The Wnt (Wingless/Integrated) signaling pathway is a highly conserved regulator of development, stem cell maintenance, and tissue homeostasis. Its dysregulation is a hallmark of cancer, driving uncontrolled proliferation, epithelial-mesenchymal transition, invasion, and therapy resistance. Increasing evidence shows that Wnt signaling in tumor cells does not operate in isolation but is dynamically shaped by reciprocal interactions with the tumor microenvironment (TME), including fibroblasts, immune and endothelial cells, extracellular matrix, and metabolic stressors. These bidirectional circuits sustain cancer stemness, remodel stromal architecture, and create immunosuppressive and pro-angiogenic conditions that foster tumor growth as well as metastatic dissemination and colonization. In this review, we examine how canonical and non-canonical Wnt pathways intersect with the TME across distinct stages of the metastatic cascade, from local invasion to the establishment of distant niches. We further evaluate therapeutic approaches targeting Wnt signaling and discuss their potential to overcome immune evasion and metastatic progression when combined with immunotherapy or stromal-targeted agents. Finally, we highlight emerging preclinical models, including organoids and tumor-on-a-chip systems, that are advancing our understanding of Wnt-TME crosstalk. Together, these insights position Wnt signaling as a central orchestrator of cancer progression and metastasis and a promising therapeutic target for improving outcomes in advanced cancer.

Host gene expression profiling holds great potential in improving the differential diagnostics of bacterial and viral infections. We investigated its discriminative value in children with suspected serious infections.

The coordination of cell migration and proliferation is essential for embryogenesis and tissue homeostasis. However, the classical gradient signaling model is insufficient to explain how stable mitogenic signaling is maintained within migratory cells. Here, we reveal that primordial germ cells (PGCs) in zebrafish employ migrasomes-vesicular organelles formed during migration-to couple their proliferation with migration, ensuring germline expansion. Migrasomes, generated at retraction fibers via tspan7-dependent biogenesis, deliver the growth factor GDF3 specifically to neighboring PGCs through contact-dependent interactions. GDF3 activates the TGF-β receptor acvr1ba, driving proliferation in a spatiotemporally restricted manner. This homocrine signaling mechanism allows migrating PGCs to autonomously sustain proliferation, circumventing signal dilution in embryonic environments. This work uncovers migrasomes as a bridge linking migration and proliferation, with implications for understanding collective cell behaviors in development and disease.

Mutations in GDP-mannose pyrophosphorylase B (GMPPB) cause dystroglycanopathy, a rare neuromuscular disorder characterized by α-dystroglycan hypoglycosylation, yet the pathogenic mechanisms and therapeutic options remain poorly defined. To dissect the molecular basis of dystroglycanopathy, we generate Gmppb knockout and knock-in (P32L and R287Q) mice. We show that homozygous Gmppb knockout and P32L mutant mice (both male and female) display embryonic lethality, while heterozygous Gmppb-P32L (GmppbP32L/+) mice (both male and female) develop progressive muscular dystrophy accompanied by Purkinje cell loss, peripheral demyelination, and impaired nerve conduction. Integrated biochemical, transcriptomic, metabolomic and glycoproteomic analyses reveal widespread protein hypoglycosylation, metabolic dysregulation and suppressed Wnt/β-catenin signaling, resulting in defective differentiation and regeneration of muscle stem cells. Pharmacological activation of Wnt signaling with CHIR-99021 restores myogenic capacity and improves regeneration after injury. Furthermore, AAV-mediated GMPPB gene replacement reinstates α-dystroglycan glycosylation, normalizes GDP-mannose levels, and rescues motor and electrophysiological defects. Collectively, our findings establish GmppbP32L/+ mice as a faithful model of GMPPB-associated dystroglycanopathy and demonstrate that Wnt pathway activation and AAV-based gene therapy represent promising strategies for treating glycosylation-defective muscular dystrophies.

