bims-fibdiv 2026-02-08 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2026–02–08
sixteen papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Direct Extracellular Matrix Modulation Attenuates Intestinal Fibrosis via a Fibronectin-Targeted Approach.
Fibroblasts as a ruler of the immune microenvironment: measurement and modulation in tissue homeostasis and disease.
From confinement to remodeling: modeling topotaxis-driven cell migration in obstacles networks.
SIRT5 induces tubulointerstitial fibrosis via GLS1 in diabetic nephropathy.
ADAMTS proteases in extracellular vesicles: emerging mediators of extracellular matrix dynamics and disease progression.
The Molecular Mechanisms and Therapeutic Potentials of Engrailed-1 in Fibrotic Scar Formation Post Glaucoma Filtration Surgery.
Mesenchymal stem cell-derived extracellular matrix for musculoskeletal tissue regeneration.
Multiomics reveals epigenetic control of fibroblast activity after myocardial infarction and a key role for RUNX transcription factors.
Fibroblast-derived CCL2 driven by MIF promotes joint capsule fibrosis via macrophage polarization regulation.
From origins to nomenclature: illuminating the landscape of CNS fibroblasts and fibroblast-like cells.
The Transcription Factor TCF21 is Necessary for Adoption of Cell Fates by Foxd1+ Stromal Progenitors during Kidney Development.
Single cell atlas decodes the molecular dynamics of scar repair after human rotator cuff tear.
Analysis of Eya1 and Tbx1 mutants highlights interactions between the muscle and developing cartilage during external ear formation.
Microenvironmental niches dictate divergent fibroblast fates in reversible versus progressive lung fibrosis.
The Significance of the Piezo1-Mediated Mechanotransduction Pathway in Normal Morphogenesis.
Stage-specific transcriptional atlas of goose satellite cells uncovers molecular dynamics driving embryonic skeletal muscle development.

Adv Sci (Weinh). 2026 Jan 30. e19433

Direct Extracellular Matrix Modulation Attenuates Intestinal Fibrosis via a Fibronectin-Targeted Approach.

Wenlong Ma, Siyu Yang, Tengkai Wang, Di Zhang, Hewei Wu, Shichen Fu, Xiaohan Wan, Lixiang Li, Xiuli Zuo, Yanqing Li, Jiaoyang Lu.

  Intestinal fibrosis can progress independently of inflammation, driven by a self-perpetuating cycle of extracellular matrix (ECM)-myofibroblast interactions. However, due to the lack of reliable therapeutic targets within the ECM, the current strategy predominantly focuses on intracellular aspects of myofibroblasts, neglecting the regulation of the ECM itself. In this study, we first performed matrisomic analysis on human (ileal/colonic) and animal (decellularized/native) intestines, identifying fibronectin as the only ECM component consistently elevated in fibrotic versus normal gut tissues across all conditions. Subsequently, immunofluorescence co-staining identified fibronectin as the principal structural scaffold of the fibrotic intestinal ECM. Furthermore, fibroblast-specific Fn1 ablation ameliorates intestinal fibrosis and transforms refractory fibrotic thickening into reversible inflammatory thickening in both innate and adaptive immune-driven models. Mechanistically, domain-specific inhibitors (pUR4, polymerization inhibition; R1R2, collagen binding inhibition; ATN161, integrin engagement inhibition), combined with ECM-mimetic platforms, demonstrated that fibronectin blockade directly inhibited its matrix assembly and impaired subsequent collagen fibrillogenesis-the major deposited component in fibrosis. Additionally, fibronectin-depleted ECM diminished α5β1 integrin-mediated mechanotransduction, thereby suppressing fibroblast activation and disrupting the self-perpetuating cycle of intestinal fibrosis. Thus, fibronectin inhibition directly impedes ECM accumulation and ameliorates intestinal fibrosis, offering a new dimension for therapeutic intervention and an immediately druggable target in fibrotic diseases.

Keywords:  Crohn's disease; extracellular matrix; fibronectin; fibrosis

DOI:  https://doi.org/10.1002/advs.202519433
Front Immunol. 2025 ;16 1752621

Fibroblasts as a ruler of the immune microenvironment: measurement and modulation in tissue homeostasis and disease.

Yanling Zhang, Xinyi Fang, Lian Yan, Lin Wang.

  Fibroblasts, once considered merely passive structural components of tissues, are now recognized as dynamic regulators of the immune microenvironment. Recent advances in single-cell and spatial multi-omics have revealed their profound heterogeneity, spatial organization, and functional plasticity, positioning them as a 'ruler' that measures, defines, and shapes local immune responses. In both homeostasis and disease contexts-such as cancer, autoimmune disorders, and fibrosis-distinct fibroblast subpopulations exhibit specialized roles: some drive immunosuppression via PD-L1 expression, TGF-β secretion, or metabolic reprogramming; others promote inflammation or fibrosis through cytokine and chemokine secretion; while a subset supports immune resolution and tissue repair. Spatially, fibroblasts organize immune territories by forming physical and chemical barriers, orchestrating tertiary lymphoid structures, and partitioning inflammatory zones. Their bidirectional crosstalk with immune cells-including T cells, macrophages, and B cells-further fine-tunes immune activation or suppression. The dysregulation of fibroblast subsets is a hallmark of disease progression and therapy resistance. Emerging therapeutic strategies aim to 'recalibrate' this dysfunctional ruler through targeted depletion, phenotypic reprogramming, or disruption of pathogenic signaling. Integrating fibroblast-centric metrics into clinical practice may enable precise assessment of the immune microenvironment and personalized interventions, heralding a new era in immunotherapy and fibrotic disease management.

Keywords:  cancer-associated fibroblasts; fibroblasts; fibrosis; heterogeneity; immune microenvironment; immunotherapy; single-cell omics; spatial organization

DOI:  https://doi.org/10.3389/fimmu.2025.1752621
J Math Biol. 2026 Feb 03. 92(2): 30

From confinement to remodeling: modeling topotaxis-driven cell migration in obstacles networks.

Rachele Allena.

  Several physiological and pathological processes, such as development, wound healing, and cancer invasion, depend on cell migration through fibrous extracellular matrix (ECM). In such contexts, topographical features of the ECM, including fiber alignment and pore size, strongly bias migration, a phenomenon known as topotaxis. To explore this guidance mechanism in a controlled theoretical setting, we present a minimal particle-based model of single-cell motility in two-dimensional environments abstracted as networks of elongated obstacles. This abstraction captures key geometric and topographical constraints of fibrous microenvironments while remaining computationally tractable. Our framework integrates chemotactic bias, stochastic polarity dynamics, steric repulsion from obstacles, escape strategies from mechanical trapping, and minimal remodeling of the obstacles network. Adaptive polarity perturbations mimic active cellular responses such as invadopodial protrusion or random reorientation, while a displacement-based criterion detects trapping events. Heterogeneity is incorporated by assigning variable repulsion strengths to obstacles, and remodeling is implemented by allowing local displacements induced by cell-obstacle contact. Simulation results show that active remodeling of obstacles consistently enhances migration efficiency and target acquisition, whereas escape strategies alone provide only partial improvement, and heterogeneity introduces directional variability. At long timescales, trajectories converge toward effective diffusion, but intermediate dynamics display nontrivial deviations due to confinement and obstacle interactions, highlighting a topotaxis-driven component of motility. Overall, this work positions cell migration within the theoretical context of obstacles networks, providing mechanistic insight into how confinement, anomalous transport, and remodeling interact to shape directional migration. While simplified to two dimensions and lacking entanglement effects characteristic of real three-dimensional ECMs, the model offers a tractable and extensible framework for future studies, including the incorporation of cell deformations or more realistic ECM architectures.

Keywords:  Cell migration; Cell polarity; Extracellular Matrix; Particle-based model; Remodelling

DOI:  https://doi.org/10.1007/s00285-026-02345-x
Eur J Pharmacol. 2026 Jan 29. pii: S0014-2999(26)00071-3. [Epub ahead of print]1016 178589

SIRT5 induces tubulointerstitial fibrosis via GLS1 in diabetic nephropathy.

Zhi Xu, Xinhao Li, Zhichen Cai, Yunye Zhang, Xiaoru Shi, Shuqing Liu, