Search Results (553)

The bone marrow microenvironment is a dynamic and complex niche that plays a central role in the development, progression, and therapeutic resistance of leukemia. Among the various stromal and immune cells that compose this microenvironment, adipocytes are increasingly recognized as active participants rather than passive bystanders. These cells contribute to leukemia pathophysiology by supplying leukemic cells with vital metabolic fuels such as free fatty acids and glutamine, which support cellular bioenergetics and biosynthesis. Furthermore, adipocytes secrete adipokines—including leptin, adiponectin, and others—that influence leukemic cell proliferation, apoptosis, and chemoresistance. Leukemic cells, in turn, are not merely recipients of these signals, but actively remodel the marrow niche to their advantage. They can suppress adipogenesis, inhibit the differentiation of mesenchymal stem cells into adipocytes, or reprogram existing adipocytes to adopt a tumor-supportive phenotype. These transformed adipocytes may enhance leukemic cell survival, dampen immune responses, and create a metabolic sanctuary that enables resistance to standard chemotherapies. This reciprocal and dynamic interaction between leukemic cells and adipocytes contributes significantly to minimal residual disease and relapse, posing a major challenge for durable remission. Recent advances in tissue engineering—such as organ-on-chip and 3D co-culture systems—offer promising platforms to recapitulate and study these leukemia–adipocyte interactions with high fidelity. These models facilitate mechanistic insights and provide a foundation for developing novel therapeutic strategies aimed at disrupting the metabolic and paracrine crosstalk within the leukemic niche. Targeting the adipocyte–leukemia axis represents a compelling and underexplored avenue for improving leukemia treatment by sensitizing malignant cells to existing therapies and overcoming the protective influence of the bone marrow microenvironment. Full article

Patients with head and neck squamous cell carcinoma (HNSCC) suffer from severe morbidity and mortality. Immunotherapy represents a novel promising treatment option. Therefore, a better understanding of the immune niche is needed. This study focuses on the spatial distribution and prognostic value of different T cell subtypes in 84 HNSCC specimens as well as chemokine and cytokine levels associated with spatial T cell infiltration. Density of T helper (T_H), cytotoxic (CTL), and regulatory T cells (T_reg) was quantified by multicolor tissue cytometry on a single cell level in whole tissue sections, discriminating between T cells located in epithelial tumor cell nests or tumor stroma, respectively. In addition, quantitative levels of 27 immune-related factors were assessed. Survival analysis of patients with p16-negative HNSCC revealed higher stromal T_reg densities to be an independent prognostic factor for better progression-free and overall survival. Furthermore, high levels of CXCL10, IL-9, and CCL4 were associated with significantly higher numbers of T cells, especially for CTL with direct contact to tumor cells, whereas for VEGF the opposite effect was observed in the tumor stroma. In conclusion, T_reg cell infiltration as well as distinct cytokine levels could serve as new immune biomarkers in p16-negative HNSCC to predict survival and the spatial distribution of T cells. Full article

Neural stem cells (NSCs) are crucial components of the nervous system, primarily located in the subventricular zone (SVZ) and subgranular zone (SGZ). The SVZ neural stem cell niche (NSCN) is a specialized microenvironment where growth factors and extracellular matrix (ECM) components collaborate to regulate NSC self-renewal and differentiation. Despite its importance, our understanding of the SVZ remains incomplete due to the inherent challenges of animal research, particularly given the tissue’s dynamic nature. To address these limitations, we developed a proof-of-concept, dynamic, and tissue-specific 3D organotypic SVZ model to reduce reliance on animal models. This static 3D organotypic model integrates a region-specific decellularized ECM derived from the SVZ, mimicking the native NSCN and supporting mouse-derived ependymal cells (ECs), radial glial cells (RGCs), astrocytes, and NSCs. To further improve physiological relevance, we incorporated a dynamic microfluidic culture system (SVZonChip), replicating cerebrospinal fluid (CSF) flow as observed in vivo. The resulting SVZonChip platform, combining region-specific ECM proteins with dynamic culture conditions, provides a sustainable and reproducible tool to minimize animal model use. It holds significant promise for studying SVZ-related diseases, such as congenital hydrocephalus, stroke, and post-stroke neurogenesis, while advancing translational research and enabling personalized medicine protocols. Full article

