bims-fibdiv 2026-02-15 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2026–02–15
27 papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Fibroblasts as regulators of lung immunity, repair and fibrosis.
Cadherin-11 integrates Piezo1 and interleukin-6 signaling to promote fibroblast activation.
The ADAMTS family: from extracellular matrix proteases to orchestrators of fibrosis.
Distinct mural cells and fibroblasts drive fibrochondrogenesis in retrodiscal tissue following temporomandibular joint disc displacement.
Oral submucous fibrosis: Regulatory mechanism of collagen metabolism and management.
Inhibition of (interstitial) P2Y 6 receptors attenuates renal fibrosis progression.
Composition and Influence of Fibrogenic Niche in Myocardial Fibrosis.
uPAR deficiency triggers TGFβ1-mediated fibrotic remodeling in a cardiac perivascular-like microenvironment.
Epithelial-mesenchymal transition and cancer-associated fibroblasts in tumor progression and therapy resistance: mechanistic convergence and therapeutic opportunities.
Prostate Cancer-Associated Fibroblasts: A Review on CAF Functions, Heterogeneity, Resistance Mechanisms, and Future in a Chip.
Methodological advances to analyze cancer-associated fibroblast-derived ECM effects on macrophage polarization.
Neuroimmune interactions in fascia and myofiber regeneration: a narrative review.
Endothelial-to-Mesenchymal Transition in Post-Myocardial Infarction Fibrosis: A Maladaptive but Targetable Pathway.
The Generation of Tissue-Specific ECM Hydrogels From Melanoma and Associated Organs to Study Cancer Biology.
GTX-11 attenuates lung fibrosis, inflammation and vascular remodeling in preclinical models of lung fibrotic disease.
The Role of Fibroblast-Epithelial Cross-Talk on the Distribution of Distinct Fibroblast Phenotypes in the Intestinal Crypt.
When healing turns fibrotic: Exploring molecular mechanisms and therapeutic strategies for knee arthrofibrosis.
Matrix stiffness-induced NARF promotes hepatocellular carcinoma progression by enhancing LEF1-mediated transcription.
The Heart's Hidden Neural Network: Interplay Between Intracardiac Ganglia, Fibrosis and Cardiac Remodeling.
Targeting the FAPα/Integrin αvβ1 complex attenuates hepatic stellate cell activation and liver fibrosis.
Profibrotic Changes Following Tension Application in a Fetal Lamb Model of Long Gap Esophageal Atresia.
PRIP/PLCL deficiency activates PI3K-AKT-YAP signaling and promotes organ fibrosis.
Epithelial-mesenchymal transition (EMT) and cellular plasticity in Ovarian cancer.
A single-dose of PDGFB circular RNA enables sustained growth factor expression to accelerate diabetic wound healing.
Matrix Stiffness Governs Fibroblasts' Regulation of Gingival Immune Homeostasis.
Wnt11 mediates fibroblast-smooth muscle cell interaction to promote neurogenic bladder fibrosis in rats.
Tenascin N contributes to spinal motor nerve morphogenesis during development.

Nat Rev Immunol. 2026 Feb 12.

Fibroblasts as regulators of lung immunity, repair and fibrosis.

Peter T Bell, Gabrielle T Belz.

Fibrosis is a complex disorder characterized by the excessive deposition of extracellular matrix, which disrupts normal tissue architecture and compromises organ function. Fibrosis can affect any organ, with pulmonary fibrosis being one of the most common and life-threatening forms. Despite marked research efforts, effective antifibrotic therapies remain limited, largely due to an incomplete understanding of the underlying disease mechanisms. At the centre of fibrotic processes are fibroblasts, which are tissue-resident mesenchymal cells responsible for extracellular matrix production, tissue remodelling, wound healing and fibrosis. For decades, the biology of fibroblasts remained poorly understood, but advances in single-cell sequencing have recently provided deeper insights into their heterogeneity, plasticity and functional diversity. These insights have prompted renewed efforts to identify the core regulatory programmes that govern fibroblast states in health and disease. In this Review, we examine how immunological, mechanical and metabolic regulators influence fibroblast function in fibrosing interstitial lung diseases. We show how loss of stromal regulation through chronic inflammation, immune dysfunction, altered tissue biomechanics and metabolic stress can tip the balance from successful tissue repair to progressive fibrosis.

DOI: https://doi.org/10.1038/s41577-026-01268-4
Biomater Sci. 2026 Feb 09.

Cadherin-11 integrates Piezo1 and interleukin-6 signaling to promote fibroblast activation.

Leilani R Astrab, Steven R Caliari.

Persistent fibroblast activation drives tissue fibrosis, yet how mechanical and inflammatory cues are integrated to promote this aberrant behavior remains unclear. Using a hyaluronic acid (HA)-based hydrogel platform to model normal and fibrotic lung mechanics, we examine the roles of Piezo1 and cadherin-11 (CDH11), both implicated in M2 macrophage-fibroblast crosstalk during pulmonary fibrosis progression, in interleukin (IL)-6-mediated fibroblast activation. While both Piezo1 and CDH11 expression increase in activated fibroblasts, blocking IL-6 signaling decreases CDH11, but not Piezo1, expression. Instead, Piezo1 activity promotes nuclear accumulation of the calcium-dependent transcription factor NFAT1. While Piezo1 inhibition moderately reduces CDH11 expression, it does not prevent fibroblast activation as measured by spreading and type I collagen expression, whereas CDH11 knockout suppresses fibroblast activation metrics, reduces Piezo1 expression, and decreases IL-6 secretion in both fibroblast only and fibroblast-M2 macrophage co-cultures. Furthermore, CDH11 levels increase in parallel with progressive fibroblast activation, highlighting its role in promoting this pro-fibrotic phenotype. Together, these findings underscore a previously unrecognized signaling axis in which CDH11 serves as a key mediator of sustained fibroblast activation, coordinating mechanical and inflammatory cues, and highlight CDH11 as a potential therapeutic target in pulmonary fibrosis.

DOI: https://doi.org/10.1039/d5bm01456e
Cell Commun Signal. 2026 Feb 13.

The ADAMTS family: from extracellular matrix proteases to orchestrators of fibrosis.

Yang Yuan, Peng Guo, Yajuan Song, Zhou Yu, Baoqiang Song.

  Fibrosis, a pathological process defined by excessive extracellular matrix (ECM) accumulation, contributes significantly to chronic organ failure worldwide. The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family proteins are secreted, multi-domain matrix-associated zinc metalloendopeptidases, which have emerged as key regulators of fibrotic pathogenesis. While the ADAMTS proteins are well known for their ability to cleave ECM components such as collagens, proteoglycans, fibronectin, and fibrillins, their roles in fibrosis extend beyond conventional ECM modulators. Through precise proteolytic modification of these ECM substrates, ADAMTS members actively orchestrate upstream and core mechanisms driving fibrosis, notably TGF-β activation and fibroblast phenotype switching. Recent studies have uncovered tissue- and substrate-specific roles of individual ADAMTS members, highlighting their dual regulatory effects in fibrotic diseases and opening avenues for targeted therapeutic strategies. Despite promising preclinical results, translating ADAMTS-targeting therapies into clinical applications for fibrosis remains challenging due to their functional duality, substrate redundancy, and poorly characterized spatiotemporal specificity. This review comprehensively summarizes the proteolytic mechanisms of ADAMTS proteases toward ECM substrates, their multifaceted roles in fibrogenesis, and discusses their translational potential as therapeutic targets.

