Cells

28 pages, 5095 KB

Open AccessReview

The Role of the KLF Family in T-Cell-Mediated Regulation of Cardiovascular Diseases: Molecular Mechanisms and Therapeutic Prospects

by Shijia Wang, Xiangbin Zhu, Na Li, Kunfu Ouyang and Zhiyong Liao

Cells 2026, 15(17), 1519; https://doi.org/10.3390/cells15171519 (registering DOI) - 24 Aug 2026

Abstract

Cardiovascular diseases are increasingly recognized as immune-inflammatory disorders in which adaptive immunity shapes tissue injury, repair, and long-term remodeling. T cells are central to these processes because they integrate antigen recognition, lineage-defining transcriptional programs, tissue trafficking, cytokine production, and immunological memory. In this [...] Read more.

Cardiovascular diseases are increasingly recognized as immune-inflammatory disorders in which adaptive immunity shapes tissue injury, repair, and long-term remodeling. T cells are central to these processes because they integrate antigen recognition, lineage-defining transcriptional programs, tissue trafficking, cytokine production, and immunological memory. In this Review, we synthesize current evidence on the Krüppel-like factor (KLF) family as a transcriptional framework linking T-cell biology to cardiovascular disease. KLF2 primarily regulates T-cell quiescence and trafficking, KLF10 supports regulatory T-cell suppressive function and immune-metabolic fitness, KLF4 contributes to inflammatory effector differentiation, and KLF13 regulates delayed inflammatory chemokine expression and, in thymocyte models, exerts a survival-restraining effect through apoptosis-related pathways. Across atherosclerosis, myocardial infarction, myocarditis, hypertension, and heart failure, these KLF-dependent programs may influence the balance between pathogenic effector responses and protective regulatory mechanisms. The strongest direct disease-specific evidence currently supports a role for KLF10 within the CD4⁺ T-cell lineage in experimental atherosclerosis, with complementary functional evidence implicating Treg–macrophage interactions, whereas the roles of KLF-dependent T-cell programs in other cardiovascular settings remain mechanistically compelling but less fully validated. Future progress will require disease-specific T-cell-restricted models, spatially resolved immune analyses, and cell-selective translational strategies to define the therapeutic relevance of the KLF–T-cell axis. Full article

(This article belongs to the Special Issue Immuno-Cardiology: Immune Mechanisms from Ischemia to Heart Failure)

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35 pages, 1459 KB

Open AccessReview

Advances in Tissue Engineering and Regenerative Medicine: Biomaterials, Biofabrication, Cell-Based and Cell-Free Therapies, and Applications in Reconstructive and Aesthetic Medicine

by Caijun Jin, Zhiyuan Ding, Huizhen Ming, JungHee Shim, Vo Tien Huy, Pham Ngoc Chien, Kyung Min Choi and Chan Yeong Heo

Cells 2026, 15(17), 1518; https://doi.org/10.3390/cells15171518 (registering DOI) - 24 Aug 2026

Abstract

Tissue engineering and regenerative medicine are shifting from passive tissue replacement toward instructive platforms that regulate cellular behavior, immune responses, vascularization, and extracellular matrix remodeling. This review examines recent advances in natural, synthetic, composite, and stimuli-responsive biomaterials, biofabrication and 3D bioprinting, stem and [...] Read more.

Tissue engineering and regenerative medicine are shifting from passive tissue replacement toward instructive platforms that regulate cellular behavior, immune responses, vascularization, and extracellular matrix remodeling. This review examines recent advances in natural, synthetic, composite, and stimuli-responsive biomaterials, biofabrication and 3D bioprinting, stem and progenitor cell therapies, extracellular vesicles and other cell-free products, immunomodulatory scaffolds, skin organoids and organ-on-a-chip systems, nanotechnology, and artificial intelligence-assisted design. Particular emphasis is placed on plastic, reconstructive, and aesthetic applications, including skin and wound repair, craniofacial bone and cartilage regeneration, peripheral nerve reconstruction, vascularization, and dental and periodontal repair. The review also considers biomodulators and skinboosters as emerging regenerative-aesthetic interventions that aim to improve dermal hydration, fibroblast activity, collagen remodeling, and skin quality rather than provide volume replacement alone. Importantly, these technologies differ substantially in translational maturity, ranging from in vitro and preclinical platforms to early clinical interventions, established clinical products, and commercially available treatments for which durable regenerative efficacy remains incompletely validated. Throughout this review, biological plausibility and preclinical efficacy are therefore distinguished from human clinical evidence, regulatory or established clinical use, and commercial availability. Progress will require standardized characterization, mechanism-linked potency assays, clinically relevant models, and outcome measures that capture functional integration, durability, safety, and aesthetic performance. Full article

(This article belongs to the Special Issue New Advances in Tissue Engineering and Regeneration)

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21 pages, 11995 KB

Open AccessArticle

Magnetic-Assisted Fractionation of Bone Marrow Cells into Subsets Differing in CD45 Expression Levels, Surface Phenotypes and Functional Properties

by Oleg F. Kandarakov, Natalia S. Polyakova and Alexander V. Belyavsky

Cells 2026, 15(17), 1517; https://doi.org/10.3390/cells15171517 (registering DOI) - 23 Aug 2026

Abstract

Cells of higher organisms express numerous cell surface proteins, and their spectrum and level of expression are directly related to cells’ functions. The technology of mass cell selection based on the surface protein expression levels may be highly important both for basic research [...] Read more.

