Advanced biology最新文献

Stem cells from human exfoliated deciduous teeth (SHED) and their derivatives have emerged as promising therapeutic agents for treating immune-mediated inflammatory diseases (IMIDs). IMIDs are characterized by dysregulated immune responses, leading to chronic inflammation and tissue damage. The current treatment landscape for IMIDs faces challenges, including the complexity of disease mechanisms and the limitations of existing therapies, which frequently fail to achieve long-term remission and are often associated with significant side effects. Consequently, there is a pressing need for innovative therapies that not only alleviate symptoms but also address the underlying immune dysfunction and promote the repair of damaged tissues. In this context, SHED and their derivatives offer a dual therapeutic advantage by harnessing both immunomodulatory and regenerative capacities. Research highlighted in this review demonstrates the therapeutic potential of SHED and their derivatives in multiple IMIDs, such as systemic lupus erythematosus, Sjögren's syndrome, multiple sclerosis, and rheumatoid arthritis. Critically, the aim of this review is not only to synthesize recent progress in SHED research for IMID treatment but also to highlight the strategic significance of innovative therapies emerging from the intersection of regenerative medicine and immunology.

KDM1A is a crucial epigenetic modulator in tumor immune escape. Nevertheless, its precise regulatory function within the immune microenvironment of lung cancer needs investigation. Using TCGA data, we analyzed KDM1A and SBNO2 expression, clinical correlation, and immune infiltration. Functional assays included co-culture of lung cancer cells with CD8⁺ T cells, flow cytometry, Transwell migration, ChIP, and luciferase reporter assays. qPCR measured gene expression. KDM1A and SBNO2 were notably upregulated in lung cancer tissues, which correlated with poor patient prognosis and reduced CD8⁺ T cell infiltration. Functional experiments demonstrated that knockdown of KDM1A enhanced T cell proliferation, chemotaxis, and cytokine production. Mechanistically, KDM1A acted as a transcription regulator binding to the SBNO2 promoter and positively regulated its mRNA expression in lung cancer cells. Importantly, rescue experiments confirmed that silencing SBNO2 expression abolished the pro-tumor immune escape effects induced by KDM1A overexpression. This study unveils a novel mechanism whereby KDM1A drives immune escape in lung cancer by transcriptionally activating SBNO2, which subsequently suppresses the anti-tumor role of CD8⁺ T cells. These findings lend strong support to targeting the KDM1A-SBNO2 axis as a promising immunotherapeutic approach for lung cancer.

Patients with densely innervated tumors suffer with poor outcomes, thus identifying them could define a cohort that could benefit from aggressive treatments. Most cases and deaths from ovarian cancer are associated with high-grade serous ovarian carcinoma (HGSOC). We immunohistochemically analyzed the histological subtypes of ovarian cancer (high-grade serous, low-grade serous, clear cell, mucinous, and endometrioid) for nerves; only HGSOCs were densely innervated. We previously defined that tumor-released small extracellular vesicles (sEVs) recruit nerves to the tumor bed and thus tested whether the difference in nerve infiltration amongst ovarian cancers was associated with sEVs. Using an in vitro neurite outgrowth assay, we found that HGSOC sEVs harbored robust neurite outgrowth activity. Importantly, sEVs from fallopian tube cell lines (the primary cell of origin of HGSOC) predominantly lacked this activity. Implantation of a syngeneic mouse model of HGSOC into transgenic mice lacking tumor-infiltrating nerves slowed tumor growth, sensitized disease to carboplatin, and improved survival. Consistent with this, we show that recurrent, treatment-resistant disease in patients is significantly more innervated than its matched naïve (untreated) malignancy. Taken together, these data identify dense nerve infiltration of HGSOCs and show that innervation contributes to treatment resistance.

Regenerative medicine is evolving exponentially due to the wide range of therapeutic applications of mesenchymal stromal cells (MSCs), including wound healing. Although the translation of tissue-derived primary MSCs (tMSCs) into clinical practice remains scarce despite preclinical success. The primary causes are donor-associated and batch-to-batch variations, replicative senescence, and the inability of large-scale manufacturing. Recent studies show that the induced MSCs (iMSCs) derived from reprogrammed induced pluripotent stem cells (iPSCs) offer distinct advantages over conventional tMSCs. This review aims to provide a comprehensive comparative analysis of the cellular characteristics, secretome composition (including growth factors, cytokines, and exosome cargo), regenerative capacities, and therapeutic potentials of tMSCs and iMSCs, with a specific focus on their applications in wound healing and tissue regeneration. The iMSCs surpass tMSCs by providing superior regenerative, immunomodulatory, and angiogenic benefits, along with unmatched consistency and scalability. iMSCs and their derivatives have exhibited remarkable capacities to promote angiogenesis, ECM production, re-epithelialization, tissue regeneration, and scarless wound healing in diabetic, cutaneous, mucosal, and burn wounds. These advantages position iMSCs as a next-generation cell therapy for managing both acute and chronic wounds, promising improved clinical outcomes and broader applicability.