Keywords:  ADAMTS; Collagen; ECM; Fibroblast; Fibrosis; TGF-β signaling

DOI:  https://doi.org/10.1186/s12964-026-02743-0
JCI Insight. 2026 Feb 10. pii: e196343. [Epub ahead of print]

Distinct mural cells and fibroblasts drive fibrochondrogenesis in retrodiscal tissue following temporomandibular joint disc displacement.

Wenlin Yuan, Yilin Chen, Ruojin Yan, Wei Liu, Chenyu Wang, Ying Wang, Qiaoli Dai, Wen Li, Mengqi Zhu, Xiao Chen, Jiejun Shi.

  Adaptive remodeling of retrodiscal tissue following anterior disc displacement (ADD) of the temporomandibular joint (TMJ) has been recognized for decades, yet the underlying cellular dynamics and molecular mechanisms remain unclear. Using a porcine ADD model, this study investigated the cellular and molecular basis driving retrodiscal tissue adaptation. Histological staining revealed adaptive remodeling of retrodiscal tissue after ADD induction, with dense connective tissue and cartilaginous masses replacing loose connective tissue. Furthermore, single-cell RNA sequencing (scRNA-seq) captured pronounced fibroblast expansion during tissue remodeling, notably the FB2 subcluster with high developmental potential, and the emergence of a mural cell subcluster MC4 associated with extracellular matrix (ECM) remodeling. CellChat analysis highlighted MC4-FB2 crosstalk via FGF2 and BMP5 signaling. The combination of pathway-aware multi-layered hierarchical network (P-NET) and Seurat with drug database screening identified five promising compounds. Among them, Zaprinast demonstrated the most robust effects by enhancing the remodeling capability of fibroblasts in vitro, and also alleviated TMJ deformation in vivo. Collectively, fibroblast activation is pivotal for early retrodiscal tissue adaptation following ADD, which is driven by MC4-derived FGF2/BMP5 signaling. Zaprinast treatment potentiates this remodeling process. These findings provide new insights into cellular basis of TMJ adaptation and identify potential therapeutic targets for ADD management.

Keywords:  Bone biology; Cartilage; Cell biology; Extracellular matrix

DOI:  https://doi.org/10.1172/jci.insight.196343
Biomed Pharmacother. 2026 Feb 10. pii: S0753-3322(26)00085-5. [Epub ahead of print]196 119053

Oral submucous fibrosis: Regulatory mechanism of collagen metabolism and management.

Zhao-Yong Hu, Yan-Li Liu, Jia-Kang Qiu, Qiao-Juan Zuo, Qun Li, Jin Tan.

  Oral submucous fibrosis (OSF) is a chronic and insidious potentially malignant disorder characterized by progressive fibrosis of the oral submucosa. It is recognized to be an irreversible disease of multifactorial origin, with limited therapeutic options due to incomplete understanding of its pathogenesis. Increased collagen synthesis or decreased collagen degradation is vital for the development of OSF. This review mainly introduces the key regulatory mechanism of collagen metabolism. Prolonged use of areca nut is arguably the major causative agents for OSF, which is vital for the myofibroblast transdifferentiation, fibroblastic proliferation, collagen synthesis, and resistance to collagenases. Chemical constituents of areca nut, and these components induced changes in epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) remodelling, inflammatory cytokines and growth factors, autoimmunity, and aberrant non-coding RNAs, are pivotal regulating factors for the myofibroblast activity and collagen metabolism in OSF. Oxidative stress following cell injury by areca nut extract, represented by reactive oxygen species (ROS) production, regulates ECM, EMT and cell cycle in OSF. Other factors such as nutrition, local stimulating factors and genetic susceptibility are also involved in the disease onset and progression. This paper summarizes both etiological factors and pathogenetic mechanisms underlying the collagen metabolism dysregulation in OSF, which provides new molecular targets and further research directions for the management of OSF.

Keywords:  collagen metabolism; epithelial-mesenchymal transition; extracellular matrix; oral submucous fibrosis

DOI:  https://doi.org/10.1016/j.biopha.2026.119053
bioRxiv. 2026 Jan 29. pii: 2026.01.27.701928. [Epub ahead of print]

Inhibition of (interstitial) P2Y 6 receptors attenuates renal fibrosis progression.

Lena Marie Süß, Anna Petzendorfer, Bettina Firmke, Anja Süß, Richard Warth, Katharina Anna-Elisabeth Broeker, Anna-Lena Forst.

Chronic kidney disease (CKD) affects over 850 million people worldwide and is characterized by progressive renal fibrosis driven by activated interstitial fibroblasts. Signaling by extracellular nucleotides and P2 receptors plays an important role in renal pathophysiology, yet its contribution to fibroblast activation and fibrosis remains poorly understood. Here, we investigated the expression and function of G q/11 -coupled P2Y receptors in renal interstitial fibroblasts and their involvement in experimental kidney fibrosis. Using highly selective RNA in situ hybridization, we detected P2Y 1 ( P2ry1 ) and P2Y 6 ( P2ry6 ) receptor expression in interstitial fibroblasts. Notably, P2Y 6 expression was markedly upregulated in several experimental mouse models of renal fibrosis. Functional assays in primary cultured renal fibroblasts confirmed G q/11 -coupled P2Y receptor activity, as evidenced by transient intracellular Ca 2+ elevations upon nucleotide stimulation. Primary cultured renal fibroblasts exhibited enhanced migration in response to extracellular uridine diphosphate (UDP). To assess the contribution of interstitial P2Y 6 receptors to fibrosis progression, we employed an adenine-induced nephropathy model with or without the selective P2Y 6 antagonist MRS2578. Pharmacological inhibition of P2Y 6 significantly reduced the mRNA expression of the myofibroblast marker α-smooth muscle actin and collagen I. Collectively, these findings suggest that upregulated P2Y 6 receptor signaling promotes the transition of resident interstitial cells into myofibroblasts during renal fibrosis, likely by modulating fibroblast migration. Inhibition of P2Y6 signaling could represent a new strategy for reducing excessive renal fibrosis.
TRANSLATIONAL STATEMENT: This study reveals the role of the P2Y 6 receptor ( P2ry6 ) in fibrotic processes in the kidney. P2Y 6 , a G q/11 protein-coupled UDP-sensitive receptor, is expressed in renal interstitial PDGFR-β-positive cells and macrophages. Its pharmacological inhibition significantly reduces fibrosis in the mouse adenine nephropathy model. Blocking P2Y 6 therefore represents a promising therapeutic strategy for kidney diseases characterized by excessive scarring.

DOI: https://doi.org/10.64898/2026.01.27.701928
Rev Cardiovasc Med. 2026 Jan;27(1): 44112

Composition and Influence of Fibrogenic Niche in Myocardial Fibrosis.