Cells of higher organisms express numerous cell surface proteins, and their spectrum and level of expression are directly related to cells’ functions. The technology of mass cell selection based on the surface protein expression levels may be highly important both for basic research and cell therapy applications. We have previously developed a method of magnetic selection of cells differing in surface marker expression levels, which we term here MACS-MEL (Magnetic-Assisted Cell Selection by Marker Expression Levels). The method demonstrated its effectiveness in the artificial model system, namely retrovirally transduced NIH 3T3 cells. However, whether it was also applicable to complex natural cell populations remained unclear. In the current study, we validated the MACS-MEL approach by separating mouse bone marrow (BM) cells into fractions according to the expression of pan-hematopoietic marker CD45. In the basic protocol, two-stage fractionation of CD45⁺ cells from BM was performed using selection of cells consecutively with 2 μL and 8 μL of anti-CD45 magnetic beads, resulting in isolation of CD45^high and CD45^int cell populations. To explore in full the potential of the method, the extended protocol was also tested, where a third selection stage with 30 μL of anti-CD45 beads was added. The isolated cell fractions were analyzed by flow cytometry for CD45 expression, as well for CD11b, Gr-1, CD117, CD115 and CD19 markers, while their in vitro progenitor function was assessed by quantitating colony-forming units (CFUs) in methyl cellulose. The results of analysis demonstrate that the isolated cell fractions significantly differed both in their surface phenotypes and CFU potential. In particular, cell fractions with progressively reduced CD45 expression were characterized by decreasing expression of myeloid differentiation markers CD11b and Gr-1, as well as B-lymphoid marker CD19. The expression of stem/progenitor cell marker CD117, on the contrary, significantly increased. The CFU frequency also strongly correlated with decrease in CD45 expression, while the differentiation potential of CFUs differed substantially in various cell fractions. In general, our results demonstrate that less differentiated hematopoietic cells in mouse BM studied using in vitro tests are characterized by lower CD45 expression levels, in full accordance with data obtained in human system. Successful validation of the MACS-MEL in a BM system, characterized by existence of multiple cell types and high phenotypic and functional heterogeneity, demonstrated the effectiveness, simplicity and affordability of this method. The MACS-MEL approach can be applied for mass selection of cells based on differential marker expression and may yield cell subsets suitable for advanced cell therapy applications. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Third Edition)

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18 pages, 6727 KB

Open AccessArticle

CRISPR-Mediated POSTN Editing Modulates Proliferation, Apoptosis, and Molecular Profiles of Primary Rabbit Hair Follicle Stem Cells via the cAMP/PKA/CREB Signaling Pathway

by Jiawei Cai, Bohao Zhao, Aoyun Fan, Yang Chen and Xinsheng Wu

Cells 2026, 15(17), 1516; https://doi.org/10.3390/cells15171516 (registering DOI) - 23 Aug 2026

Abstract

Hair follicle stem cells (HFSCs) are critical for hair follicle (HF) morphogenesis and cyclic hair regeneration. Periostin (POSTN), an extracellular matrix protein involved in tissue development and skin cell regulation, remains poorly characterized in HFSCs. In this study, we constructed CRISPR/Cas9 vectors targeting [...] Read more.

Hair follicle stem cells (HFSCs) are critical for hair follicle (HF) morphogenesis and cyclic hair regeneration. Periostin (POSTN), an extracellular matrix protein involved in tissue development and skin cell regulation, remains poorly characterized in HFSCs. In this study, we constructed CRISPR/Cas9 vectors targeting POSTN and validated their editing efficiency in primary HFSCs. POSTN editing significantly suppressed cell proliferation and promoted apoptosis. Transcriptomic analysis identified 988 differentially expressed genes (DEGs) enriched in immune responses and MAPK, PI3K–Akt, and cAMP pathways. Metabolomic analysis revealed 98 differential metabolites (DMs) associated with nucleotide metabolism and FoxO, AMPK, and cAMP pathways. Integrated multi-omics analysis showed extensive correlations between DEGs and DMs, and highlighted the cAMP pathway as the core regulatory axis. Western blot (WB) validation confirmed that POSTN editing reduced PKA and CREB phosphorylation, indicating inhibition of the cAMP/PKA/CREB signaling. These findings demonstrate that POSTN regulates HFSCs’ proliferation and apoptosis partially via the cAMP/PKA/CREB pathway, providing novel insights into the functional regulation of HFSCs. Full article

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20 pages, 8769 KB

Open AccessArticle

Association of Hypoxia-Induced Lactate Accumulation with AARS2 Expression, PDHA1/CPT2 Lactylation, and Energy Metabolism in Yak Skeletal Muscle Cells

by Tianshuai Li, Zhengbo Li, Jialin Wang, Miaoran Li, Kangfei An, Qixin Wang, Guoxiu Li, Lingxia Li, Jianshu Lv, Xiangdong Ye and Xiaodong Ling

Cells 2026, 15(17), 1515; https://doi.org/10.3390/cells15171515 (registering DOI) - 23 Aug 2026

Abstract

Yaks (Bos grunniens) are a typical species inhabiting high-altitude environments; however, their molecular responses to hypoxic conditions remain incompletely understood. This study aimed to investigate associations among alanyl-transfer RNA synthetase 2 (AARS2) expression, lactylation of pyruvate dehydrogenase E1 alpha 1 (PDHA1) [...] Read more.

