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Background Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. Methods The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. Results Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1β. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. Conclusions GC cells p65/INHBB/activin B and fibroblasts p65/IL-1β signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC. Highlights Tumor-secreted activin B promotes gastric cancer via fibroblast reprogramming. Activin B activates the NF-κB pathway by inducing auto-ubiquitination of TRAF6 in fibroblasts. Activin B stimulates the production of a pro-tumorigenic secretome and matrisome. Activin B activates NF-κB pathway of fibroblasts to up-regulate IL-1β secretion. IL-1β activates transcription factor p65 of gastric cancer to up-regulate INHBB expression.

Background Migraine, characterized by recurrent episodes of severe headache, remains mechanistically enigmatic. While traditional theories emphasize trigeminovascular activation, the role of meningeal stromal-immune crosstalk in disease chronicity is poorly understood. Methods A migraine-related chronic hypersensitivity model was utilized via intermittent intraperitoneal nitroglycerin (NTG, 10 mg/kg, every other day for 9 days) and peripheral mechanical hypersensitivity was assessed using von Frey filaments. Single-cell RNA sequencing (scRNA-seq) was performed on dura tissues to construct a cellular atlas of NTG-induced remodeling. These data were then integrated with migraine genome-wide association study (GWAS) risk genes, cell-cell interaction networks, and transcriptional regulation analysis to dissect NTG-driven meningeal remodeling. Results The NTG-induced migraine-related chronic hypersensitivity model demonstrated sustained mechanical allodynia, as evidenced by significantly decreased paw withdrawal thresholds ( p  < 0.0001). Single-cell profiling of the dura mater revealed a 2.4-fold expansion of a pro-inflammatory fibroblast subpopulation (Fibro_c5: 1.9% in Vehicle vs. 4.6% in NTG group), which exhibited marked activation of TNF-α/NF-κB signaling pathways (normalized enrichment score [NES] = 1.83). Concomitantly, we observed an 82% increase in meningeal monocytes (5.7–10.4%) that showed preferential interaction with Fibro_c5 fibroblasts through Angptl1-mediated stromal-immune crosstalk (log2 fold change = 1.41). Regulatory network analysis identified Mafk as the upstream transcriptional regulator orchestrating Angptl1 expression in this pathological communication axis. Conclusion Our study reveals that NTG reprograms meningeal fibroblasts to expand a pro-inflammatory fibroblast subtype, which drives migraine-related chronic hypersensitivity through TNF-α/NF-κB signaling and Angptl1-mediated monocyte crosstalk. The identified Mafk-Angptl1 axis presents a potential therapeutic target, though human validation remains essential.

This study aims to explore the effects of graphene oxide (GO) particles on the RepSox-mediated transdifferentiation of fibroblasts into mammary epithelial cells. GO was synthesized using the Hummers method, and its structure was characterized by Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. Its biocompatibility was verified through CCK - 8 and EdU assays. The effects of the GO/RepSox composite system on the transdifferentiation process of fibroblasts and the potential regulatory mechanisms were comprehensively evaluated using morphological observation, immunofluorescent staining, Western blot analysis, real - time quantitative PCR (qRT - PCR), and RNA sequencing techniques. The synthesized GO not only had good biocompatibility but also promoted cell proliferation. GO significantly improved the efficiency of RepSox-mediated transdifferentiation of fibroblasts into mammary epithelial cells and enhanced the lactation function of mammary epithelial cells. Mechanistically, GO may create favorable conditions for transdifferentiation by coordinately regulating mitochondrial energy metabolism (the ATP level was significantly increased in the R + GO group) and cell cycle progression (the proportion of cells in the G1 phase was significantly increased). This study first elucidates the regulatory role of GO in cell fate determination and provides innovative research ideas and experimental evidence for the application of nanomaterials in cell reprogramming and transdifferentiation.

Cardiac fibrosis is a major component of heart failure (HF) and develops when reparative wound healing becomes chronic, leading to excessive extracellular matrix accumulation. Cardiac fibroblasts (CFs), the main regulators of matrix remodeling, are heterogeneous in developmental origins, regional localizations, and activation states. This diversity determines whether tissue repair resolves normally or progresses into maladaptive scarring that disrupts myocardial structure and function after injuries. Recent single-cell and spatial transcriptomic studies show that CFs exist in distinct yet interrelated molecular states in murine models and human cardiac tissue with specialized roles in matrix production, angiogenesis, immune signaling, and mechanical sensing. These insights redefine cardiac fibrosis as a dynamic and context-dependent process rather than a uniform cellular response. Although CFs are promising targets for preventing HF progression and enhancing cardiac remodeling, translation into effective therapies remains limited by the unclear heterogeneity of pathological fibroblasts, the lack of distinctive CF markers, and the broad activity of fibrogenic signaling pathways. In this review, we discuss the dynamics of CF activations during the development and progression of HF and assess the underlying pathways and mechanisms contributing to cardiac dysfunction. Additionally, we highlight the potential of targeting CFs for developing therapeutic strategies. These include nonspecific suppression of fibroblast activity and targeted modulation of the signaling pathways and cell populations that sustain chronic remodeling. Furthermore, we assess regenerative approaches that can reprogram fibroblasts or modulate their paracrine functions to restore functional myocardium. Integrating antifibrotic and regenerative strategies with advances in precision drug discovery and gene delivery offers a path toward reversing established fibrosis and achieving recovery in HF.