Understanding the heterogeneity of Rheumatoid Arthritis (RA) and identifying therapeutic targets remain challenging using traditional bulk transcriptomics alone, as it lacks the spatial and protein-level resolution needed to fully capture disease and tissue complexities. In this study, we applied Laser Capture Microdissection (LCM) coupled with mass spectrometry-based proteomics to analyze histopathological niches of the RA synovium, enabling the identification of protein expression profiles of the diseased synovial lining and sublining microenvironments compared to their healthy counterparts. In this respect, key pathogenetic RA proteins like membrane proteins (TYROBP, AOC3, SLC16A3, TCIRG1, and NCEH1), and extracellular matrix (ECM) proteins (PLOD2, OGN, and LUM) showed different expression patterns in diseased synovium compartments. To enhance our understanding of cellular dynamics within the dissected regions, we further integrated the proteomic dataset with single-cell RNA sequencing (scRNA-seq), and deduced cell type enrichment, including T cells, fibroblasts, NK cells, myeloid cells, B cells, and synovial endothelial cells. By combining high-resolution spatial proteomics and transcriptomic analyses, we provide novel insights into the molecular mechanisms driving RA, and highlight potential protein targets for therapeutic intervention. This integrative approach offers a more comprehensive view of RA synovial pathology, and mitigates the limitations of traditional bulk transcriptomics in target discovery. Full article

Cancer initiation and early tumour growth are complex processes influenced by multiple cellular and microenvironmental factors. A critical aspect of tumour progression is the dynamic interplay between cancer cells and the extracellular matrix (ECM), which undergoes significant alterations to support malignancy. The loss of cell polarity is an early hallmark of tumour progression, disrupting normal tissue architecture and fostering cancerous transformation. Circumstantially, cancer-associated microRNAs (miRNAs) regulate key oncogenic processes, including ECM remodelling, epithelial-to-mesenchymal transition (EMT), and tumorigenic vascular development, further driving tumour growth. ECM alterations, particularly changes in stiffness and mechanotransduction signals, create a supportive niche for cancer cells, enhancing their survival, proliferation, and invasion. EMT and its subtype, epithelial-to-endothelial transition (EET), contribute to tumour plasticity, promote the generation of cancer stem cells (CSCs), and support tumour vascularisation. Furthermore, processes of vascular development like vasculogenesis and angiogenesis are critical for sustaining early tumour growth, supplying oxygen and nutrients to hypoxic malignant cells within the evolving cancerous microenvironments. This review explores key mechanisms underlying these changes in tumorigenic microenvironments, with an emphasis on their collective role for tumour initiation and early tumour growth. It will further delve into present in vitro modelling strategies developed to closely mimic early cancer pathophysiology. Understanding these processes is crucial for developing targeted therapies aimed at disrupting key cancer-promoting pathways and improving clinical outcomes. Full article

Breast cancer remains the most common malignancy in women, yet, many patients fail to achieve full remission despite significant advancements. This is largely due to tumour heterogeneity and the limitations of current experimental models in accurately replicating the complexity of in vivo tumour environment. In this study, we present a compartmentalised alginate hydrogel platform as an innovative in vitro tool for three-dimensional breast cancer cell culture. To mimic the heterogeneity of tumour tissues, we developed a core–shell structure (3.5% alginate core and 2% alginate shell) that mimic the stiffer, denser internal tumour matrix. The human triple-negative breast cancer cell line (MDA-MB-231) was embedded in core–shell alginate gels to assess viability, proliferation and hypoxic activity. Over one week, good cells proliferation and viability was observed, especially in the softer shell. Interestingly, cells within the stiffer core were more positive to hypoxic marker expression (HIF-1α) than those embedded in the shell, confirming the presence of a hypoxic niche, as observed in vivo. When cultured in the MIVO^® milli fluidic organ-on-chip resembling the physiological fluid flow conditions, cancer cells viability became comparable between core and shell hydrogel area, emphasising the importance of the fluid flow in nutrients diffusion within three-dimensional matrixes. Cisplatin chemotherapy treatment further highlighted these differences: under static conditions, cancer cell death was prominent in the softer shell, whereas cells in the stiffer core remained resistant to cisplatin. Conversely, drug diffusion was more homogeneous in the core–shell structured treated in the organ-on-chip, leading to a uniform reduction in cell viability. These findings suggest that integrating a compartmentalised core–shell cell laden alginate model with the millifluidic organ on chip offers a more physiologically relevant experimental approach to deepening cancer cell behaviour and drug response. Full article

