Search Results (404)

Neurodevelopmental disorders (NDDs), including autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder, are increasingly recognized as disorders of early brain construction arising from defects in neural stem and progenitor cell (NSPC) proliferation. NSPCs are responsible for generating the diverse neuronal and glial lineages that establish cortical architecture and neural circuitry; thus, their expansion must be tightly coordinated by intrinsic cell cycle regulators and extrinsic niche-derived cues. Disruption of these mechanisms—through genetic mutations, epigenetic dysregulation, or environmental insults—can perturb the balance between NSPC self-renewal and differentiation, resulting in aberrant brain size and connectivity. Recent advances using animal models and human pluripotent stem cell-derived brain organoids have identified key signaling pathways, including Notch, Wnt, SHH, and PI3K–mTOR, as central hubs integrating proliferative cues, while transcriptional and chromatin regulators such as PAX6, CHD8, SETD5, and ANKRD11 govern gene expression essential for proper NSPC cycling. Furthermore, prenatal exposure to teratogens such as Zika virus infection, valproic acid, or metabolic stress in phenylketonuria can recapitulate proliferation defects and microcephaly, underscoring the vulnerability of NSPCs to environmental perturbation. This review summarizes emerging insights into the molecular and cellular mechanisms by which defective NSPC proliferation contributes to NDD pathogenesis, highlighting convergence among genetic and environmental factors on cell cycle control. A deeper understanding of these pathways may uncover shared therapeutic targets to restore neurodevelopmental trajectories and mitigate disease burden. Full article

Hair follicle stem cells (HFSCs) are resident stem cells within hair follicles (HFs) that possess self-renewal and differentiation capacities, serving as a critical model for regenerative medicine research. Their dynamic interaction with dermal papilla cells (DPCs) plays a decisive role in HF development and cycling. FGF22 is a paracrine fibroblast growth factor that can regulate the proliferation, differentiation and migration of epithelial cells. This study established a DPC-HFSC co-culture system, revealing that FGF22 overexpression in DPCs significantly upregulated FGFR1/FGFR2 mRNA expression levels in HFSCs (p < 0.05), with a 1.67-fold increase in EdU-positive cell proportion (p < 0.01). CCK-8 assays demonstrated markedly enhanced HFSC viability (p < 0.01), with a 17% reduction in HFSC apoptosis (p < 0.05). Conversely, FGF22 knockout downregulated FGFR1/FGFR2 expression (p < 0.05), reduced HFSC proliferation capacity by 25% (p < 0.01), and increased HFSC apoptosis levels by 1.81-fold (p < 0.05). In addition, FGF22 overexpression promotes the proliferation and differentiation of HFSCs by activating Wnt/β-Catenin, Sonic Hedgehog (Shh) and Notch signaling pathways, or inhibiting BMP signaling pathways. Knockout of FGF22 weakens these processes and inhibits the activation and differentiation of HFSCs. This study, through the DPCs-HFSCs co-culture system, revealed the regulatory mechanism of FGF22 secreted by DPCs on the proliferation and differentiation of HFSCs, thereby providing theoretical references for fields such as fine-wool sheep breeding, human regenerative medicine, and hair loss treatment. Full article

Extracellular vesicles (EVs) express features of parental cells and are fundamental in modulating the crosstalk between cancer cells and their environment. Increasing evidence suggests that EVs have a pivotal role in tumorigenesis, cancer development, and drug resistance. EVs are also involved in controlling the communication between hematopoietic stem cells and the surrounding microenvironment in the bone marrow (BM), during several processes such as self-renewal, mobilization, and lineage differentiation. Proteins expressed in cancer cell-derived EVs can be useful to further understand the regulation of hematopoietic stem cell fate, a fundamental mechanism in acute myeloid leukemia (AML). Furthermore, EVs are implicated in transmitting drug-resistance mechanisms in solid and not-solid cancer types. Here, using a proteomic approach, we analyze and validate the protein profile of EVs from three AML cell lines with different genotypes, namely OCI-AML-2, OCI-AML-3, and HL-60. The majority of the identified proteins were significantly enriched in the Gene Ontology category ‘Extracellular Exosome’. Network model analysis of EV proteins revealed several significantly modulated pathways, including inflammation activation and metastatic processes in AML cell-derived EVs. The EVs proteomic profiling allows us to identify the EVs-associated molecules and pathways that could impact cancer progression and drug resistance. Full article