Yaks (Bos grunniens) are a typical species inhabiting high-altitude environments; however, their molecular responses to hypoxic conditions remain incompletely understood. This study aimed to investigate associations among alanyl-transfer RNA synthetase 2 (AARS2) expression, lactylation of pyruvate dehydrogenase E1 alpha 1 (PDHA1) and carnitine palmitoyltransferase 2 (CPT2), and energy metabolism under hypoxic conditions in yaks. Oxygen-sensitive tissues (skeletal muscle, cardiac muscle, and lungs) collected from yaks at different altitudes, along with primary yak skeletal muscle cells, were analyzed using RT-qPCR, Western blotting, immunofluorescence (IF), and co-immunoprecipitation (co-IP). In tissues from the three altitude groups, AARS2 expression was higher in the higher-altitude groups (p < 0.05), whereas PDHA1 and CPT2 expression was lower (p < 0.01). Overall protein lactylation levels were also higher in tissues from the higher-altitude groups. Under hypoxic conditions, lactate levels and AARS2 expression increased in skeletal muscle cells, accompanied by increased activities of key glycolytic enzymes and decreased activities of enzymes related to mitochondrial oxidative phosphorylation. Galloflavin treatment reduced lactate levels and partially attenuated these metabolic changes. Endogenous co-IP detected lactylation of both PDHA1 and CPT2. Following siRNA-mediated knockdown of AARS2, the protein abundance of PDHA1 and CPT2 increased. Taken together, these findings support an association between hypoxia-induced lactate accumulation, increased AARS2 expression, PDHA1/CPT2 lactylation, and a shift in cellular energy metabolism toward glycolysis. This study provides a theoretical basis for further understanding hypoxia-related metabolic remodeling in yaks. Full article

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35 pages, 1884 KB

Open AccessReview

From Organoids to Organ-on-Chip: Advancing Human-Relevant Models for Viral Pathogenesis and Antiviral Drug Discovery

by Vaibhav Tiwari, Joanna Choe, Aryan Vora, Ishita Kataki, Sara A. L. Roujouleh, Karin Allenspach, Michelle Swanson-Mungerson, Michael V. Volin and Sinju Sundaresan

Cells 2026, 15(17), 1514; https://doi.org/10.3390/cells15171514 (registering DOI) - 22 Aug 2026

Abstract

Organoid and organ-on-chip technologies are rapidly evolving platforms for viral research that integrate stem cell biology, tissue engineering, and microfluidics to recapitulate key structural, mechanical, biochemical, and cellular features of human and animal physiology. By incorporating multicellular organoids into perfused microfluidic systems, these [...] Read more.

Organoid and organ-on-chip technologies are rapidly evolving platforms for viral research that integrate stem cell biology, tissue engineering, and microfluidics to recapitulate key structural, mechanical, biochemical, and cellular features of human and animal physiology. By incorporating multicellular organoids into perfused microfluidic systems, these models can provide complex, dynamic, and physiologically relevant micro-environments for investigating virus–host interactions that are difficult to capture in conventional two-dimensional cultures and static organoids. Controlled flow, shear stress, extracellular matrix organization, tissue–tissue interfaces, and multicellular signaling enable mechanistic investigation of viral infectivity, dissemination, tissue injury and immune activation. Integration of real-time imaging and biosensors further permits longitudinal monitoring of viral replication, host responses, and tissue integrity, expanding the potential of these platforms for antiviral drug discovery. Recent organoid-on-chip studies using brain, skin, vaginal, respiratory, and intestinal models have demonstrated how tissue architecture, mechanical forces, glycocalyx dynamics, and immune–stromal interactions influence viral tropism and pathogenesis. In this review, we provide a mechanistic and translational overview of organoid and organ-on-chip technologies for studying viral infections, with particular emphasis on models of herpes simplex virus (HSV)-mediated disease. We further examine advances in immune integration, multi-organ systems, biosensing, and computational approaches that are expanding the complexity and predictive potential of these models. Importantly, patient-derived organoids and organ-on-chip platforms can capture interindividual differences in viral susceptibility, host responses, and therapeutic efficacy, providing pharmaceutical research with more precise, patient-relevant data to support drug prioritization and precision antiviral medicine. Finally, we discuss key barriers to broader adoption, including organoid maturation, biological and technical variability, reproducibility, scalability, biosafety, cost, standardization, and regulatory validation. Collectively, these advances position organoid and organ-on-chip technologies as powerful human-relevant models that bridge reductionist in vitro systems and human disease, while continued optimization, standardization, and validation will be essential to realize their full potential for mechanistically informed antiviral discovery, therapeutic development, and precision medicine. Full article

(This article belongs to the Special Issue Organs-on-Chips and Organoids: From Disease Modeling to Advanced Therapeutics)

30 pages, 4485 KB

Open AccessReview

Cancer Immune Responsiveness and MHC Class I Antigen Presentation: Mechanisms of Immune Escape and Immunotherapy Resistance in Gastrointestinal Cancers

by Fabio Grizzi, Maurizio Chiriva-Internati, Mohamed A. A. A. Hegazi, Federica Rubbino, Fabio Pasqualini, Marco Spadaccini, Marta Andreozzi, Miriana Mercurio, Federico Cassano, Maria Terrin, Cesare Hassan, Robert S. Bresalier, Alessandro Repici and Silvia Carrara

Cells 2026, 15(17), 1513; https://doi.org/10.3390/cells15171513 (registering DOI) - 22 Aug 2026

Abstract

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), [...] Read more.