The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME. Full article

Prolonged breastfeeding (BF), as opposed to artificial infant formula feeding (FF), has been shown to prevent the development of obesity later in life. The aim of our narrative review is to investigate the missing molecular link between postnatal protein overfeeding—often referred to as the “early protein hypothesis”—and the subsequent transcriptional and epigenetic changes that accelerate the expansion of adipocyte stem cells (ASCs) in the adipose vascular niche during postnatal white adipose tissue (WAT) development. To achieve this, we conducted a search on the Web of Science, Google Scholar, and PubMed databases from 2000 to 2025 and reviewed 750 papers. Our findings revealed that the overactivation of mechanistic target of rapamycin complex 1 (mTORC1) and S6 kinase 1 (S6K1), which inhibits wingless (Wnt) signaling due to protein overfeeding, serves as the primary pathway promoting ASC commitment and increasing preadipocyte numbers. Moreover, excessive protein intake, combined with the upregulation of the fat mass and obesity-associated gene (FTO) and a deficiency of breast milk-derived microRNAs from lactation, disrupts the proper regulation of FTO and Wnt pathway components. This disruption enhances ASC expansion in WAT while inhibiting brown adipose tissue development. While BF has been shown to have protective effects against obesity, the postnatal transcriptional and epigenetic changes induced by excessive protein intake from FF may predispose infants to early and excessive ASC commitment in WAT, thereby increasing the risk of obesity later in life. Full article

It has been previously shown that a selenium (Se) nanocomposite (NC) based on the natural polysaccharide arabinogalactan (AG) produced from Siberian larch wood (Larix sibirica Ledeb.), containing 0.000625% of Se, has antibacterial properties against phytopathogens, such as Clavibacter sepedonicus, Pectobacterium carotovorum, and Phytophthora cactorum. The same concentration of Se/AG NC stimulated the growth and development of potato plants in vitro, as well as the formation of their roots, while Se did not accumulate in potato tissues after plant treatment. However, to realize the full potential of Se/AG NC in agriculture for fighting phytopathogens with the aim of developing commercial nanopreparations, additional toxicological studies are needed to fully address their effects. In this study, to assess the environmental risk of using Se/AG NCs, it was applied to a number of bacteria isolated from soil (Escherichia coli, Bacillus cereus, and B. megaterium), water (Micrococcus luteus, B. subtilis, and Sarcina flava), and activated sludge and wastewater of treatment facilities (Serratia marcescens, M. luteus, B. cereus, and Pseudomonas aeruginosa). When studying the antibacterial activity of Se/AG NC against 11 test cultures of bacteria using the agar diffusion method, it was shown that Se/AG NC had a toxic effect only at high concentrations in the range from 40 mg/mL Se/AG NC (1.68 mg/mL Se) to 0.625 mg/mL Se/AG NC (0.026 mg/mL Se) on two types of bacteria M. luteus isolated from the waters of Lake Baikal and B. cereus obtained from activated sludge of treatment facilities. The maximum diameter of the growth inhibition zone of the test cultures after exposure to different concentrations of Se/AG NC was noted for M. luteus (water) and E. coli (soil) at 40 mg/mL − 26.3 and 20.3 mm, respectively. Thus, the negative impact of Se/AG NC on bacteria from different ecological niches was registered only at high concentrations, similar to the predicted concentrations of Se/AG NC in wastewater, which demonstrates the environmental safety of Se/AG NC for use in agriculture. Full article