Xiaohe Wang, Liwei Fan, Qiang Yuan, Yuhang Luo, Zhengyi Cheng, Yi Chen, Chen Gong.

  Myocardial fibrosis represents the initial stage of cardiac failure and is characterized by the accumulation of extracellular matrix proteins. The fibrogenic niche provides a unique microenvironment for myocardial fibrosis and consists primarily of extracellular matrix proteins, various types of cardiac resident cells, inflammatory cells, extracellular vesicles, and soluble factors. Meanwhile, the composition and contents of this microenvironment undergo dynamic changes during the repair of damaged tissues. Several studies have demonstrated that the fibrogenic niche plays a key role in the activation of fibroblasts, the development of inflammation, and the onset of microvascular dysfunction. Studying the fibrogenic niche has emerged as a new method to clarify the mechanisms involved in myocardial fibrosis, and can potentially facilitate the early diagnosis and individualized medical treatment for the disease.

Keywords:  extracellular matrix; fibroblast activation; fibrogenic niche; myocardial fibrosis

DOI:  https://doi.org/10.31083/RCM44112
Stem Cell Res Ther. 2026 Feb 13.

uPAR deficiency triggers TGFβ1-mediated fibrotic remodeling in a cardiac perivascular-like microenvironment.

Yulia Goltseva, Zoya Tsokolaeva, Irina Beloglazova, Victoria Stepanova, Maria Boldyreva, Elizaveta Ratner, Andrew Mazar, Alexander Andreev, Andrey Shiryaev, Yelena Parfyonova, Konstantin Dergilev.

   BACKGROUND: Cardiac fibrosis represents a significant health burden, with endothelial dysfunction and damaged perivascular microenvironment increasingly recognized as key contributors to fibrotic remodeling. The urokinase plasminogen activator receptor (uPAR), a critical component of the urokinase system, plays a pivotal role in vascular remodeling and fibrosis. While prior evidence indicates that uPAR deficiency leads to microvascular dysfunction and perivascular fibrosis, the underlying mechanisms remain poorly defined. This study investigates how uPAR deficiency contributes to fibrotic remodeling of the cardiac perivascular-like microenvironment.
METHODS: Single-cell RNA sequencing data analysis and immunofluorescence staining on mouse heart cryosections were performed to characterize uPAR expression within the cardiac perivascular microenvironment. To model this microenvironment in vitro, cardiospheres (CSs) were generated from non-myocyte cardiac cells of wild-type and uPAR-knockout mice. CRISPR/Cas9-generated Plaur knockout (KO) 3T3 fibroblasts (FBs) were employed as model stromal cells. Pro-fibrotic activation of FBs was induced by TGFβ1 treatment. Comparative analyses of extracellular matrix (ECM) deposition, fibrotic cell transformation, and comprehensive secretome profiling was conducted using western blotting.
RESULTS: Our findings demonstrated that uPAR was expressed by endothelial cells (ECs) and FBs within the cardiac perivascular microenvironment. uPAR deficiency exacerbated profibrotic stimuli in CSs, including elevated active TGFβ1, impaired integrin functions, and altered cell secretome. These alterations collectively disrupt critical cell-cell and cell-matrix interactions, leading to increased ECM deposition, EC loss and decreased cell viability. Using Plaur KO FBs, we demonstrated that uPAR deficiency amplified TGFβ1-mediated Akt signaling pathway and ECM deposition.
CONCLUSIONS: Our study reveals that uPAR loss drives fibrotic remodeling of the cardiac perivascular-like microenvironment and exacerbates TGFβ1-mediated effects, highlighting its potential as a therapeutic target for cardiac fibrosis.

Keywords:  3D cell culture; Cardiosphere; Fibroblasts; Fibrosis; Heart; Perivascular microenvironment; Spheroid; TGFβ1; UPAR; Urokinase receptor

DOI:  https://doi.org/10.1186/s13287-026-04923-8
Clin Transl Oncol. 2026 Feb 11.

Epithelial-mesenchymal transition and cancer-associated fibroblasts in tumor progression and therapy resistance: mechanistic convergence and therapeutic opportunities.

Dhiraj Kumar Singh, Rashmi Gupta, Umesh Kumar, Saurabh Gupta.

  Cancer progression and treatment failure are driven not only by tumor-intrinsic alterations but also by dynamic interactions within the tumor microenvironment (TME). Epithelial-mesenchymal transition (EMT) and cancer-associated fibroblasts (CAFs) represent two interlinked mechanisms that promote tumor invasion, metastatic dissemination, stemness, immune evasion, and resistance to therapy. EMT is regulated by transcription factors, such as Snail, ZEB, and Twist, and by signaling pathways including TGF-β, Wnt/β-catenin, and Notch, enabling cancer cells to adopt hybrid epithelial-mesenchymal states that confer phenotypic plasticity and drug tolerance. CAFs, derived from multiple cellular sources, further reinforce EMT programs through paracrine signaling, extracellular matrix remodeling, and metabolic reprogramming. This review critically synthesizes current evidence on EMT-CAF crosstalk in oncogenesis and therapeutic resistance, highlighting emerging clinical strategies, translational challenges, and lessons from failed or limited therapeutic approaches. By emphasizing EMT plasticity and CAF heterogeneity as convergent drivers of tumor adaptability, this work provides a refined framework for developing rational combination therapies targeting both cancer cells and their supportive stroma.

Keywords:  Cancer; Cell signaling; EMT; Fibroblast; Notch; TGF-β1; Tumor microenvironment; Wnt

DOI:  https://doi.org/10.1007/s12094-026-04255-2
Int J Mol Sci. 2026 Feb 05. pii: 1585. [Epub ahead of print]27(3):

Prostate Cancer-Associated Fibroblasts: A Review on CAF Functions, Heterogeneity, Resistance Mechanisms, and Future in a Chip.

Nikolett Lupsa, Erika Heninger, Adeline B Ding, Cristina Sanchez De Diego, Katherine Vietor, Shannon R Reese, Aaron M LeBeau, David Kosoff, David J Beebe, Sheena C Kerr, Joshua M Lang.

  Cancer-associated fibroblasts (CAFs) are key regulators of the prostate tumor microenvironment (TME) with influence on disease progression and therapeutic response. CAFs originate from multiple precursors and retain remarkable plasticity while tumors evolve. Therefore, the CAF pool displays considerable functional heterogeneity, which is well-reflected in complex molecular signatures. However, overlapping biomarker patterns with other stromal subsets make it challenging to identify and assess the role of specific CAF subpopulations. Through reciprocal tumor-stroma interactions, CAFs promote extracellular matrix (ECM) remodeling, angiogenesis, metabolic reprogramming, and immune evasion, collectively fostering an adaptive niche that supports tumor survival, though some CAF subsets have been shown to support anti-tumor response. In prostate cancer (PCa), CAFs promote resistance to androgen receptor pathway inhibitor therapy, chemotherapy, and radiotherapy, emphasizing their potential value as therapeutic targets. However, CAF targeting has shown limited clinical benefit in PCa, due to complex, context-dependent CAF functions that make it challenging to exploit this unique stromal population for therapeutic gain. Recent advances in organ-on-a-chip (OOC) models offer new opportunities to investigate the mechanisms behind TME interactions and evaluate CAF-targeted strategies in physiologically relevant fully humanized environments. This review provides current insights into CAF heterogeneity and therapy resistance in PCa and highlights emerging translational OOC models to guide the development of more effective therapies to disrupt the TME.