Postoperative fibrotic complications persistently challenge urethral reconstruction due to dysregulated stromal repair and poor graft integration. Conventional rigid ultrasound transducers lack anatomical conformity on dynamic tissues, limiting therapeutic efficacy. Here, we introduce a conformal, wearable low‐intensity pulsed ultrasound (LIPUS) bioelectronic system that overcomes these constraints via controlled adhesion printing and liquid metal interconnects. This low‐cost (<$20), flexible device ensures stable acoustic coupling and programmable mechanostimulation while maintaining mechanical integrity and biocompatibility under repeated use. In a rabbit model of full‐thickness urethral defect, LIPUS significantly improves luminal patency and urinary flow function, promotes angiogenesis and elastic fiber regeneration, while suppressing collagen deposition and pro‐inflammatory macrophage infiltration. Integrated multi‐omics and single‐nucleus RNA sequencing reveal that LIPUS activates the Wnt pathway to drive fibroblast differentiation into a terminally differentiated FGF10 + subset (FB3), which engages in regenerative crosstalk with mural cells via FGF10‐FGFR2b signaling and calcium dynamics. Wnt inhibition abrogates this process, confirming mechanistic specificity. This study bridges flexible bioelectronics with deep mechanobiology, providing new insights into how mechanical stimulation can redirect fibroblast fate and override pathological fibrosis, offering a scalable therapeutic framework for fibrotic disorders.

Direct cardiac reprogramming represents a promising strategy to regenerate damaged myocardium by converting cardiac fibroblasts into induced cardiomyocytes (iCMs). Transient delivery of a four-microRNA cocktail (miRcombo: miR-1, miR-133, miR-208, and miR-499) has been shown to activate cardiac transcriptional programs in adult human cardiac fibroblasts (AHCFs). However, reprogramming efficiency remains limited compared to significantly higher outcomes observed in vivo, suggesting that microenvironmental cues present in the native myocardium play a crucial role in facilitating lineage conversion. This study investigated how extracellular matrix (ECM) proteins modulate miRcombo-mediated reprogramming. An cardiac ECM termed \"biomatrix\" was developed and characterized from long-term cultured AHCFs. An optimized decellularization protocol was applied to preserve major ECM components, including laminin, fibronectin, and collagen type I, while minimizing residual DNA content. Lipoplexes composed of [2-(2,3-didodecyloxypropyl)-hydroxyethyl] ammonium bromide (DE) and dioleoyl phosphatidylethanolamine (DOPE) were used to transiently transfect AHCFs with miRcombo. Cells were cultured on coatings of individual ECM proteins (laminin, fibronectin, collagen I) or biomatrix to assess the influence of cell-substrate interactions on reprogramming efficiency. Analyses were conducted at 7 and 15 days post-transfection. Biomatrix significantly enhanced reprogramming efficiency, yielding approximately 20% cardiac Troponin T (cTnT) cells compared to other substrates. Gene expression analyses demonstrated marked upregulation of cardiac markers TNNT2, ACTC1, and CACNA1C in biomatrix-cultured cells. Structural assessment revealed improved cytoskeletal alignment and sarcomeric organization on laminin and biomatrix, whereas fibronectin and collagen I supported poorer structural maturation. At 3 days post-seeding, fibronectin and collagen I promoted higher proliferation rates and increased nuclear localization of YAP, while laminin and biomatrix reduced YAP activation, favoring cardiac transdifferentiation over proliferation. These findings demonstrate that ECM biochemical cues are key regulators of direct cardiac reprogramming. Laminin- and biomatrix-enriched microenvironments enhance miRcombo-mediated iCM induction efficiency , potentially by modulating YAP signaling and balancing proliferation versus transdifferentiation. This study highlights the importance of recapitulating native cardiac microenvironmental signals to improve the efficacy of direct cardiac reprogramming strategies.

The purpose of our study is to explore the potential of a transcription factor-based strategy for directly converting mouse fibroblasts into photoreceptor-like cells. The mouse cDNAs of Ascl, Crx, Ngn1, Nrl, and Otx2 were cloned into a modified commercial adenoviral vector. Mouse embryonic fibroblasts (MEFs) were isolated from E13.5 embryos, and mouse postnatal fibroblasts (MPFs) were isolated from three-day-old mice. A pool of adenoviruses containing five genes was prepared to infect MEFs or MPFs once daily for two days. The MEFs or MPFs were incubated in a specific medium supplemented with forskolin and were changed every two days. After 7 or 14 days, the photoreceptor-like cells were assayed via immunofluorescence or polymerase chain reaction with reverse transcription (RT–PCR). The photoreceptor-like cells were then transplanted into adult C57BL/6 mouse retinas and were assessed by immunofluorescence 14 days following transplantation. Screening from a pool of five candidate genes, we reported that a combination of only three factors—Crx, Nrl, and Otx2—was sufficient to convert mouse embryonic and postnatal fibroblasts into photoreceptor-like cells. The induced photoreceptor-like cells expressed photoreceptor-specific proteins such as Recoverin, Rhodopsin, and Opsin and integrated into the outer nuclear layer of the retina following transplantation. This exploratory study provides preliminary evidence that fibroblasts can be directly converted into photoreceptor-like cells, suggesting a cellular model and potential source for future transplantation strategies aimed at retinal repair.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis, largely due to its unique tumor microenvironment (TME) and dense fibrotic stroma. Cancer-associated fibroblasts (CAFs) play a crucial role in promoting tumor growth and metastasis, contributing to the metabolic adaptation of PDAC cells. However, the metabolic interactions between PDAC cells and CAFs are not well-understood. In this study, an in vitro co-culture model was used to investigate these metabolic interactions. Metabolomic analysis was performed under monoculture conditions of Capan−1 PDAC cells and CAF precursor cells, as well as co-culture conditions of PDAC cells and differentiated inflammatory CAF (iCAF). Co-cultured Capan−1 cells displayed significant metabolic changes, such as increased 2-oxoglutaric acid and lauric acid and decreased amino acids. The metabolic profiles of co-cultured Capan−1 and CAFs revealed differences in intracellular metabolites. Analysis of extracellular metabolites in the culture supernatant showed distinct differences between Capan−1 and CAF precursors, with the co-culture supernatant exhibiting the most significant changes. A comparison of the culture supernatants of Capan−1 and CAF precursors revealed different metabolic processes while co-culturing the two cell types demonstrated potential metabolic interactions. In conclusion, this study emphasizes the importance of metabolic interactions between cancer cells and CAFs in tumor progression and highlights the role of TME in metabolic reprogramming.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, due to dense stromal tumor microenvironment. Cancer-associated fibroblasts are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy. Targeting cancer-associated fibroblasts has been considered a promising therapeutic strategy. However, depleting cancer-associated fibroblasts may also have tumor-promoting effects due to their functional heterogeneity. Several subtypes of cancer-associated fibroblasts have been suggested to exhibit tumor-restraining function. This review article summarizes recent preclinical and clinical investigations addressing pancreatic cancer therapy through targeting specific subtypes of cancer-associated fibroblasts, deprogramming activated fibroblasts, administration of mesenchymal stem cells, as well as reprogramming tumor-promoting cancer-associated fibroblasts to tumor-restraining cancer-associated fibroblasts. Further, inter-cellular mediators between cancer-associated fibroblasts and the surrounding tissue microenvironment are discussed. It is important to increase our understanding of cancer-associated fibroblast heterogeneity and the tumor microenvironment for more specific and personalized therapies for pancreatic cancer patients in the future.

Testosterone production by Leydig cells (LCs) plays a crucial role in male reproduction. The functional degeneration of LCs can cause testosterone deficiency, ultimately resulting in primary male hypogonadism. Transplantation of exogenous LCs with the ability to produce testosterone in response to the regulation of the hypothalamus-pituitary-gonad axis could be a promising alternative option to treat male primary hypogonadism. Recent studies have shown that it is possible to generate Leydig-like cells from stem cells by various approaches. In addition, somatic cells, such as embryonic or adult fibroblasts, have also been successfully reprogrammed into Leydig-like cells. In this review, we summarized the recent advances in the generation of Leydig-like cells, with an emphasis on comparing the effectiveness and safety of different protocols used and the cells generated. By further analyzing the characteristics of Leydig-like cells generated from fibroblasts based on small signaling molecules and regulatory factors, we found that although the cells may produce testosterone, they are significantly different from real LCs. For future in vivo applications, it is important that the steroidogenic cells generated be evaluated not only for their steroidogenic functions but also for their overall cell metabolic state by proteomics or transcriptomic tools.