaging confirmed that RIPC stimulated the recruitment of EPCs into the flap tissue, accompanied by increased microvessel density. These effects collectively enhanced angiogenesis and significantly reduced the area of flap necrosis. RIPC improves flap survival by modulating the ZNF667–VHL–SDF1 axis and augmenting the function of EPCs. These findings not only provide a potential therapeutic strategy for flap transplantation but also advance our understanding of the mechanisms underlying flap survival.
BACKGROUND:In cartilage tissue engineering, successfully mimicking the natural extracellular matrix is essential for promoting hyaline cartilage regeneration. The triple-helix structure of collagen has been identified as a critical element in this process, though preserving this structure while minimizing immunogenicity remains a significant challenge. METHODS:This study employed high-precision enzymatic digestion technology to specifically remove immunogenic terminal fragments from collagen while preserving its functional triple-helix configuration. The resulting collagen-based hydrogel was engineered with thermosensitive properties, enabling it to adaptively fill irregular cartilage defects and undergo rapid gelation at body temperature. RESULT:The modified collagen hydrogel demonstrated significantly improved biological safety, with complement activation levels substantially decreasing following removal of terminal peptide segments-confirming the immunogenic role of these regions. Mechanically, the hydrogel successfully replicated the viscoelastic characteristics of natural cartilage, exhibiting matched dynamic mechanical properties capable of cushioning shear-induced damage. Its porous architecture facilitated accelerated nutrient transport while supporting effective cell adhesion and guiding organized proteoglycan deposition with minimal fibrosis. In vivo evaluation revealed a 30.7% higher MOCART score in the experimental group compared to controls, with mechanical properties closely approximating those of healthy native cartilage. CONCLUSION:Collagen hydrogels that maintain the triple-helix structure represent a highly promising biomaterial platform for cartilage regeneration, combining excellent biocompatibility, functional mechanical properties, and significant tissue repair capability while effectively addressing the critical challenge of immunogenicity through targeted terminal peptide removal.
Asherman's Syndrome or intrauterine adhesions develop due to acquired endometrium damage, resulting in partial to complete dysfunction of the endometrium within the uterine cavity. The pathophysiology of these adhesions is not clear. Still, the widely accepted mechanism for the development of these adhesions is attributed to three different causes: i. iatrogenic or mechanical, including curettage; ii. pathophysiological conditions, including infection, miscarriage, and Müllerian malformations; and iii. idiopathic. This review critically evaluates the different therapeutic strategies used to manage or treat Asherman’s syndrome and the various issues associated with each treatment. A thorough literature review was performed for other types of polymers currently used or tested for the regeneration of endometrium both clinically and preclinically, and the issues associated with each of the polymers are also discussed. Finally, we conclude the manuscript by exploring Artificial Intelligence’s role in predicting, classifying, and identifying intrauterine adhesions, including machine learning and deep learning algorithms. We also discuss the role of AI in improving biomaterial properties, enhancing stem cell viability, and refining AI-driven diagnostic and therapeutic strategies for better clinical outcomes. In alignment with the United Nations Sustainable Development Goal 4 (Quality Education), this review aims to promote advanced interdisciplinary learning by integrating biomedical engineering, materials science, and artificial intelligence to educate and empower future researchers in regenerative medicine.