Keywords:  CAF heterogeneity; cancer associated fibroblasts; organ-on-a-chip models; prostate cancer; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms27031585
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00227-4. [Epub ahead of print]202 223-240

Methodological advances to analyze cancer-associated fibroblast-derived ECM effects on macrophage polarization.

Annalisa Tocci, Lorenzo Valenti, Nicla Porciello, Belinda Palermo, Anna Di Carlo, Francesca Di Modugno, Paola Nisticò.

  The tumor microenvironment (TME) represents a complex ecosystem composed of tumor cells and various non-cancerous cell types, embedded within an altered extracellular matrix (ECM). In solid tumors, the ECM plays multiple roles: it provides mechanical support, delivers signaling molecules and transmits biophysical stimuli that influence cellular functions. Various cell types, primarily cancer-associated fibroblasts (CAFs) and immune cells such as macrophages, actively participate in the secretion and remodeling of ECM. However, whether the ECM directly instructs or educates immune cells, particularly macrophages within the TME, remains poorly understood. Here, we present a protocol to investigate the impact of ECM derived from non-small cell lung cancer (NSCLC) CAFs on macrophage state.

Keywords:  Cancer-associated fibroblasts; Decellularized extracellular matrix; Extracellular matrix; Flow cytometry; Macrophage polarization; Macrophages; Non-small cell lung cancer

DOI:  https://doi.org/10.1016/bs.mcb.2025.11.002
Musculoskelet Sci Pract. 2026 Feb 05. pii: S2468-7812(26)00022-6. [Epub ahead of print] 103507

Neuroimmune interactions in fascia and myofiber regeneration: a narrative review.

Robbert N van Amstel, Ivo J Lutke Schipholt, Guido Weide, Annelies L Pool-Goudzwaard, Richard T Jaspers.

  When not treated adequately, neuromusculoskeletal, tendinous, and joint tissue injuries may become chronic, leading to impaired tissue function due to fibrosis, extracellular matrix densification, and fatty connective tissue accumulation, ultimately resulting in reduced joint and muscle mobility. Timely treatment involving the mobilization of fascia and targeted muscle exercise has been shown to enhance and promote tissue regeneration. Key phases in tissue regeneration after injury include the activation of the innate immune system, followed by its resolution. Although several treatment modalities are effective in restoring tissue function, their success rate and time to recovery may still need optimization. Over recent decades, increasing attention has been given to the role of fascia in neuromuscular tissue function, adaptation, and regeneration. However, the complex interactions between fasciae, myofibers, and the immune system remain insufficiently understood, particularly regarding the mechanisms underlying fibrosis, extracellular matrix densification, and chronic pain. Fasciae are interconnected connective tissue sheaths that maintain anatomical organization, allow tissue gliding, and facilitate mechanical force transmission between structures. Because of their mediating role in mechanical and biochemical signalling, fascial tissues are also involved in injury and regeneration processes. Pathological stiffening of fascial connections may impair regeneration by limiting mobility and disrupting mechanotransduction. Therefore, treatment strategies that target both muscle and fascial tissues may offer improved outcomes in the recovery of neuromusculoskeletal function.

Keywords:  Fascia; Muscle; Musculoskeletal manipulations; Neuroimmunomodulation; Regeneration

DOI:  https://doi.org/10.1016/j.msksp.2026.103507
EJIFCC. 2026 Feb;37(1): 26-41

Endothelial-to-Mesenchymal Transition in Post-Myocardial Infarction Fibrosis: A Maladaptive but Targetable Pathway.

Duong Le.

Myocardial infarction (MI) initiates a healing response in which fibroblasts and other cells deposit extracellular matrix to form a stabilizing scar. This scarring is essential for preventing ventricular rupture, yet when excessive or diffuse, it becomes maladaptive: fibrosis stiffens the ventricle, impairs filling, and drives progression to heart failure. Traditional antifibrotic approaches, such as broad TGF-β blockade or collagen cross-linking inhibition, have largely failed because fibroblast activity is required for early scar integrity, while established fibrosis is difficult to reverse. This review highlights endothelial-to-mesenchymal transition (EndMT) as a distinct and underappreciated contributor to post-MI fibrosis. Experimental studies indicate that EndMT supplies 10-30% of fibroblast-like cells, and evidence of EndMT is present in human ischemic cardiomyopathy. Unlike fibroblast-driven repair, EndMT is maladaptive in the adult heart: it promotes fibrosis without enhancing scar strength and reduces endothelial cell numbers, leading to microvascular rarefaction and impaired perfusion. EndMT is regulated by discrete, targetable pathways-including TGF-β/Smad, Notch, Wnt/β-catenin, HIF-1α, and microRNA networks (e.g., miR-21, miR-29)-and exhibits partial reversibility. This opens opportunities for time-limited, pathway-specific interventions during the proliferative phase of healing. Emerging diagnostic tools, such as extracellular volume mapping, fibroblast activation protein PET, collagen peptide assays, and circulating fibrosis-related microRNAs, provide clinical means to detect EndMT activity. By integrating mechanistic insights with advances in molecular imaging and biomarker profiling, this review proposes EndMT-directed, biomarker-guided therapies as a precision strategy to limit maladaptive fibrosis, preserve vascular networks, and improve outcomes after MI.

Keywords: Anti-fibrotic Therapy; Biomarkers; Cardiac Fibrosis; Endothelial-to-Mesenchymal Transition (EndMT); Myocardial Infarction; TGF-β Signaling; Translational Cardiology
Bio Protoc. 2026 Feb 05. 16(3): e5586

The Generation of Tissue-Specific ECM Hydrogels From Melanoma and Associated Organs to Study Cancer Biology.

Yuval Mogilevsky, Chen Sharon-Yagol, Bar Manobla, Shahaf Saad, Ziv Raviv, Yuval Shaked.

  The extracellular matrix (ECM) critically shapes melanoma progression and therapeutic response, yet commonly used matrices such as Matrigel fail to capture tissue- and disease-specific ECM properties. This protocol provides a streamlined and scalable method for generating murine, tissue-specific ECM hydrogels from skin, lung, and melanoma tumors, therefore overcoming the restricted materials of mouse-derived ECM. The workflow integrates tissue-tailored decellularization, lyophilization, mechanical fragmentation, pepsin digestion, and physiological polymerization to produce hydrogels that reliably preserve fibrillar collagen architecture and organ-specific ECM cues. Decellularization efficiency and ECM integrity are validated by DNA quantification, H&E staining, and Picrosirius Red staining analysis. These hydrogels provide a species- and tissue-matched platform for studying melanoma-ECM-immune interactions, pre-metastatic niche features, and therapy-induced ECM remodeling. Overall, this protocol offers a reproducible and physiologically relevant ECM model that expands experimental capabilities for melanoma biology and treatment-resistance research and that can be easily extended to other tumors and tissues. Key features • A miniaturized, tissue-specific workflow for generating ECM hydrogels from small murine skin, lung, and melanoma tissues, overcoming size limitations of existing protocols. • Preservation of native ECM architecture using tailored decellularization steps validated by DNA quantification, H&E, and Picrosirius Red staining. • A standardized digestion-gelation process optimized for heterogeneous and lipid-rich murine tissues, enabling reproducible hydrogel formation at defined ECM concentrations. • A physiologically relevant platform capturing melanoma- and organ-specific ECM cues for studying ECM-tumor-immune interactions and therapy-induced remodeling.