Amyloid-β (Aβ) aggregation is targeted with small molecules as a pathway toward developing potential Alzheimer's disease (AD) therapies. Resveratrol, a natural polyphenol, has been proposed as an inhibitor of Aβ aggregation, but its mechanistic effects across distinct Aβ42 aggregates remain unresolved. To better evaluate resveratrol's potential to treat AD, here we focus on molecular-level insights into the mechanisms that underlie its interaction with several distinct classes of Aβ42 aggregates. In contrast to published approaches that are based on monitoring the evolution of the total fibrillar mass, we employ time-resolved in situ atomic force microscopy to explore the effects of resveratrol on Aβ42 amyloid and non-amyloid assemblies. While data suggest a weak interaction between resveratrol and low-molecular-weight Aβ42 species, we also observe a concentration-dependent reduction in fibrillization. In the presence of resveratrol, we observe a decrease in fibril thickness and end-dependent slowing of elongation; furthermore, the fibrils exhibit reduced mechanical integrity and fragment under minimal scanning stress. Importantly, resveratrol does not affect the formation or morphology of oligomers and amorphous aggregates. These findings suggest that resveratrol selectively targets the fibril pathway while leaving oligomeric assemblies unaltered. The results provide mechanistic insights into the differential effects of small molecules on Aβ42 assemblies and establish a framework for evaluating inhibitors of aggregation with single-aggregate resolution.

Carbonated Hydroxyapatite (CHA) has attracted widespread attention in bone tissue regeneration due to its chemical composition and crystal structure, which are similar to natural bone tissue. This review summarizes the basic characteristics of CHA, preparation methods, and advances in its application in bone repair. First, the crystal structure, chemical composition, and the effect of carbonate doping on its physicochemical properties are discussed, focusing on how preparation techniques such as the wet chemical method, sol-gel method, and hydrothermal synthesis regulate CHA's properties. Second, the biological mechanisms of CHA in bone tissue regeneration are outlined, including its role in promoting osteoblast proliferation and differentiation, regulating the bone repair microenvironment, and mediating related signaling pathways (e.g., Wnt/β-catenin and bone morphogenetic protein (BMP)/Smad). Furthermore, the research progress of CHA in repairing cranial, alveolar, and long bone defects is systematically reviewed through animal models and clinical studies to evaluate its bone repair capacity and biocompatibility. In addition, the composite application of CHA with polymers and bioactive glass and its potential development in frontier technologies such as 3D printing and smart drug delivery are discussed. Finally, the challenges in mechanical properties, degradation rate, and preparation processes are analyzed, and the future application prospects of CHA as an intelligent, multifunctional bone repair material are envisaged. This review aims to provide theoretical support and research insights to optimize the design and application of CHA in bone tissue engineering.

Bone regeneration requires a finely tuned interplay between osteogenesis and angiogenesis. While current treatments, such as auto/allografts, provide support, they often fail to promote adequate vascularization necessary for complete repair. Extracellular vesicles (EVs), as mediators of intercellular communication, have emerged as promising acellular nanotechnologies for tissue regeneration due to their bioactive cargo and low immunogenicity. Mechanical stimulation, a known enhancer of bone cell function, can modulate EV cargo and potentially improve regenerative efficacy. In this study, we investigated how mechanical stimulation and the stage of mesenchymal lineage commitment influence the angiogenic potential of secretomes and EVs derived from mesenchymal stromal/stem cells, osteoblasts, and osteocytes. Our findings reveal that both cell mechanical stimulation and their differentiation stage significantly modulate the angiogenic properties of the resulting EVs. Among the tested conditions, mechanically-stimulated osteocyte-derived EVs demonstrate superior angiogenesis, promoting endothelial cell migration, tube formation, and CD31 expression. These effects were further validated in a pre-clinical ex ovo chick chorioallantoic membrane assay, where robust neovascularization was observed. This work highlights the critical role of both mechanical cues and cell differentiation stage in regulating the angiogenic capacity of EVs and proposes mechanically activated osteocyte-derived EVs as a novel pro-angiogenic nanotherapeutic for bone repair.

The epithelial gut barrier and gut microbiota significantly contribute to human health by controlling molecule absorption, a regulated transport that dictates bioavailability. Effective public health strategies, like dietary reference values, require a complete understanding of nutrient absorption. However, the lack of internationally harmonized nutritional recommendations indicates that gut barrier mechanisms are not fully unraveled. The conventional in vitro model Caco-2/HT29-MTX cultured on cell culture inserts, established for drug development, is limited in representing complex human gut physiology. The new bioelectronic e-transmembrane platform leverages technological and biological advances to generate more meaningful in vitro predictions. The soft electroactive Poly (3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) scaffold enables direct cell-electrode coupling for more sensitive barrier impedance measurements, especially required for testing commonly low physiological nutrient concentrations. Promoted epithelial-fibroblast interactions result in modulated protein signal transduction and expression of genes regulating gut barrier integrity. Overall, the e-transmembrane gut barrier more closely mimicked physiological effects for humans as demonstrated using the dietary compound butyrate.