Pluripotent stem cells (PSCs) exhibit remarkable self-renewal capacity and differentiation potential, necessitating tight regulation of gene expression at both transcriptional and post-transcriptional levels. Among post-transcriptional mechanisms, RNA turnover and degradation together play pivotal roles in maintaining transcriptome homeostasis and controlling RNA stability. RNA degradation plays a pivotal role in determining transcript stability for both messenger RNAs (mRNAs) and non-coding RNAs (ncRNAs), thereby influencing cell identity and fate transitions. The core RNA decay machinery, which includes exonucleases, decapping complexes, RNA helicases, and the RNA exosome, ensures timely and selective decay of transcripts. In addition, RNA modifications such as 5′ capping and N6-methyladenosine (m⁶A) further modulate RNA stability, contributing to the fine-tuning of gene regulatory networks essential for maintaining PSC states. Recent single-cell and multi-omics studies have revealed that RNA degradation exhibits heterogeneous and dynamic kinetics during cell fate transitions, highlighting its role in preserving transcriptome homeostasis. Conversely, disruption of RNA decay pathways has been implicated in developmental defects and disease, underscoring their potential as therapeutic targets. Collectively, RNA degradation emerges as a central regulator of PSC biology, integrating the decay of both mRNAs and ncRNAs to orchestrate pluripotency maintenance, lineage commitment, and disease susceptibility. Full article

The roles of PIWI in mammalian spermatogenesis have been well-studied but are largely unknown in invertebrates such as the Chinese mitten crab (Eriocheir sinensis), which produces non-flagellar sperm. Here, we demonstrate that knockdown of PIWIs significantly promotes the proliferation of spermatogonia and the transformation into spermatocytes. Expression of PIWIs in HEK 293T significantly inhibits cell proliferation through the Wnt-signaling pathway. PIWIs suppress transcriptional activity of the Wnt pathway to down-regulate Cyclin D and Cyclin E by inhibiting β-catenin and the phosphorylation of β-catenin at Ser552. The intracellular structure of the adherens junction is destroyed by PIWIs due to downregulated α-catenin, β-catenin, and ZO1. Overall, our results suggest that PIWIs regulate spermatogonia self-renewal and differentiation through inhibiting the Wnt-signaling pathway and stabilize the structure of the adherens junction by regulating the expression and location of α-catenin, β-catenin, and ZO1 in E. sinensis, which are different from the functions in mammals. Our findings revealed novel functions and molecular mechanisms of PIWIs in regulating spermatogonia self-renewal and differentiation during the Crustacea spermatogenesis. Full article

Skeletal muscle homeostasis is dependent on the satellite cell pool, which is regulated by numerous signaling pathways. Estradiol (E2) function via estrogen receptor alpha (ERα, Esr1) plays an important role in satellite cell regulation in females, being necessary for satellite cell maintenance, proliferation and differentiation. Here we investigate this signaling axis in male satellite cells. Male satellite cells express Esr1 mRNA at similar levels to female satellite cells, and E2 enhances the proliferation of male satellite cell-derived myoblasts in vitro. Deletion of Esr1 specifically in male satellite cells has no effect on satellite cell number, nor on their ability to self-renew after injury, during regeneration, or when transplanted into male hosts. However, Esr1 deletion severely reduces self-renewal of male satellite cells when transplanted into female hosts. These data suggest that male satellite cells are competent for E2-ERα signaling, but that this signaling is not efficacious in the male environment, though E2-ERα signaling does become necessary when the male cells are transplanted into a female environment. Full article

The growth plate is a specialized cartilage structure near the ends of long bones that orchestrates longitudinal bone growth during fetal and postnatal stages. Within this region reside a dynamic population of growth plate skeletal stem cells (gpSSCs), primarily located in the resting zone, which possess self-renewal and multilineage differentiation capacity. Recent advances in cell-lineage tracing, single-cell transcriptomics, and in vivo functional studies have revealed distinct subpopulations of gpSSCs, which are defined by markers such as parathyroid hormone-related protein (PTHrP), CD73, axis inhibition protein 2 (Axin2), forkhead box protein A2 (FoxA2), and apolipoprotein E (ApoE). These stem cells interact intricately with their niche, particularly after the formation of the secondary ossification center, through stage-specific regulatory mechanisms involving several key signaling pathways. This review summarizes the current understanding of gpSSC identity, behavior, and regulation, focusing on how these cells sustain growth plate function through adapting to biomechanical and molecular cues. Full article