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour’s capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, β2-microglobulin (β2-m), or interferon-γ (IFN-γ) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies. Full article

(This article belongs to the Special Issue Novel Insights into Cancer Immune Responsiveness)

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20 pages, 18664 KB

Open AccessArticle

Asymmetric Functional Divergence of alx4a and alx4b in Iridophore Differentiation and Cranial Development in Nile Tilapia

by Hongsheng Shi, Fugui Fang, Jiawen Yao, Siyu Ju, Minghui Li and Deshou Wang

Cells 2026, 15(17), 1512; https://doi.org/10.3390/cells15171512 (registering DOI) - 22 Aug 2026

Abstract

Neural crest cells give rise to the craniofacial skeleton and multiple pigment cell lineages, yet how duplicated developmental regulators partition their ancestral functions after teleost-specific whole-genome duplication remains unclear. Here, we employed CRISPR/Cas9 to generate alx4a and alx4b single and double mutants in [...] Read more.

Neural crest cells give rise to the craniofacial skeleton and multiple pigment cell lineages, yet how duplicated developmental regulators partition their ancestral functions after teleost-specific whole-genome duplication remains unclear. Here, we employed CRISPR/Cas9 to generate alx4a and alx4b single and double mutants in Nile tilapia (Oreochromis niloticus). By integrating phenotype, skeleton, transcriptome, quantitative PCR, and AlphaFold-based structural modeling analyses, we revealed their functional divergence. Loss of alx4a caused a regionally restricted reduction in iridophore-derived reflectance and abnormal cranial morphology, whereas alx4b single mutants showed no obvious phenotype under the conditions examined. By contrast, double mutants exhibited an almost complete loss of iridophore-derived structural coloration and substantially more severe cranial defects, accompanied by reduced calcein labeling in the opercular region, consistent with altered cranial mineralization. Skin transcriptomic and quantitative PCR analyses revealed marked downregulation of pnp4a and tfec, which are associated with iridophore differentiation and coloration, whereas no significant expression differences were detected for the iridophore survival-related genes ltk and mpv17. AlphaFold2-assisted HDOCK protein–DNA modeling yielded more favorable docking metrics for Alx4a than for Alx4b with the pnp4a promoter, supporting a potential Alx4a–pnp4a promoter interaction that requires experimental validation. In contrast, no significant genotype-dependent differences were detected in the measured abundance of melanophores, xanthophores, or erythrophores, and no obvious difference in gross dorsal-fin spine formation was observed under the conditions examined. Together, these findings reveal unequal functional contributions of alx4a and alx4b, with alx4a acting as the dominant paralog in iridophore-associated structural coloration and both paralogs contributing unequally to cranial development, and support pnp4a as a candidate downstream gene associated with Alx4a activity. Full article

(This article belongs to the Section Cell Proliferation and Division)

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28 pages, 4024 KB

Open AccessReview

Piezo1 as a Key Mechanosensitive Ion Channel Linking Mechanical Overload to Mitochondrial Dysfunction, Mitophagy, and Immunometabolic Dysregulation in Osteoarthritis

by Hechmi Toumi, Ahmad Almhdie-Imjabbar and Eric Lespessailles

Cells 2026, 15(17), 1511; https://doi.org/10.3390/cells15171511 (registering DOI) - 22 Aug 2026

Abstract

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking [...] Read more.

Osteoarthritis (OA) is increasingly recognized as a mechanically driven whole-joint disease in which abnormal mechanotransduction initiates a cascade of mitochondrial dysfunction, chronic inflammation, and progressive cartilage degeneration. Among the mechanosensitive molecules identified to date, Piezo1 has emerged as a key mechanosensitive regulator linking pathological mechanical loading to intracellular calcium signaling and downstream cellular responses. Growing evidence indicates that persistent Piezo1 activation promotes mitochondrial calcium overload, excessive reactive oxygen species production, ATP depletion, mitochondrial membrane depolarization, and impaired mitophagy, ultimately amplifying chondrocyte dysfunction and extracellular matrix degradation. In parallel, mitochondrial damage triggers immunometabolic reprogramming through activation of the cGAS–STING pathway and the NLRP3 inflammasome. It also promotes pro-inflammatory cytokines, including interleukin-1β, tumor necrosis factor-α, and interleukin-6. Together, these responses may contribute to a self-perpetuating cycle of inflammation and tissue destruction. This review provides a comprehensive synthesis of recent advances regarding the role of Piezo1 in OA, focusing on the mechanistic links between mechanotransduction, mitochondrial dysfunction, mitophagy, and immunometabolic dysregulation. We further discuss the contribution of mitochondrial quality-control pathways, including PINK1/Parkin-, BNIP3-, and FUNDC1-mediated mitophagy, as well as alterations in mitochondrial dynamics involving DRP1, MFN1, MFN2, and OPA1. Emerging experimental models are discussed as valuable tools for accelerating therapeutic discovery. Finally, we critically evaluate current therapeutic strategies targeting the Piezo1–mitochondria axis, including mechanosensitive channel modulation, mitochondrial protection, mitophagy enhancement, gene therapy, biomaterial-assisted delivery, and nanomedicine. Collectively, current evidence supports the Piezo1–mitochondria–immune axis as an important mechanistic framework contributing to OA pathogenesis and as a potential therapeutic target. Integrating mechanobiology, mitochondrial medicine, and precision-engineered experimental models may facilitate the development of next-generation disease-modifying therapies capable of slowing or preventing osteoarthritis progression. Full article