Background/Objectives: The MAST kinases are ancient AGC kinases associated with many human diseases, such as cancer, diabetes, and neurodevelopmental disorders. We set out to describe the origins and diversification of MAST kinases from a structural and bioinformatic perspective to inform future research directions. Methods: We investigated MAST-lineage kinases using database and sequence analysis. We also estimate the functional consequences of disease point mutations on protein stability by integrating predictive algorithms and AlphaFold. Results: Higher-order organisms often have multiple MASTs and a single MASTL kinase. MAST proteins conserve an AGC kinase domain, a domain of unknown function 1908 (DUF), and a PDZ binding domain. D. discoideum contains MAST kinase-like proteins that exhibit a characteristic insertion within the T-loop but do not conserve DUF or PDZ domains. While the DUF domain is conserved in plants, the PDZ domain is not. The four mammalian MASTs demonstrate tissue expression heterogeneity by mRNA and protein. MAST1-4 are likely regulated by 14-3-3 proteins based on interactome data and in silico predictions. Comparative ΔΔG estimation identified that MAST1-L232P and G522E mutations are likely destabilizing. Conclusions: We conclude that MAST and MASTL kinases diverged from the primordial MAST, which likely operated in both biological niches. The number of MAST paralogs then expanded to the heterogeneous subfamily seen in mammals that are all likely regulated by 14-3-3 protein interaction. The reported pathogenic mutations in MASTs primarily represent alterations to post-translational modification topology in the DUF and kinase domains. Our report outlines a computational basis for future work in MAST kinase regulation and drug discovery. Full article

Background/Objectives: Bone metastasis is a frequent and life-threatening event in advanced cancers, affecting up to 70–85% of prostate cancer patients. Understanding the cellular and molecular mechanisms underlying bone metastasis is essential for developing targeted therapies. This study aimed to systematically characterize the heterogeneity and microenvironmental adaptation of prostate cancer bone metastases using single-cell transcriptomics. Methods: We integrated the largest single-cell transcriptome dataset to date, encompassing 124 samples from primary prostate tumors, various bone metastatic sites, and non-malignant tissues (e.g., benign prostatic hyperplasia, normal bone marrow). After quality control, 602,497 high-quality single-cell transcriptomes were analyzed. We employed unsupervised clustering, gene expression profiling, mutation analysis, and metabolic pathway reconstruction to characterize cancer cell subtypes and tumor microenvironmental remodeling. Results: Cancer epithelial cells dominated the tumor microenvironment but exhibited pronounced heterogeneity, posing challenges for conventional clustering methods. By integrating genetic and metabolic features, we revealed key evolutionary trajectories of epithelial cancer cells during metastasis. Notably, we identified a novel epithelial subpopulation, NEndoCs, characterized by unique differentiation patterns and distinct spatial distribution across metastatic niches. We also observed significant metabolic reprogramming and recurrent mutations linked to prostate-to-bone microenvironmental transitions. Conclusions: This study comprehensively elucidates the mutation patterns, metabolic reprogramming, and microenvironment adaptation mechanisms of bone metastasis in prostate cancer, providing key molecular targets and clinical strategies for the precise treatment of bone metastatic prostate cancer. Full article

Regenerative processes occur at various levels in all organisms, yet their complexity continues to raise new questions about their mechanisms. It has been demonstrated that small extracellular vesicles (sEVs), secreted by all cells and influencing their function, play a significant role in regeneration. In the context of regenerative processes, oral mucosal tissues consistently receive interest, as they are among the most rapidly healing tissues in the human body. In this study, we utilized spatial transcriptomics to map gene expression to specific spatial locations within the gingiva tissue section, using publicly available transcriptomic data. This analysis revealed new insights into this tissue and the biogenesis of sEVs within it. The identified clusters encompassed two main regions—the epithelium and lamina propria—as well as minor niches within them. Using Gene Ontology (GO) analysis, we identified two clusters most enriched in extracellular vesicle-related GO processes. These included the superficial and deeper layers of the sulcular epithelium, one of the most peripheral regions of the gingiva. Of the 43 genes identified in the literature as having a potential or documented role in sEVs biogenesis, 12 were selected for further analysis. MUC1, SDCBP2, and VPS37B showed clear specificity and the highest expression in the superficial layer of the sulcular epithelium. CHMP4C also exhibited high expression in this layer, though its levels were comparable to the outer layer of the oral epithelium. Other well-established sEVs marker genes, such as ANXA2, CD9, CD63, CD81, FLOT1, RAB22A, RAB27B, and RAB5A, were also expressed in the examined tissue; however, their expression was not specifically exclusive to the sulcular epithelium. Our study is the first to perform a meta-analysis of available gingival transcriptomic data in the specific context of sEVs biogenesis. The presented data and conclusions provide new insights into the role of different structures within healthy human gingiva and shed new light on both known and potential markers of sEVs biogenesis. These findings may contribute to the development of regeneration-targeted research, especially on oral tissues. Full article