Keywords:  Collagen; Decellularization; Extracellular matrix (ECM); Hydrogel; Melanoma; Tumor microenvironment

DOI:  https://doi.org/10.21769/BioProtoc.5586
Front Pharmacol. 2025 ;16 1671132

GTX-11 attenuates lung fibrosis, inflammation and vascular remodeling in preclinical models of lung fibrotic disease.

Ana Montes-Worboys, Javier Milara, Consol Farrera, Cristina Fernández-Asensio, Silvia Sánchez-Díez, Jaume Mercadé, Paula Montero, Inés Roger, María Molina-Molina, Eugènia Ruiz-Cánovas, Julio Cortijo.

   Background: Fibrotic interstitial lung diseases (ILDs) are characterized by different degrees of inflammation and fibrosis of the lung parenchyma that are associated with progressive loss of breath, high morbidity and mortality. Current therapeutic options are limited, so there remains a significant need for effective and well-tolerated treatments. GTX-11 is an orally available small molecule in development for the treatment of fibrotic diseases. In this study, we aimed to assess the therapeutic potential of GTX-11 in different preclinical models of lung fibrotic disease.
Methods: We assessed the activity of GTX-11 and its active metabolite, GTX-11m, in the bleomycin-induced pulmonary fibrosis model and in vitro in primary fibroblast cell cultures, including human normal lung fibroblasts (hNLFs) and ILD patient-derived fibroblasts.
Results: In the murine model, GTX-11 treatment improved animal survival and significantly reduced lung fibrosis as measured by Ashcroft score and collagen deposition. GTX-11 also reduced the inflammatory cell count in bronchoalveolar lavage fluid and pro-inflammatory factors in lung tissue. Additionally, GTX-11 significantly improved lung vascular dysfunction and reduced pulmonary vascular remodeling. The preclinical anti-fibrotic effects of GTX-11 were comparable to, or in some cases exceeded, those of currently approved anti-fibrotic drugs used in clinical practice. In vitro, GTX-11m demonstrated anti-fibrotic and anti-inflammatory activity in hNLFs and ILD patient-derived fibroblasts. GTX-11m inhibited TGFβ-induced expression of key fibrotic markers and reduced fibroblast-to-myofibroblast transition and inflammatory cytokine production. The effects were consistent across the different tested ILD cultures and resulted from the prevention of SMAD2 and SMAD3 activation by TGFβ. The GTX-11m anti-fibrotic and anti-inflammatory effects were comparable or better than nintedanib.
Conclusion: Altogether, our studies reveal that GTX-11 is an effective antifibrotic both in vivo and in vitro, suggesting that GTX-11 has potential as a therapeutic option for fibrotic ILDs.

Keywords:  GTX-11; TGFβ signaling; antifibrotic therapy; bleomycin; fibroblast activation; inflammatory cytokine; interstitial lung disease (ILD); lung fibrosis

DOI:  https://doi.org/10.3389/fphar.2025.1671132
Bull Math Biol. 2026 Feb 09. 88(3): 36

The Role of Fibroblast-Epithelial Cross-Talk on the Distribution of Distinct Fibroblast Phenotypes in the Intestinal Crypt.

George Atkinson, Simon Leedham, Helen M Byrne.

  Intestinal crypts are test tube-like structures lined with an epithelial monolayer. Under homeostasis, mitotic forces drive epithelial cells to migrate up the crypt, from the stem cell niche. As the cells migrate up the crypt, they differentiate into specialised cells. This process is regulated by morphogen gradients established by distinct populations of subepithelial fibroblasts, and recent studies suggest fibroblasts and epithelial cells have co-evolved to maintain crypt structure and function via complementary morphogen expression. We present a mathematical model of fibroblast-epithelial cross-talk, in which fibroblast and epithelial phenotypes emerge from morphogen binding to cell surface receptors. The model predicts the formation of distinct zones of mutually supporting phenotypes at different crypt heights. These findings support the idea that fibroblast and epithelial cell phenotypes are an emergent property of the crypt microenvironment. We use the model to investigate how mutations in the fibroblasts may disrupt these phenotypic zones. Our results suggest that such mutations may lead to uncontrolled epithelial cell growth and, as such, indicate how dysfunctional fibroblasts may contribute to the emergence of colorectal cancer.

Keywords:  BMP; BMPi; Cross-talk; Epithelial cells; Fibroblasts; Hedgehog; Intestinal crypts; Phenotype; WNT

DOI:  https://doi.org/10.1007/s11538-025-01588-x
Eur J Pharmacol. 2026 Feb 06. pii: S0014-2999(26)00127-5. [Epub ahead of print]1017 178645

When healing turns fibrotic: Exploring molecular mechanisms and therapeutic strategies for knee arthrofibrosis.

Ines Nikolic, Luca Morici.

  Knee arthrofibrosis is a serious complication most commonly arising after anterior cruciate ligament reconstruction or total knee arthroplasty, as well as a part of knee osteoarthritis pathology. It is characterized by excessive extracellular matrix deposition, joint stiffness and loss of joint mobility. Fibrosis has been extensively studied in organs such as the liver, lung, and heart, but knee joint fibrosis remains largely neglected, with no approved therapies or ongoing clinical trials targeting its underlying mechanisms. This review presents a comprehensive overview of the cellular and molecular pathways driving pathological fibrosis. We detail the activation and phenotypic diversity of macrophages and fibroblasts, highlighting how dysregulated interactions between these cell types establish self-perpetuating fibrotic loops. The most important mediators and signalling pathways are discussed, as well as the role of enzymes lysyl oxidase, transglutaminase-2 and matrix metalloproteinases in the formation of the fibrotic tissue. An overview of the latest drug candidates under clinical investigation in the last 5 years for other fibrotic conditions was provided, while potential directions for druggable targets specifically related to the knee joint arthrofibrosis were proposed, such as hypoxia inducible factor 1-alpha, nuclear protein 1, Hippo signalling pathway, and Wnt signalling. Particular emphasis is given to some innovative local (intra-articular) drug delivery systems based on micro- and nanoparticles, hydrogels, and extracellular vesicles. Advancing our understanding of knee-specific fibrotic mechanisms is critical to developing effective, mechanism-driven treatments for knee arthrofibrosis.

Keywords:  Cyclops syndrome; Fibrocartilage; Fibrosis; Knee arthrofibrosis; Knee arthroplasty; Macrophage-fibroblast crosstalk; Synovial fibrosis

DOI:  https://doi.org/10.1016/j.ejphar.2026.178645
Biochim Biophys Acta Mol Cell Res. 2026 Feb 06. pii: S0167-4889(26)00018-2. [Epub ahead of print] 120122

Matrix stiffness-induced NARF promotes hepatocellular carcinoma progression by enhancing LEF1-mediated transcription.

Xuelian Xiao, Kangsheng Tu.

  Liver fibrosis and cirrhosis generate a stiff extracellular matrix (ECM) niche that is closely associated with hepatocellular carcinoma (HCC) initiation and progression. Although multiple pathways and molecules are implicated in ECM rigidity-induced mechanical force transduction, the precise mechanism by which ECM rigidity drives HCC progression remain to be fully elucidated. In this study, we identified nuclear prelamin A recognition factor (NARF) as a novel matrix stiffness-responsive gene, whose transcription is directly regulated by the mechanosensor Yes-associated protein (YAP). Clinically, NARF exhibited high expressions in HCC tissues, and its overexpression was closely correlated with poor prognostic outcomes in HCC patients. Functionally, NARF knockdown significantly inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells in vitro, whereas NARF overexpression enhanced these cellular processes. NARF silencing attenuated HCC cell growth and lung metastasis in vivo. RNA-sequencing analysis revealed a strong correlation of NARF with Wnt signaling activation. Further experiments confirmed that NARF positively regulated the expression of key Wnt target genes (MYC, CCND1, SNAIL, and TWIST1) in HCC cells. Mechanistically, NARF recruited acetyltransferase EP300 to enhance H3K27 acetylation at lymphoid enhancer binding factor 1 (LEF1)-binding sites, thereby amplifying LEF1-dependent transcriptional activity. LEF1 knockdown markedly abrogated NARF-mediated oncogenic activity in vitro and in vivo, confirming LEF1 as a critical downstream effector of NARF. Collectively, our findings identify NARF as stiffness-responsive driver that is transcriptionally regulated by YAP protein in HCC. By activating LEF1-mediated Wnt signaling in an EP300 dependent manner, NARF promotes HCC growth and metastasis, highlighting its potential as a prognostic biomarker and therapeutic target for HCC.

Keywords:  EP300; Hepatocellular carcinoma; LEF1; NARF; Tumor progression

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120122
Int J Mol Sci. 2026 Feb 05. pii: 1582. [Epub ahead of print]27(3):

The Heart's Hidden Neural Network: Interplay Between Intracardiac Ganglia, Fibrosis and Cardiac Remodeling.

Jacques-Antoine Gemayel, Aurelien Chatelier, Patrick Bois, Nassim Fares.

  The heart's performance relies on its contractile and rhythmic properties, which are modulated not only by extrinsic autonomic inputs but also by the intrinsic cardiac nervous system (ICNS), a distributed network of intracardiac ganglia and neurons that integrates local sensory, autonomic, and inflammatory signals. Growing evidence indicates that cardiac fibrosis and neuronal remodeling are intertwined processes within this network. This review synthesizes current knowledge on molecular, structural, and functional remodeling of the ICNS to drive neurofibrosis, autonomic imbalance, and arrhythmogenesis. We outline ICNS anatomy and neurochemical diversity, then summarize core fibrotic mechanisms, fibroblast activation, extracellular matrix dynamics, and inflammatory signaling, and map these onto intracardiac ganglia. Across diabetes, myocardial infarction, heart failure, and neuroinflammatory states, shared pathways (e.g., IL-6/STAT3, TGF-β/SMAD, PI3K/AKT, MAPK/ERK, oxidative stress) suppress neuronal excitability, promote neuron-glia-fibroblast coupling, and culminate in neurofibrotic remodeling. We integrate functional data linking these changes to autonomic dysregulation and arrhythmia vulnerability. Future priorities involve constructing detailed human ICNS atlases and applying single-cell and spatial multi-omics to better characterize intracardiac neurons, their circuitry, and their interactions with fibroblasts and immune cells. These insights will be essential to inform targeted neuromodulation and anti-fibrotic interventions. The ICNS is a dynamic regulatory hub whose cells and circuits participate directly in cardiac fibrosis and electrical instability. Recognizing neurofibrosis as a companion process to myocardial fibrosis reframes therapeutic strategy toward preserving both neural and myocardial integrity.

Keywords:  IL-6/STAT3; PI3K/AKT; TGF-β signaling; arrhythmogenesis; autonomic remodeling; cardiac neurons; diabetic cardiac remodeling; intracardiac ganglia; intrinsic cardiac nervous system; neurofibrosis; neuroinflammation; neuromodulation

DOI:  https://doi.org/10.3390/ijms27031582
Biochem Pharmacol. 2026 Feb 11. pii: S0006-2952(26)00132-2. [Epub ahead of print] 117801

Targeting the FAPα/Integrin αvβ1 complex attenuates hepatic stellate cell activation and liver fibrosis.

Chun Guan, Nuo Cheng, Yu Tong, Yifei Li, Jiayi Liu, Haishan Luo, Shihao Liu, Jihai Chen, Cong Wang.

  Hepatic stellate cell (HSC) activation is central to liver fibrosis. Fibroblast activation protein α (FAPα) is highly expressed in activated HSCs, yet its regulatory role remains unclear. This study investigates the function and mechanism of FAPα in HSC activation and fibrosis progression. Using TGF-β1-induced LX2 cells and CCl4-induced mouse models, along with small-molecule inhibitors and multi-omics analyses, we found that inhibiting FAPα suppressed HSC activation, proliferation, migration, and ameliorated fibrosis. Notably, FAPα formed a functional complex with Integrin αvβ1 in activated HSCs. Dual inhibition of FAPα/Integrin αvβ1 more effectively attenuated HSC activation and fibrosis than single-agent treatment. Transcriptomic and proteomic studies revealed that the complex acts through the GPC3/FGF21 axis. This study identifies the FAPα/Integrin αvβ1 complex as a key regulator of liver fibrosis and provides a novel combinatory therapeutic strategy for anti-fibrotic drug development.

Keywords:  Combination therapy; FAPα; Hepatic stellate cells; Integrinαvβ1; Liver fibrosis

DOI:  https://doi.org/10.1016/j.bcp.2026.117801
bioRxiv. 2026 Jan 28. pii: 2026.01.26.701811. [Epub ahead of print]

Profibrotic Changes Following Tension Application in a Fetal Lamb Model of Long Gap Esophageal Atresia.

Jessica C Pollack, Nicolas Vinit, Shelley Jain, Rachel Conan, Melanie Bates, Mia Kwechin, Alicia Eubanks, Mike Xie, Amanda Muir, Emily Partridge.