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35 pages, 9296 KB

Open AccessReview

Extrinsic Regulation of Optic Nerve Axon Regeneration in the Adult Central Nervous System

by Arissa Adhikary, Emily Dorairaj, Alex Arshavsky, Shanti Ramcharan, Krishna S. Kishor and Sanjoy K. Bhattacharya

Cells 2026, 15(17), 1510; https://doi.org/10.3390/cells15171510 (registering DOI) - 22 Aug 2026

Abstract

Adult optic nerve axon regeneration has traditionally been framed as a problem of limited intrinsic growth capacity in central nervous system neurons. However, growing evidence suggests that intrinsic factors alone cannot account for regenerative failure: restrictive extrinsic environmental factors largely govern optic nerve [...] Read more.

Adult optic nerve axon regeneration has traditionally been framed as a problem of limited intrinsic growth capacity in central nervous system neurons. However, growing evidence suggests that intrinsic factors alone cannot account for regenerative failure: restrictive extrinsic environmental factors largely govern optic nerve regeneration, dictating the intrinsic capacity axons can express. In this review, we frame the extrinsic optic nerve environment as a dynamic regenerative niche, in which vascular, immune, glial, matrix, and metabolic compartments are spatially co-localized and temporally coordinated rather than acting as independent barriers. These compartments follow a shared trajectory, broadly protective in the acute phase, then inhibitory once the underlying response fails to resolve, while also actively driving one another, such as reactive astrocytes promoting the matrix remodeling that subsequently restricts axon regrowth. Consequently, the niche’s overall permissiveness for regeneration reflects the aggregate and interdependent state of these compartments rather than the action of any single barrier. This review integrates current evidence on extrinsic barriers, intervention opportunities, and disease-specific variability relevant to RGC axon regeneration after injury. These interventions must incorporate the spatial, temporal, and metabolic factors that shape the goal of functional recovery and vision restoration. Full article

(This article belongs to the Section Cell and Gene Therapy)

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41 pages, 6704 KB

Open AccessArticle

Exploring the Utility of ALDH1 as a Marker for the Cancer Stem Cell Population in OCCC Cell Lines

by Blane Gebreyes, Bart Kolendowski, Yudith Ramos-Valdes, Trevor G. Shepherd and Gabriel E. DiMattia

Cells 2026, 15(17), 1509; https://doi.org/10.3390/cells15171509 (registering DOI) - 22 Aug 2026

Abstract

Metastasis, chemoresistance, and tumour recurrence are facilitated by cancer stem cells (CSCs), a small subpopulation of cells capable of regenerating a primary tumour while maintaining the tumour’s genetic and phenotypic features. CSCs can be identified by the expression of specific markers; however, the [...] Read more.

Metastasis, chemoresistance, and tumour recurrence are facilitated by cancer stem cells (CSCs), a small subpopulation of cells capable of regenerating a primary tumour while maintaining the tumour’s genetic and phenotypic features. CSCs can be identified by the expression of specific markers; however, the CSC population in ovarian clear cell carcinoma (OCCC), a rare histotype of ovarian cancer, remains poorly defined. Given the well-established role that CSCs play in cancer progression and metastasis, it is critical to identify reliable markers of CSCs in OCCC. Here, we endeavoured to determine whether ALDH1 expression could be used to define OCCC stem cells in OCCC cell lines using a variety of methods including assessing ALDH1A1 expression in spheroids generated under distinct conditions. We also generated and used chemo-resistant cell lines to assess the enrichment of cancer stem cells. Human OCCC cell lines were enriched for CSCs using selective culture conditions and drug resistance methods. CSC-enriched spheroids demonstrated increased expression of stemness markers NANOG and SOX2, while ALDH1A1 expression was enriched only in drug-resistant cell lines, relative to parental cell lines. RNA-seq analyses of CSC-media-derived spheroids versus standard media spheroids provided novel data supporting CSC enrichment and identified transcription factors induced by CSC media. These findings highlight the ambiguous role of ALDH1A1 as a CSC marker in OCCC and demonstrates the utility of CSC enrichment methods for identifying CSC populations in OCCC cell lines. Full article

(This article belongs to the Section Cell Proliferation and Division)

25 pages, 3273 KB

Open AccessReview

MAP3K1 Integrates Genetic and Environmental Signals in Eyelid Morphogenesis

by Bo Xiao, Winston Kao and Ying Xia

Cells 2026, 15(17), 1508; https://doi.org/10.3390/cells15171508 (registering DOI) - 22 Aug 2026

Abstract

Developmental disorders often arise from complex interactions between genetic variation and environmental factors, yet the molecular mechanisms underlying gene-gene (G × G) and gene-environment (G × E) interactions remain poorly understood. Mouse embryonic eyelid closure provides a genetically tractable in vivo model for [...] Read more.

Developmental disorders often arise from complex interactions between genetic variation and environmental factors, yet the molecular mechanisms underlying gene-gene (G × G) and gene-environment (G × E) interactions remain poorly understood. Mouse embryonic eyelid closure provides a genetically tractable in vivo model for investigating these mechanisms. Eyelid closure requires coordinated epithelial migration and cytoskeletal remodeling orchestrated by interconnected signaling pathways. Among these pathways, MAP3K1 functions as a critical signaling hub that integrates inputs from S1PR-RHOA-ROCK and other upstream regulators to activate JNK and promote eyelid closure. Genetic studies show that multiple components within the GPCR-RHOA-ROCK-MAP3K1-JNK network cooperate to maintain developmental robustness. Reducing the activity of pathway components dose-dependently impairs eyelid closure and produces the characteristic eye-open-at-birth (EOB) phenotype. Environmental factors also converge on this network. Although exposure to dioxin does not impair eyelid closure in wild-type embryos, it induces EOB in embryos harboring otherwise phenotypically silent mutations in the MAP3K1 network, such as Map3k1^+/−, Jnk1^−/− and S1pr2^−/−. These findings identify the MAP3K1 pathway as a point of convergence of genetic and environmental signals and establish embryonic eyelid closure as a powerful model for elucidating molecular mechanisms underlying developmental robustness, susceptibility and resilience. Full article

(This article belongs to the Special Issue Cellular Signaling Networks in Development, Homeostasis, and Disease)

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29 pages, 6354 KB

Open AccessReview

Cardiovascular Toxicity in Cancer Therapy: Potential Mechanisms of Ferroptosis and Treatment Strategies

by Jiani Dai, Yufei Wang, Chunna Jin, Liuguang Song, Yao Xie, Liangliang Jia and Meixiang Xiang

Cells 2026, 15(17), 1507; https://doi.org/10.3390/cells15171507 (registering DOI) - 22 Aug 2026

Abstract

Advances in anticancer therapies have substantially improved cancer survival but have also highlighted the growing challenge of cancer therapy-related cardiac dysfunction. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron dysregulation, lipid peroxidation, and impaired antioxidant defense, has emerged as a [...] Read more.

Advances in anticancer therapies have substantially improved cancer survival but have also highlighted the growing challenge of cancer therapy-related cardiac dysfunction. Ferroptosis, an iron-dependent form of regulated cell death characterized by iron dysregulation, lipid peroxidation, and impaired antioxidant defense, has emerged as a promising strategy for eliminating therapy-resistant tumors. However, the lack of tissue specificity in ferroptosis regulation raises concerns regarding its potential contribution to cardiovascular injury during anticancer treatment. This review summarizes the dual roles of ferroptosis in cancer biology and cardio-oncology. We first discuss the molecular mechanisms governing ferroptosis, including iron metabolism, lipid peroxidation, and antioxidant defense systems. We then highlight the context-dependent roles of ferroptosis in tumor progression, immune regulation, and metabolic adaptation. Furthermore, we systematically review how chemotherapy, targeted therapy, immunotherapy, and radiotherapy contribute to ferroptosis-associated cardiovascular toxicity. Finally, we discuss emerging approaches to minimize cardiac injury, including tissue-specific ferroptosis-targeting and cardioprotective strategies. Understanding tissue-specific ferroptosis regulation may facilitate the development of safer and more precise therapeutic approaches in cardio-oncology. Full article

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21 pages, 5481 KB

Open AccessArticle

Mechanical Suppression of Sonic Hedgehog Signaling by Nucleus Pulposus Cells Underlies Early Disc Degeneration in Mouse

by Sohrab Virk, Veeraj Shah, Vikrant Piprode, Claire Marie Kemp, Harshith Alluri, Kathleen F. Vincent, Ravi Krishnan, Justin Hong, Todd J. Albert and Chitra L. Dahia

Cells 2026, 15(17), 1506; https://doi.org/10.3390/cells15171506 (registering DOI) - 22 Aug 2026

Abstract

Sonic hedgehog (SHH) expression by nucleus pulposus (NP) cells is important for intervertebral disc development and maintenance. The lumbosacral disc, the most immobile region of the spine, lies adjacent to the sacrum and is most vulnerable to degeneration. We hypothesized that a lack [...] Read more.

Sonic hedgehog (SHH) expression by nucleus pulposus (NP) cells is important for intervertebral disc development and maintenance. The lumbosacral disc, the most immobile region of the spine, lies adjacent to the sacrum and is most vulnerable to degeneration. We hypothesized that a lack of mobility represses SHH expression by NP cells, leading to degenerative changes in the intervertebral disc. To test this hypothesis, we employed a Shh-LacZ reporter mouse and a tail-loop surgical model of constant compression and immobility. Using a comprehensive level-by-level analysis, we first determined the coccygeal level most affected by geometric and histopathological changes. We next determined the effects of constant compression and immobility on the subset of SHH-expressing cells compared with sham controls. Multiplex qPCR analysis validated a decline in Shh and its target Gli1 expression by NP cells in the tail-looped discs that was associated with an increase in Piezo1 expression compared to sham controls. In summary, the findings support a model in which restricted mobility and sustained compression in lumbosacral discs accelerate pathology by prematurely silencing developmental signaling programs, such as SHH, required for NP homeostasis. Full article

(This article belongs to the Special Issue Novel Insights into Mechanism and Treatment of Degenerative Disc Disease)

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30 pages, 5416 KB

Open AccessArticle

Effects of α-Synuclein on the Lipid Phenotype of SZ95 Human Sebocytes: A Preliminary Study in the Context of Parkinson’s Disease

by Sarah Mosca, Grazia Bottillo, Enrica Flori, Daniela Kovacs, Miriam Maiellaro, Francesca Lozzi, Alessia Cavallo, Christos C. Zouboulis, Giulia Simmini, Alessia Luppino, Claudia Novello, Valentina Leta, Gianfranco Gaudiano, Grazia Devigili, Roberto Eleopra, Fabrizio Tagliavini, Samanta Mazzetti, Emanuela Camera and Giorgia Cardinali

Cells 2026, 15(16), 1505; https://doi.org/10.3390/cells15161505 (registering DOI) - 21 Aug 2026

Abstract

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis [...] Read more.

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis (SD), a chronic inflammatory condition linked to sebocyte dysfunction and altered sebum production. Marked differences in sebum composition between PD patients and healthy controls have been described. We aimed to investigate whether pathological αSyn could contribute to dysregulated sebum production and composition by assessing key markers of sebocyte differentiation and lipogenesis in human sebaceous gland cells and skin biopsies from PD patients (n = 5) and matched controls (n = 5) without clinically recorded SD. O-αSyn exposure of immortalized sebaceous gland cells (SZ95) altered the transcriptional programs related to sebocyte differentiation, inflammation, metabolism, and lipogenesis. Consistently, protein markers of mid-to-late sebocyte differentiation were increased. Upregulation of PLIN2, together with elevated PPARγ, SREBP1, SCD1, and FADS2, indicated progression toward a mature and lipid-producing phenotype characterized by enhanced accumulation of neutral lipids within lipid droplets. Lipidomic profiling revealed remodeling of multiple lipid classes, with increases in triglycerides, ceramides, and selected phospholipids. Increased expression of PLIN2 and PPARγ was also observed in sebaceous glands from PD skin biopsies compared to controls. Collectively, our findings indicate that O-αSyn exposure is associated with molecular changes consistent with altered sebocyte differentiation and lipid remodeling. These results support a potential association between αSyn and lipid dysregulation in sebocytes and suggest that these cells may represent unrecognized peripheral targets of αSyn. Full article

(This article belongs to the Special Issue Turning Points in α-Synuclein Biology: From Function to Dysfunction)

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18 pages, 5601 KB

Open AccessArticle

Effects of Wharton’s Jelly Mesenchymal Stem Cell-Derived Secretome on Cell Functions in Human Endometrium

by Silviya Doneva, Kalina Belemezova, Vesela Stoycheva, Ivan Bochev, Tanya Timeva, Maria Yunakova, Petya Andreeva, Katerina Kavaldzhieva, Atanas Shterev and Stanimir Kyurkchiev

Cells 2026, 15(16), 1504; https://doi.org/10.3390/cells15161504 - 21 Aug 2026

Abstract

Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of [...] Read more.

Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of Wharton’s jelly-derived MSC secretome (WJ-MSCsec) on human endometrial stromal cells (EnSCs) and endothelial cells in vitro. Methods: WJ-MSCs were isolated from umbilical cord tissue, characterized, and cultured under serum-free conditions. The concentrated secretome was analyzed using a human angiogenesis proteome array. EnSCs were isolated from endometrial biopsies. EnSC proliferation and migration in the presence of WJ-MSCsec were assessed using CCK-8 and scratch wound-healing assays. Pro-angiogenic activity of WJ-MSCsec was evaluated using a Matrigel tube formation assay with human umbilical vein endothelial cells (HUVECs). Results: Proteomic analysis of WJ-MSCsec revealed the presence of angiogenic, mitogenic, immunomodulatory, and chemotactic factors. Treatment with WJ-MSCsec significantly enhanced EnSC proliferation and accelerated wound closure. Furthermore, WJ-MSCsec markedly promoted endothelial tube formation, increasing total tube length, junction number, and mesh formation. Conclusions: WJ-MSCsec stimulates EnSC proliferation and migration while enhancing angiogenesis in vitro. WJ-MSCsec represents a promising cell-free therapeutic strategy for endometrial regeneration and reproductive disorders associated with impaired endometrial function. Full article

(This article belongs to the Section Stem Cells)

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38 pages, 3144 KB

Open AccessReview

AMPK Therapy—A Little Goes A Long Way

by Hannah Ceballos, Eryun Zhang and Wendong Huang

Cells 2026, 15(16), 1503; https://doi.org/10.3390/cells15161503 - 20 Aug 2026

Abstract

AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that integrates energetic, nutrient, hormonal, redox, and stress signals to coordinate cellular and whole-body energy homeostasis. Although AMPK was initially characterized primarily as a sensor of changes in cellular AMP/ATP ratios, recent studies [...] Read more.

AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that integrates energetic, nutrient, hormonal, redox, and stress signals to coordinate cellular and whole-body energy homeostasis. Although AMPK was initially characterized primarily as a sensor of changes in cellular AMP/ATP ratios, recent studies have revealed additional layers of regulation involving upstream kinases, post-translational modifications, heterotrimeric isoform composition, subcellular compartmentalization, and tissue-specific signaling. In this review, we provide an updated overview of the molecular mechanisms regulating AMPK activity, its major downstream metabolic and homeostatic pathways, its roles in metabolic, cardiovascular, neurodegenerative, muscular, malignant, and age-associated diseases, and current strategies for pharmacological AMPK modulation. We compare indirect activators, including metformin and naturally derived compounds, with direct small-molecule agonists targeting the allosteric drug and metabolite (ADaM) site, and emerging activators that selectively engage specific AMPK isoforms, tissues, or subcellular pools. We also discuss endogenous AMPK regulators, including microbiota-derived metabolites, and critically evaluate the potential adverse consequences of sustained or systemic AMPK activation. Collectively, current evidence indicates that the therapeutic effects of AMPK activation are highly dependent on tissue, heterotrimer composition, subcellular localization, disease stage, and the magnitude and duration of activation. Rather than indiscriminate systemic activation, future AMPK-directed therapies are therefore likely to benefit from isoform-, tissue-, and compartment-selective approaches that preferentially engage disease-relevant AMPK signaling while minimizing off-target effects. Continued characterization of AMPK signaling specificity and the development of selective pharmacological modulators should facilitate the translation of AMPK biology into more precise therapies for metabolic and other chronic diseases. Full article

(This article belongs to the Special Issue AMPK: From Mechanisms to New Therapies)

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35 pages, 5572 KB

Open AccessReview

Emerging Roles of Extracellular Vesicle-Mediated Transfer of Mitochondrial and Mitochondrial Components in Cancer

by Yue Gu, Chen Gu, Runfang Pan and Baonian Liu

Cells 2026, 15(16), 1502; https://doi.org/10.3390/cells15161502 - 20 Aug 2026

Abstract

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate [...] Read more.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate the mechanisms governing the packaging of mitochondria and their constituents into EVs and subsequently highlight their multifaceted functions across various malignancies, including breast cancer, prostate cancer, blood malignancies, head and neck squamous cell carcinoma, digestive system cancers, etc. Mitochondrial cargo, such as intact mitochondria, mitochondrial DNA (mtDNA), and RNA (mtRNA), are shown to reconfigure metabolism, enhance bioenergetics, promote proliferation and invasion, induce drug resistance, and remodel TME by suppressing antitumor immunity. While previous reviews have predominantly focused on the role of mitochondrial transfer in individual cancers or specific systemic diseases, we made a comprehensive overview encompassing diverse cancer types. These findings suggest that EV-mediated mitochondrial cargo transfer represents a biological intercellular communication mechanism with implications for tumor progression and therapeutic resistance. It is worth noting that we also apply standardized evidence-grading frameworks (C1–C4) across cancer types to provide a critical assessment of the current evidence and identify key methodological gaps that must be addressed in future studies. Collectively, this review underscores the significance of EV-mediated mitochondrial transfer as an important biological process in cancer, presenting it as a promising frontier for novel diagnostic and therapeutic interventions. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Exosomes: Novel Insight and Therapeutic Applications in Cancer)

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19 pages, 25622 KB

Open AccessArticle

PHGDH Promotes Synovial Aggression and Inflammation via Upregulating ADRA2A Expression in Rheumatoid Arthritis

by Kai Sun, Ting Liu, Xuanxian Xu, Huan Dong, Huijuan Hu, Chenxi Peng, Xiaofan Ge, Liuqin Liang, Youjun Xiao, Hanshi Xu and Qian Qiu

Cells 2026, 15(16), 1501; https://doi.org/10.3390/cells15161501 - 20 Aug 2026

Abstract

Objectives: The role of Phosphoglycerate Dehydrogenase (PHGDH), the first key enzyme in the serine biosynthesis pathway, is important in controlling cancer survival; however, its role in rheumatoid arthritis (RA) remains unknown. Here, we investigated the functional involvement of PHGDH in RA pathogenesis, as [...] Read more.

Objectives: The role of Phosphoglycerate Dehydrogenase (PHGDH), the first key enzyme in the serine biosynthesis pathway, is important in controlling cancer survival; however, its role in rheumatoid arthritis (RA) remains unknown. Here, we investigated the functional involvement of PHGDH in RA pathogenesis, as well as its underlying molecular mechanisms. Methods: mRNA and protein expression in RA fibroblast-like synoviocytes (FLS) was measured by RT-qPCR and Western blot, respectively. Immunohistochemistry (IHC) was used to detect the protein expression in RA synovium. Cellular and tissue localization of the protein was assessed using IHC and immunofluorescence. The functional role of PHGDH in RA FLS was evaluated using multiple approaches: Transwell assays to assess cell migration and invasion, Annexin V/PI staining to detect apoptosis, and EdU assays to measure cell proliferation. Key downstream targets of PHGDH were identified via RNA sequencing (RNA-seq). The therapeutic potential of PHGDH targeting was further assessed in a rat collagen-induced arthritis (CIA) model following intra-articular administration of PHGDH-shRNA. Results: PHGDH expression was markedly elevated in RA synovial tissues and FLS. Functionally, knockdown of PHGDH suppressed proliferation, migration, invasion, and inflammatory cytokine production of RA FLS. Mechanistic studies revealed that PHGDH exerts its effects, at least in part, by inhibiting the expression of adrenoceptor alpha 2A (ADRA2A). The therapeutic relevance of these findings was further supported by in vivo experiments, where intra-articular delivery of PHGDH-shRNA significantly ameliorated the severity of arthritis in rats with CIA. Conclusions: Our results indicate that the PHGDH-ADRA2A axis critically drives the inflammatory and aggressive phenotype of RA FLS, suggesting that PHGDH might be as a promising therapeutic target for RA. Full article

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