Enhancer of Zeste Homolog 2 (EZH2) is a key epigenetic regulator known for its role in global gene silencing and is involved in a variety of cellular processes, including cell survival, proliferation, invasion, and self-renewal. As a core component of the Polycomb Repressive Complex 2 (PRC2), EZH2 catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), leading to chromatin compaction and transcriptional repression. Dysregulated EZH2 expression is observed in a wide range of solid tumors and hematological malignancies and is frequently associated with increased metastatic potential and poor clinical outcomes. While EZH2 primarily mediates gene silencing through its canonical PRC2-dependent activity, it also exerts oncogenic effects via non-canonical mechanisms. In its non-canonical role, EZH2 acts independently of PRC2, interacting with other signaling molecules as a transcriptional activator or co-activator, thereby promoting the activation of oncogenic pathways. Through both canonical and non-canonical mechanisms, EZH2 significantly contributes to tumor initiation and its subsequent progression. Given its critical role in oncogenesis and cancer progression, EZH2 is under investigation as a potential biomarker for cancer diagnosis and prognosis. This review provides a comprehensive overview of EZH2’s function and oncogenic roles across human cancers. Enhanced insight into EZH2’s complex regulatory network may facilitate the development of more effective strategies to manage EZH2-driven malignancies. Full article

As many German SMEs approach the end of their photovoltaic (PV) feed-in tariff period, the challenge of maintaining economic viability for these installations intensifies. This study addresses the integration of intermittent renewable energy sources (iRES) into production processes by proposing a method to identify and exploit industrial flexibility. A detailed case study of a German carpentry factory designed as a Net-Zero Energy Factory (NZEF) illustrates the approach, combining energy monitoring with blockchain technology to enhance transparency and traceability. Flexibility is exploited through a three-layer control system involving passive operator guidance, battery storage, and electric vehicle charging. The installation of a 40 kWh battery raises self-consumption from 50 to 70%, saving approximately EUR 4270 annually. However, this alone does not offset the investment. Blockchain-based transparency adds economic value by enabling premium pricing, potentially increasing revenue by up to 10%. This dual benefit supports the financial case for NZEFs. The framework is replicable and particularly relevant for low-automation industries, offering small and medium enterprises (SMEs) a viable pathway to decarbonization. The results align with the European Clean Industrial Deal, demonstrating how digitalization and industrial flexibility can reinforce competitiveness, sustainability, and digital trust in Europe’s transition to a resilient, low-carbon economy. Full article

Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance. Full article

Breast cancer is one of the most common cancers globally. Unfortunately, many patients with breast cancer develop resistance to chemotherapy and tumor recurrence, which is primarily driven by breast cancer stem cells (BCSCs). BCSCs behave like stem cells and can self-renew and differentiate into mature tumor cells, enabling the cancer to regrow and metastasize. Key markers like CD44 and aldehyde dehydrogenase-1 (ALDH1), along with pathways like Wingless-related integration site (Wnt), Notch, and Hedgehog, are critical to regulating this stem-like behavior of BCSCs and, thus, are being investigated as targets for various new therapies. This review summarizes marker-dependent strategies for targeting BCSCs and expands on the challenges for the development of anti-BCSC drugs. We explore cutting-edge approaches like artificial intelligence (AI)-driven drug discovery and urge readers to seriously consider biological clocks and chronotherapy as experimental variables in drug discovery. Collectively, the task of cancer researchers is to overcome the many hurdles targeting BCSCs if we hope to tangibly improve breast cancer treatment outcomes and reduce mortality. Full article

Direct electrification and hydrogen utilization represent two key pathways for decarbonizing the glass industry, with their effectiveness subject to adequate furnace design and renewable energy availability. This study presents a techno-economic assessment for optimal solar energy integration in a representative 300 t/d oxyfuel container glass furnace with a specific energy consumption of 4.35 GJ/t. A mixed-integer linear programming formulation is developed to evaluate specific melting costs, carbon emissions, and renewable energy self-consumption and self-production rates across three scenarios: direct solar coupling, battery storage, and a hydrogen-based infrastructure. Battery storage achieves the greatest reductions in specific melting costs and emissions, whereas hydrogen integration minimizes electricity export to the grid. By incorporating capital investment considerations, the study quantifies the cost premiums and capacity requirements under varying decarbonization targets. A combination of 30 MW of solar plant and 9 MW of electric boosting enables the realization of around 30% carbon reduction while increasing total costs by 25%. Deeper decarbonization targets require more advanced systems, with batteries emerging as a cost-effective solution. These findings offer critical insights into the economic and environmental trade-offs, as well as the technical constraints associated with renewable energy adoption in the glass industry, providing a foundation for strategic energy and decarbonization planning. Full article