Diabetic foot is one of the leading complications of diabetes mellitus that affects millions of people around the world and involves the presence of ulcers, infections, tissue destruction, and loss of sensation and can even lead to limb amputation. This research explores trends in diabetic foot global research through a bibliometric analysis of publications indexed in Scopus in the period 2004–2023. A total of 7136 documents were analysed using Excel, Python, Biblioshiny, and VOSviewer. Scientific production has multiplied by a factor of 6.6 from the first to the last year analysed. Armstrong D.G. is the most productive and cited author. China is the most productive country, and the United States is the most cited. The most productive journal is the International Journal of Lower Extremity Wounds, and the most cited journal is Diabetes Care. Research on diabetic foot is mainly focused on the complications of diabetes mellitus; the treatment and healing of wounds; infections; and epidemiology and patient care. Infections and antibiotic treatment are emerging topics, while deep learning and machine learning are among the niche topics in this area of knowledge. The present study allows us to identify current trends and future directions of research in diabetic foot. Full article

Alginate hydrogels are integral to many cell-based models in tissue engineering and regenerative medicine. As a natural biomaterial, the properties of alginates can vary and be widely adjusted through the gelation process, making them versatile additives or bulk materials for scaffolds, microcarriers or encapsulation matrices in tissue engineering and regenerative medicine. The requirements for alginates used in biomedical applications differ significantly from those for technical applications. Particularly, the generation of novel niches for stem cells requires reliable and predictable properties of the resulting hydrogel. Ultra-high viscosity (UHV) alginates possess alginates with special physicochemical properties, and thus far, numerical simulations for the gelation process are currently lacking but highly relevant for future designs of stem cell niches and cell-based models. In this article, the gelation of UHV alginates is studied using a microscopic approach for disc- and sphere-shaped hydrogels. Based on the collected data, a multiphase continuum model was implemented to describe the cross-linking process of UHV alginate polysaccharides. The model utilizes four coupled kinetic equations based on mixture theory, which are solved using finite element software. A good agreement between simulation results and experimental data was found, establishing a foundation for future refinements in the development of an interactive tool for cell biologists and material scientists. Full article

Besides alternative surgical methods for bilateral limbal deficiency, such as KLAL (keratolimbal allograft), living-related conjunctival limbal allograft (LR-CLAL), and keratoprosthesis, regenerative medicine often necessitates the use of alternative sources of limbal cells in cases where access to fellow eye source cells is limited. Mucosal cells are most commonly used to restore limbal tissue in such scenarios. Current techniques involving mucosal cells include cultivated oral mucosal transplantation (COMT), oral mucosal graft transplantation (OMGT), and simple oral mucosal transplantation (SOMT). COMT requires suspension of cells and a culturing process that is time-consuming and cost-prohibitive. In contrast, OMGT requires solely a strip of mucosal graft for transplanting into the deficient eye. The most recently developed practice, SOMT, in which chopped biopsy tissue is transplanted into the deficient area, compensates for problems associated with both COMT and OMGT, making the process of addressing bilateral limbal deficiency easy, time-saving, and affordable. Although some undesirable outcomes, such as angiogenesis, can occur post-transplantation, and the ultimate goal of differentiation into limbal epithelial stem cells may not be achieved, mucosal cell sources can be a good alternative for stabilizing the ocular surface. Some studies emphasize that co-culturing limbal niches in mucosal cell cultures can enhance differentiation capability. This concept highlights the importance of the limbal environment in the differentiation process. In this review, we demonstrate the ongoing changes in surgical technique trends and how they have made mucosal cell transplantation easier and more effective for limbal regeneration. Full article