SLC25A10, the mitochondrial dicarboxylate carrier, plays a crucial role in mitochondrial metabolism and protects against liver lipotoxicity. Moreover, its frequent amplification or mutation in cancers, particularly hepatocellular carcinoma (HCC), correlates with a poor prognosis. This study aimed to investigate the role of SLC25A10 in chemotherapy resistance in HCC and elucidate the underlying mechanisms. In this study, we found that hypoxia increased SLC25A10 expression with a preferential shift toward isoform 3 in HCC. This isoform interacts with the nuclear transporter IPO7 to translocate into the nucleus, where it binds to transcription factor CEBPB. This interaction upregulates the transcription of the anti-apoptotic gene BCL2A1, thereby enhancing HCC cell resistance to the chemotherapeutic agent, etoposide. Notably, disruption of the SLC25A10 isoform 3-IPO7 interaction significantly sensitized HCC tumors to etoposide in vivo, suggesting that targeting this interaction could be a promising therapeutic strategy to improve chemotherapy efficacy in HCC. This study reveals a novel nuclear function of the mitochondrial dicarboxylate carrier SLC25A10 in transcriptional regulation under hypoxic conditions, distinct from its canonical mitochondrial role. These findings expand our understanding of SLC25A10 biology and uncover a previously unrecognized mechanism that drives hypoxia-induced chemoresistance in HCC. Our findings suggest that SLC25A10 is a potential therapeutic target to overcome drug resistance in HCC.

Serum ferritin is an independent prognostic marker in myelodysplastic neoplasms (MDS) and serves as a surrogate parameter for iron overload. Oxidative stress derived from iron overload may induce genomic damage, thereby promoting genetic instability and disease progression in MDS. We aimed to evaluate a possible association between iron overload via serum ferritin and various parameters for genetic instability in MDS.

Expanded potential stem cells (EPSCs) represent a distinct and developmentally primitive stem cell population characterized by their broad developmental potential, which encompasses both embryonic and extra-embryonic lineages. In this study, we employed a polycistronic cassette to directly reprogram human fibroblasts into induced Expanded Potential Stem Cells (iEPSCs). Substituting SOX2 with engineered SOX17 transcription factors resulted in an approximately five-fold increase in the average yield of iEPSC colonies, while maintaining the molecular and functional integrity of the resulting clonal lines. Notably, under feeder-free conditions, SOX2 occasionally failed to reprogram and yielded inconsistent colony numbers, whereas engineered SOX17 and miniaturized SOX17 reproducibly produced feeder-free iEPSCs. In summary, the use of engineered SOX17 enables efficient and robust reprogramming of human fibroblasts into EPSCs, allowing for modeling of early human pre-implantation development, investigating placental disorders, and expanding the toolkit for drug development with a versatile model of pluripotent stem cells that exhibit broader developmental capabilities.

Glioblastoma (GBM) remains a highly aggressive brain tumor with poor prognosis despite surgical resection and standard chemoradiation. Induced neural stem cell (iNSC)-based therapies offer a promising strategy owing to their inherent tumor-homing ability and capacity to deliver therapeutics selectively to the tumor site; however, their poor retention within the tumor resection cavity limits clinical potential. Herein, we evaluated next-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-secreting iNSCs (hiNeuroS) in combination with a biodegradable, thermo-responsive chitosan hydrogel for localized and sustained delivery of high densities of hiNeuroS. Direct comparisons with first-generation iNSCs (hiNSCs) demonstrated that hiNeuroS achieved faster and more extensive tumor cell kill across multiple tumor-to-therapeutic cell ratios in both U87 and patient-derived GBM8 models. Injectable chitosan scaffolds supported stem cell densities up to 2 × 10⁷ cells/mL, maintained > 90% viability, preserved scaffold microstructure, and maintained rapid gelation at physiological conditions. Gravimetric analysis revealed stable 30-day mass change profiles, with minimal net mass loss indicating preserved scaffold integrity. Moreover, encapsulated hiNeuroS retained their migratory capacity and robust TRAIL secretion, inducing significant tumor cell death in both GBM models. Collectively, these findings demonstrate that hiNeuroS maintain functional potency in GBM and are compatible with scaffold-based delivery. This work provides a foundation for future in vivo studies to assess scaffold-mediated retention, persistence, and therapeutic efficacy in an established GBM mouse model, supporting the development of an injectable hydrogel platform for next-generation cell-based therapies for treatment of GBM and other malignant tumors.

Bromodomain (BD) and extra-terminal domain (BET) proteins are key regulators of RNA polymerase II (Pol II)-mediated transcription and their BDs represent promising drug targets. Yet, the interplay between histone acetylation and the chromatin dynamics of individual BET proteins with respect to transcriptional regulation is not fully understood. Here in mouse embryonic stem cells, we uncover an essential role of BRD2 in maintaining Pol II recruitment at promoters through its interaction with TFIID, which becomes particularly critical under the conditions of impaired pause release. Combining rapid protein degradation, chemogenomics and super-resolution microscopy, we show that MOF-mediated histone H4 acetylation promotes BRD2 chromatin association, which in turn enables BRD2 clustering. Accordingly, MOF depletion or deletion of the BRD2's intrinsically disordered region largely recapitulates defects in promoter enrichment and clustering of the transcription machinery observed upon BRD2 loss. Thus, these findings support a model in which histone acetylation-dependent spatiotemporal dynamics of BRD2 coordinate the transcription machinery to regulate transcription initiation.

As an emergent acellular therapeutic tool, mesenchymal stem cell-derived exosomes (MSC-Exos) have demonstrated good application prospects in the prevention and treatment of liver diseases. MSC-Exos exhibit a lower immunogenicity and tumorigenic risk in comparison to traditional stem cell therapy and can also exert multiple therapeutic effects in liver diseases by carrying various active factors, including miRNAs and proteins, which play anti-inflammatory, anti-cell death, anti-fibrosis roles among others. In recent years, MSC-Exos have demonstrated effective therapeutic outcomes in different liver disease models, particularly receiving widespread attention in the field of acute and chronic liver injury and liver fibrosis. This article systematically reviews the mechanistic research of MSC-Exos and key variables influencing their efficacy in liver disease treatment, including exosome preparation techniques, tissue sources, drug administration plans, and delivery routes. Additionally, it focuses on discussing its functional optimization strategies, such as pretreatment, engineering modifications, and intelligent delivery systems, and explores the synergistic advantages of combined intervention with MSC-Exos and traditional Chinese and Western medicine. MSC-Exos is still considered a hot direction for achieving precise treatment of liver disease, although current research still faces challenges such as inconsistent standards and insufficient clinical evidence. In the future, it will be necessary to strengthen standardized production and clinical translation research to promote its clinical application in individualized interventions.

Emerging evidence supports the maintenance of cellular proteostasis as a key process in resisting age-related diseases. Its intervention by natural compounds is expected to benefit the healthcare system. In the current study, we recruited a unique amyloid beta (Aβ) aggregation-based in vitro screening system and identified fucoxanthin (Fx) as a candidate compound possessing protein de-aggregation potential. Phenotypic and molecular analyses revealed that Fx mitigated endoplasmic reticulum and heat stress by modulating the cellular unfolded protein response and heat shock response, respectively. Furthermore, Fx alleviated senescence-associated markers and restored proteostasis by rescuing chaperone expression and proteasome activity in human senescent fibroblasts. The above protective effect of Fx was further validated in human induced pluripotent stem cells (hiPSC)-derived neurons and Aβ-GFP transgenic Caenorhabditis elegans (C. elegans). Altogether, our results demonstrate the proteostasis-promoting potential of Fx that may be useful for managing degenerative diseases and promoting healthy aging.

Limbal melanocytes (LMs) are neural crest-derived cells that have emerged as multifunctional regulators of ocular surface homeostasis beyond their traditional role in pigmentation and photoprotection. Residing within the basal limbal epithelium, LMs form functional units with limbal epithelial stem/progenitor cells (LEPCs) through cadherin-mediated adhesion and paracrine signaling through soluble factors and extracellular vesicles. LMs contribute to photoprotection by transferring melanosomes to LEPCs, which subsequently organize these organelles into supranuclear melanin caps that may shield LEPC DNA from ultraviolet-induced damage. In parallel, LMs regulate LEPCs stemness, proliferation, and differentiation through direct cell-cell interactions and paracrine signaling mechanisms. LMs exhibit pronounced immunomodulatory properties, including a hypoimmunogenic phenotype, T-cell suppressive capacity, and anti-inflammatory, anti-angiogenic potential. Recent technical advances-such as CD117+CD90- flow cytometric isolation and laminin-based culture systems-have enabled long-term LM expansion. Dysregulation of LMs has been reported in association with several pathological conditions, including corneal inflammation, aniridia-associated keratopathy, pterygium, and rare limbal melanomas. This review integrates current knowledge on LMs embryological origin, anatomical localization, molecular and cellular characteristics, interactions with LEPCs, and functional contributions to ocular surface homeostasis. We discuss the pathological implications of LMs dysfunction and critically evaluate emerging therapeutic strategies, including LMs-enriched tissue-engineered constructs for limbal stem cell deficiency and other ocular surface disorders. By synthesizing the current knowledge and identifying key gaps in understanding, this review aims to guide further research and accelerate the clinical translation of LMs-based regenerative therapies.

Endothelial cell dysfunction and loss are key drivers of acute and chronic liver disease, underscoring a critical unmet need for liver vascular-targeted therapies. Liver sinusoidal endothelial cells are specialized endothelial cells that form a fenestrated microvascular niche regulating hepatocyte metabolism, immune homeostasis, and hepatic stellate cell activation. Repopulating this niche through transplantation of primary liver sinusoidal endothelial cells, endothelial progenitor cells, induced-pluripotent stem cell-derived liver sinusoidal endothelial cells, or engineered endothelial cells delivered within biomaterial aims to restore microvascular architecture, reestablish supportive angiocrine signaling, attenuate fibrosis, and promote liver regeneration. This review summarizes the biological rationale for endothelial cell-based therapy, compares cell sources and engineering strategies, evaluates cell delivery and engraftment approaches, and synthesizes preclinical evidence demonstrating therapeutic benefits across diverse animal models of liver injury. Finally, we highlight key translational challenges and propose future directions to accelerate the clinical development of endothelial cell-based therapies for liver disease.

The regulation of mesenchymal stem cell (MSC) differentiation is a complex process influenced by multiple factors, among which autophagy has emerged as a key determinant of stem cell fate. Here, we investigated its role in MSC differentiation into hepatocyte-like cells. Autophagy was first assessed during basal hepatic differentiation of adipose tissue-derived MSCs (AD-MSCs) in the absence of modulators. Subsequently, we evaluated the impact of autophagy modulation by chemical agents on the functionality of the derived hepatocyte-like cells. Isolated AD-MSCs were induced to differentiate, and hepatocyte formation was assessed by morphological, molecular, and biochemical analyses. Macroautophagy was examined via protein and mRNA expression of key autophagy‑related markers, supplemented with transmission electron microscopy (TEM) and acridine orange staining. To confirm the role of autophagy in hepatic differentiation, differentiating MSCs were subjected to autophagy induction by serum starvation or treatment with rapamycin (50nM), and inhibition using 3‑methyladenine (3‑MA, 5µM). Autophagy activation was observed during baseline differentiation (days 0, 7, 14, and 21 post-induction), as indicated by increased Beclin‑1, LC3B, and ATG7 expression; reduced p62; and accumulation of autophagic vacuoles confirmed by TEM and acridine orange staining. Induction of autophagy by rapamycin or serum starvation enhanced hepatic functional markers, as evidenced by higher levels of secreted albumin and urea, along with increased ALT and AST activities, whereas 3‑MA impaired these parameters. Collectively, these findings indicate that autophagy supports the acquisition of hepatic functional and metabolic characteristics in MSC‑derived hepatocyte-like cells, providing insight into its regulatory role during MSC differentiation toward hepatocyte-like cells.

Galectin-9 (Gal-9) is a tandem-repeat β-galactoside-binding lectin increasingly recognized as a context-dependent regulator of cancer biology that extends well beyond its canonical role as an immune checkpoint ligand. While Gal-9-mediated immune modulation (e.g., via TIM-3/VISTA) remains important, emerging evidence positions Gal-9 as an upstream organizer of tumor-intrinsic programs and microenvironmental crosstalk that shape angiogenesis, invasion and metastasis, therapy resistance, and maintenance of cancer stem-like states. These divergent outcomes are driven by multi-layered regulation of Gal-9, encompassing transcriptional and epigenetic control, post-translational modification, and context-specific processing/secretion, together with dynamic remodeling of the tumor glycome. In addition, Gal-9 signaling is contingent on cell type-specific receptor repertoires (e.g., TIM-3, VISTA, CD44 and related glycan-binding partners) across malignant, stromal, and immune compartments. This review proposes an integrated, mechanism-based framework to clarify why Gal-9 can exert either tumor-promoting or tumor-suppressive effects, depending on the cancer type and biological context. Rather than cataloging reported effects, we synthesize evidence to propose a context "decision model" in which Gal-9 activity is predicted by (i) the cellular source of Gal-9 (tumor cell vs myeloid/stromal compartments), (ii) Gal-9 biochemical state and post-translational processing, (iii) receptor expression and signaling competence of recipient cells, and (iv) the glycan landscape that governs ligand engagement. We further integrate these determinants with clinical observations to clarify why Gal-9 associates with opposite prognoses in different tumors, and we outline how this framework can stratify patients and guide therapeutic design. Finally, we evaluate Gal-9-targeted interventions-neutralizing antibodies, decoy receptors, and rational combinations with immunotherapy and standard modalities-through the lens of context dependence, highlighting actionable biomarkers and experimental readouts needed to translate Gal-9 biology into precision oncology.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is definitive, potential curative therapy for various hematological diseases. Poor graft function (PGF) remains a significant complication, characterized by persistent cytopenia despite complete donor chimerism. The bone marrow microenvironment, particularly endothelial cells expressing CD31 (PECAM-1), plays a crucial role in the maintenance and proliferation of hematopoietic stem cells. This study examines the expression of CD31 in the bone marrow endothelial microenvironment of patients with Poor Graft Function (PGF) are compared with those exhibiting Good Graft Function (GGF) following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Paullinia pinnata Linn (Sapindaceae) is used in Cameroonian ethnomedicine for the treatment of arthritis. Its leafy aqueous (AEPP) and methanol (MEPP) extracts have shown potent preventive effects in mono-arthritis but their curative effects and their mechanism of action remain unknown.

Mammalian thyroid status is governed by thyroid secretion of L-thyroxine (T4) as a prohormone that is monodeiodinated in peripheral tissues to bioactive T3 (3,5,3'-triiodo-l-thyronine). T4 secretion is controlled by the hypothalamic-pituitary-thyroid (HPT) axis (central control) whereas T3 availability to target cells depends mainly on mechanisms in extrathyroidal tissues such as cellular transport and deiodination (peripheral control). Does this model apply to poikilothermic teleost fish which in contrast to homeothermic mammals may show major surges in plasma T4 due to season, feeding, reproductive state or stressors? We have evaluated the contributions of central and peripheral mechanisms to fish thyroid status in light of recent discoveries employing both traditional endocrine approaches and more modern molecular biological techniques, focusing primarily on salmonid species which may undergo a unique thyroid-implicated premigratory parr-smolt transition (PST), and which as tetraploids may express multiple paralogs of regulatory peptides. Most teleost research has focused on peripheral control by the three classic deiodinases (D1, D2 and D3). In salmonids they determine systemic (D1, D2) and tissue-specific (D2) T3 generation from T4 and the equally critical T4 and T3 degradations (D1, D3). Tetraploid salmonids may express up to four paralogs for a given deiodinase, providing the potential for species-specific or tissue-specific T3 production, curtailment of T3 action, or iodine recapture. Critical as they appear, salmonid deiodinases do not function in isolation but in concert with, and dependence on, TH plasma transport, cell-membrane translocation, hepatic conjugation, biliary excretion and gastrointestinal metabolism. Two rainbow trout properties are particularly distinct from the mammalian model: i) T3, but not T4, exchanges rapidly between plasma and erythrocytes permitting plasma T3 stability despite marked acute changes in plasma T4 and ii) in contrast to ingested T4, which is unavailable from food due to complete gastrointestinal deiodination, ingested T3 contributes to the plasma T3 pool. Thus the teleost liver, poised at the confluence of exogenous and endogenous T3 sources, may play a strategic role through its TH biliary excretion, deiodination and other pathways in regulating systemic T3 availability involved in anabolic/catabolic balance and somatic growth. A major consequence of ingested T4 degradation is the exclusive delegation of T4 availability to the HPT axis. Since mammalian TSH consistently stimulates teleost T4 secretion a mammal-like HPT central control model has been assumed. However, teleost HPT function differs from that of homeotherms in both its hypothalamic control and response to external stimuli. T4 secretion could be regulated mainly by T4 negative feedback with the HPT axis playing a subsidiary role of merely ensuring adequate T4 substrate for regulated peripheral deiodination to proceed. However, this does not account for the notable surges in salmonid plasma T4 and implies resetting of the HPT 'thyrostat'. Thus the role of central TSH control in the regulation of plasma T4 changes remains unclear, awaiting further characterization of endogenous TSH secretion. Furthermore, discoveries of TSH-subunit and TSH-receptor expression in piscine peripheral tissues such as the CNS, liver, and gonad require reassessment of TSH function with a focus not only on its traditional endocrine actions but also on its potential as a paracrine regulator of TH action in peripheral tissues. In conclusion, while there are many similarities in thyroid regulation between mammals and salmonids there are also key differences. These likely stem from the evolution of homeothermy, the constraints of terrestrial iodine availability and a plasticity in salmonid peripheral and central control resulting from tetraploidy.

In this issue of Developmental Cell, Vijaykumar et al. interrogate the fetal liver (FL) hematopoietic stem and progenitor cell (HSPC) niche using 3D quantitative microscopy, fluorescent genetic reporters, and transcriptomics, thereby illuminating important HSPC support cells and mechanisms impacting HSPC FL egress across this window of ontogeny.1.

The colonic epithelium is organized in functional regions and interacts with an abundant microbial community. In Cell, Rispal et al. discover that regionalization depends on microbes, with proximal identity regulated by microbial nicotinic acid-induced PPARα activation in the epithelium. Changes in tissue identity reshape zones of tissue injury.