Cutaneous malignant melanoma is an extraordinarily aggressive and heterogeneous cancer that contains a small subpopulation of tumor stem cells (CSCs) responsible for tumor initiation, metastasis, and recurrence. Identification and characterization of CSCs in melanoma is challenging due to tumor heterogeneity and the lack of specific markers (CD271, ABCB5, ALDH, Nanog) and the ability of cells to dynamically change their phenotype. Phenotype-maintaining signaling pathways (Wnt/β-catenin, Notch, Hedgehog, HIF-1) promote self-renewal, treatment resistance, and epithelial–mesenchymal transitions. Tumor plasticity reflects the ability of differentiated cells to acquire stem-like traits and phenotypic flexibility under stress conditions. The interaction of CSCs with the tumor microenvironment accelerates disease progression: they induce the formation of cancer-associated fibroblasts (CAFs) and neo-angiogenesis, extracellular matrix remodeling, and recruitment of immunosuppressive cells, facilitating immune evasion. Emerging therapeutic strategies include immunotherapy (immune checkpoint inhibitors), epigenetic inhibitors, and nanotechnologies (targeted nanoparticles) for delivery of chemotherapeutic agents. Understanding the role of CSCs and tumor plasticity paves the way for more effective innovative therapies against melanoma. Full article

Murine microglia exhibit rapid self-renewal upon removal from the postnatal brain. However, the signaling pathways that regulate microglial repopulation remain largely unclear. To address this knowledge gap, we depleted microglia from mixed glial cultures using anti-CD11b magnetic particles and cultured them for 4 weeks to monitor their repopulation ability in vitro. Flow cytometry and immunocytochemistry revealed that anti-CD11b bead treatment effectively eliminated >95% of microglia in mixed glial cultures. Following removal, the number of CX3CR1-positive microglia gradually increased; when a specific threshold was reached, repopulation ceased without any discernable rise in cell death. Cell cycle and 5-ethynyl-2′-deoxyuridine incorporation assays suggested the active proliferation of repopulating microglia at d7. Time-lapse imaging demonstrated post-removal division of microglia. Colony-stimulating factor 1 receptor-phosphoinositide 3-kinase-protein kinase B signaling was identified as crucial for microglial repopulation, as pharmacological inhibition or neutralization of the pathway significantly abrogated repopulation. Transwell cocultures revealed that resident microglia competitively inhibited microglial proliferation probably through contact inhibition. This in vitro microglial removal system provides valuable insights into the mechanisms underlying microglial proliferation. Full article

(1) Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the BCR::ABL oncoprotein. During the chronic phase, Philadelphia chromosome-positive hematopoietic stem cells generate proliferative myeloid cells with various stages of maturation. Despite this expansion, leukemic stem cells (LSCs) retain self-renewal capacity via asymmetric cell divisions, sustaining the stem cell pool. Quiescent LSCs are known to be resistant to tyrosine kinase inhibitors (TKIs), potentially through BCR::ABL-independent signaling pathways. We hypothesize that dysregulation of genes governing asymmetric division in LSCs contributes to disease progression, and that their expression pattern may serve as a prognostic marker during the chronic phase of CML. (2) Methods: Genes related to asymmetric cell division in the context of hematopoietic stem cells were extracted from the PubMed database with the keyword “asymmetric hematopoietic stem cell”. The collected relative gene set was tested on two independent bulk transcriptome cohorts and the results were confirmed by single-cell RNA sequencing. (3) Results: The expression of genes involved in asymmetric hematopoietic stem cell division was found to discriminate disease phases during CML progression in the two independent transcriptome cohorts. Concordance between cohorts was observed on asymmetric molecules downregulated during blast crisis (BC) as compared to the chronic phase (CP). This downregulation during the BC phase was confirmed at single-cell level for SELL, CD63, NUMB, HK2, and LAMP2 genes. Single-cell analysis during the CP found that CD63 is associated with a poor prognosis phenotype, with the opposite prediction revealed by HK2 and NUMB expression. The single-cell trajectory reconstitution analysis in CP samples showed CD63 regulation highlighting a trajectory cluster implicating HSPB1, PIM2, ANXA5, LAMTOR1, CFL1, CD52, RAD52, MEIS1, and PDIA3, known to be implicated in hematopoietic malignancies. (4) Conclusion: Regulation of CD63, a tetraspanin involved in the asymmetric division of hematopoietic stem cells, was found to be associated with poor prognosis during CML progression and could be a potential new therapeutic target. Full article