Introduction: Esophageal atresia is a common congenital anomaly, occurring in 1 in 3,500 live births. The Foker process has revolutionized the treatment of long gap esophageal atresia (LGEA). It is well established that the Foker process causes tension accelerated growth of the esophagus, but what occurs at the molecular level during tension accelerated growth is still unknown. We aimed to create tension accelerated growth in a fetal lamb model of LGEA in order to answer this question.
Methods: Following IACUC approval, time-dated fetal lambs (108 to 120 days of gestation) underwent thoracic esophagectomy. Both esophageal ends were ligated and sutured together to create an internal pexy under high tension. Lambs were delivered on postoperative day 2 (POD2) (n=7), POD6 (n=9) or term (n=5). The native esophagus collected at model creation served as control tissue. Specimens were bluntly separated into two layers: inner layer (IL) (epithelium, lamina propria, muscularis mucosa, submucosa) and outer layer (OL) (submucosa, muscle layer, adventitia). RNA sequencing (RNAseq), proteomics, immunohistochemistry, western blotting and real-time qRT-PCR were performed on the specimens. Mann-Whitney's or unpaired t-test were used for statistical analyses. Esophageal fibroblast cell lines established from human biopsy specimens were cultured and stimulated with TGF-beta for in vitro studies on collagen expression.
Results: 23 lambs underwent esophagectomy with tension suture placement at 108 to 120 days gestation. Histologic analysis of tension conditioned compared to control esophagus by trichrome staining demonstrated an increase in collagen deposition in tension conditioned esophagus compared to controls. High throughput bulk RNA sequencing and proteomic analysis were performed with a focus on pathways implicated in fibrosis. GSEA analysis of the inner layer demonstrates upregulation of TGFB signaling, extracellular matrix organization, and collagen deposition at all timepoints. Further analysis was performed to evaluate specific collagen subtypes contributing to this profibrotic phenotype, and COL8A1 and COL12A1 were both significantly upregulated in both RNA and proteomic analysis at all timepoints, with Western blotting confirming up regulation in stretched tissue. In order to evaluate the relationship between TGFB signaling and collagen deposition in the esophagus, we stimulated esophageal fibroblasts with TGFB, qRT-PCR was performed to evaluate the expression of COL8A1, COL12A1, and COL6A3. Expression of all three of these collagen subtypes was noted to be significantly upregulated at all timepoints following TGFB stimulation when compared to non-stimulated controls.
Conclusions: Tension accelerated growth can safely be achieved in a fetal ovine model of long gap esophageal atresia. Additionally, esophageal atresia can be modeled in the ovine fetus as early as 92 days gestation. Our results demonstrate that esophageal tissue subjected to sustained tension undergoes significant profibrotic changes, as evidenced by upregulation of TGFB signaling, alterations in extracellular matrix organization, and increased collagen deposition. While it is well documented that patients with LGEA have an increased risk of post operative esophageal strictures, these findings provide the first in vivo proof of the role of tension in conferring a profibrotic phenotype in the tension-lengthened esophagus.

DOI: https://doi.org/10.64898/2026.01.26.701811
Cell Commun Signal. 2026 Feb 12.

PRIP/PLCL deficiency activates PI3K-AKT-YAP signaling and promotes organ fibrosis.

Meiqun Yuan, Tomomi Sano, Jing Gao, Akiko Mizokami, Takashi Kanematsu.

   BACKGROUND: Fibrosis, a hallmark of multiple chronic diseases, is regulated by transforming growth factor beta (TGF-β)-mediated PI3K-AKT signaling. Phospholipase C-related catalytically inactive protein (PRIP), also known as phospholipase C-like protein (PLCL) in humans, acts as a negative regulator of PI3K-AKT signaling. However, the role of PRIP/PLCL in fibrotic remodeling and its underlying molecular mechanisms remain unclear. Therefore, we investigated the involvement of PRIP/PLCL in fibrogenesis.
METHODS: Bioinformatics analyses were performed to determine the relationship between PRIP/PLCL and fibrosis, as well as its involvement in fibrotic signaling pathways. For in vivo experiments, we developed a mouse fibrosis model using male wild-type (WT) and Prip- knockout (KO) mice treated with angiotensin II (Ang II) to evaluate fibrogenesis in the kidney and heart. For in vitro experiments, we treated mouse embryonic fibroblasts (MEFs) from WT and Prip-KO mice with TGF-β1 (5 ng/ml) to verify PRIP/PLCL-modulated signaling in fibrosis using qPCR and western blotting.
RESULTS: Bioinformatics analyses revealed that PRIP/PLCL expression was significantly downregulated in fibrotic tissues and negatively correlated with the severity of renal fibrosis. Prip-KO mice exhibited accelerated fibrogenesis in the kidneys and heart following Ang II treatment. Consistently, PRIP deficiency exacerbated TGF-β1-induced fibroblast activation in MEFs. Gene set enrichment analysis of genes ranked by their correlation with PLCL expression revealed significant negative enrichment of the PI3K-AKT and Hippo signaling pathways. Accordingly, loss of PRIP enhanced AKT activation, promoted MST2 phosphorylation at Thr117, and facilitated the nuclear translocation of yes-associated protein (YAP), a core effector of the Hippo pathway and driver of fibrogenesis, leading to increased YAP-dependent profibrotic activity in TGF-β1-stimulated Prip-knockout MEFs.
CONCLUSION: PRIP/PLCL deficiency mediates YAP activation via the PI3K-AKT-MST2 axis, thereby accelerating fibroblast activation and organ fibrotic remodeling. Collectively, PRIP/PLCL acts as a novel anti-fibrotic factor, and restoring its activity could be an effective therapeutic approach for treating fibrotic diseases.

Keywords:  AKT; Fibrosis; PI3K; PLCL; PRIP; TGF-β; YAP

DOI:  https://doi.org/10.1186/s12964-026-02717-2
Pathol Res Pract. 2026 Feb 05. pii: S0344-0338(26)00049-X. [Epub ahead of print]280 156398

Epithelial-mesenchymal transition (EMT) and cellular plasticity in Ovarian cancer.

Afsheen Raza, Sadaf Khursheed Baba, Dina Moustafa Abo El-Ella, Sameer Mirza, Asiya Nazir.

  Epithelial-mesenchymal transition (EMT) is essentially a way for epithelial cells to loosen their structure and take on a more mobile, survival-driven identity. In ovarian cancer, this shift may be one of the reasons the disease spreads so readily and comes back despite intensive treatment. A mix of transcription factors Snail, Slug, Twist, the ZEB family and signals from pathways like TGF-β, Wnt, Notch, and PI3K/Akt seem to push cells in this direction. MicroRNAs add small but critical nudges that can either hold the process back or move it further along. But EMT rarely happens as a one-way switch. Ovarian cancer cells often sit somewhere between the two ends of the spectrum, switching identities when needed. This fluid behavior, sometimes called epithelial-mesenchymal plasticity, might help explain why tumors become more diverse, more stem-like, and harder to eliminate. Conditions around the tumor also play a role. Hypoxic pockets, a stiff extracellular matrix, and inflammatory signals not only surround the cancer but may also encourage EMT and help maintain drug-tolerant cells. It's still unclear which of these influences is most decisive, and that uncertainty leaves room for debate. Targeting EMT directly is an appealing idea, and a few strategies are being tested. Whether reversing EMT or stabilizing epithelial features will make standard therapies more effective is not yet settled, but the possibility is driving new interest in combination approaches for ovarian cancer.

Keywords:  Cancer stem cells; Cellular plasticity; Chemoresistance; Epithelial–mesenchymal transition (EMT); Metastasis; Ovarian cancer; Signaling pathways; Targeted therapy; Transcription factors; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2026.156398
J Nanobiotechnology. 2026 Feb 07.

A single-dose of PDGFB circular RNA enables sustained growth factor expression to accelerate diabetic wound healing.

Yi-Qi Shen, Yan Zhang, Liu-Yi Yao, Ru-Ke Zhang, Bin Yang, Cheng-Cheng Deng.

  Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes and lack effective treatment options. Although platelet-derived growth factor-B (PDGFB) has been approved for the treatment of diabetic wounds, it is difficult to sustainably deliver PDGFB to the wound site of DFU owing to its poor stability and easy degradation. To address these limitations, we developed a lipid nanoparticle (LNP)-encapsulated PDGFB circular RNA (LNP-circPDGFB) formulation designed to achieve sustained local expression and release of PDGFB for enhanced diabetic wound healing. The therapeutic circRNA was synthesized via in vitro transcription (IVT), followed by microfluidic encapsulation into ionizable LNPs to generate LNP-circPDGFB. LNP-circPDGFB facilitated highly efficient and prolonged expression of PDGFB both in vitro and in vivo. It exhibited pleiotropic effects by promoting the proliferation and migration of vascular endothelial cells and fibroblasts, as well as the angiogenesis of vascular endothelial cells. In diabetic mice, a single administration of LNP-circPDGFB could significantly accelerate diabetic wound healing and improved histopathological outcomes without obvious immunogenicity. Single cell RNAseq results also highlighted the potential of LNP-circPDGFB to promote proliferation, migration and extracellular matrix deposition of fibroblasts and vascular repair and angiogenesis of vascular endothelial cells. Taken together, we established LNP-circPDGFB as a promising "single-dose, long-acting" therapeutic platform for DFU treatment, addressing key limitations of current therapies. By leveraging the stability of circRNA and efficient LNP delivery, this approach not only enhances diabetic wound healing but also offers a versatile framework for protein delivery in regenerative medicine.

Keywords:  Circular RNA; Diabetic wound healing; Lipid nanoparticles; PDGFB; Single cell RNAseq

DOI:  https://doi.org/10.1186/s12951-026-04106-w
Adv Mater. 2026 Feb 08. e20717

Matrix Stiffness Governs Fibroblasts' Regulation of Gingival Immune Homeostasis.

Hardik Makkar, Nghi Tran, Yu-Chang Chen, Kang I Ko, Rebecca G Wells, Kyle H Vining.

  Periodontal disease is characterized by inflamed gingival tissues and degradation of the gingival extracellular matrix (ECM), yet the role of mechanical cues remains poorly understood. Gingival ECM in periodontal disease showed reduced fibrillar collagen compared to healthy samples. We hypothesized that ECM softening in periodontal disease contributes to inflammation by dysregulating gingival fibroblasts (GFs). A mechanically tunable hydrogel model of the gingival ECM was developed to investigate the mechano-immune crosstalk. Stiff and soft collagen-alginate hydrogels matched the rheological properties of healthy and diseased gingival biopsies respectively. Human donor GFs encapsulated in these stiff hydrogels showed significantly suppressed toll-like receptor-mediated inflammatory responses compared to those in soft hydrogels. The non-canonical NFκB pathway and epigenetic nuclear organization directed stiffness-dependent inflammatory responses of GFs. The direct impact of mechanical cues on immune responses was investigated ex vivo by co-culture of donor-derived human GFs with myeloid cells and in human gingival explants. Myeloid progenitors co-cultured with GFs in stiff hydrogels differentiated into immunomodulatory dendritic cells. Ex vivo crosslinking of human gingival tissue increased stiffness and reduced the production of inflammatory cytokines. Gingival mechano-immune regulation offers a novel approach to biomaterial-based treatments for periodontitis.

Keywords:  fibroblast–immune crosstalk; gingival extracellular matrix; matrix stiffness; mechanotransduction; nuclear organization; periodontal disease

DOI:  https://doi.org/10.1002/adma.202520717
Commun Biol. 2026 Feb 09. 9(1): 194

Wnt11 mediates fibroblast-smooth muscle cell interaction to promote neurogenic bladder fibrosis in rats.

Qingyu Ge, Junjie Zhang, Zongyao Fan, Yan Wang, Xinglin Chen, Dongdong Guo, Tao Wang, Cheng Ma, Xinyu Zhai, Guanqun Ju, Baixin Shen, Mingyue Tan, Zhongqing Wei, Dongliang Xu.

Neurogenic bladder (NB) is a lower urinary tract dysfunction caused by lesions in the nervous system that regulate urine storage and micturition. Fibrosis is considered the basic pathological alteration of NB, whereas the underlying mechanism remains unclear. Here, we find that Wnt11 is significantly up-regulated in the rat fibrotic bladders induced by bilateral pelvic nerve injury (BPNI) and spinal cord injury (SCI) and promotes bladder fibroblasts (BFs)-to-myofibroblasts transition and smooth muscle cells (SMCs) phenotypic transformation. Selective inhibition or gene silencing of Wnt11 in vivo and in vitro attenuates BFs and SMCs activation, and mitigates the development of NB fibrosis. Mechanistically, Wnt11 specifically binds to Vangl2 receptor to activate downstream JNK/c-JUN signaling via the membrane recruitment of DVL2. Further research shows that Wnt11 signaling interacts with transforming growth factor beta 1 (TGF-β1)/Smad-dependent pathway through the binding of membrane receptors (Vangl2 and TβR1) and the crosstalk of nuclear transcription factors. These findings uncover the regulatory mechanism and may provide a new therapeutic strategy for NB fibrosis.

DOI: https://doi.org/10.1038/s42003-026-09647-2
bioRxiv. 2026 Feb 01. pii: 2026.01.29.702601. [Epub ahead of print]

Tenascin N contributes to spinal motor nerve morphogenesis during development.

Charles G Marcucci, Marieke Jones, Coleman Blanton, Sarah Kucenas.

Spinal motor nerves are an integral component of the nervous system whose development requires the coordination of many diverse cell types, including motor neurons, glia, and muscle. Although several molecular mechanisms guiding these interactions are known, many remain to be uncovered. Extracellular matrix (ECM) proteins also play a critical role in motor nerve assembly, yet their functions are less understood compared to classical pathfinding and guidance cues. Here, we identify a role for tenascin-n ( tnn ), an ECM glycoprotein, in spinal motor nerve development in zebrafish. Using in situ hybridization and immunohistochemistry, we show that tnn/ Tnn is expressed and localized along vertical myosepta and the border of the ventral neural tube during spinal motor nerve development. To assess its function, we generated a CRISPR/Cas9 mutant allele, tnn uva96 , and performed in vivo imaging and morphological analysis throughout motor nerve development. Loss of tnn leads to a subtle and transient increase in ectopic motor axon exit and aberrant motor axon branching in the zebrafish trunk. Our findings reveal a previously unrecognized role for tnn in spinal motor nerve assembly and expand our understanding of the diverse molecular contributors to spinal motor nerve development and morphogenesis.

DOI: https://doi.org/10.64898/2026.01.29.702601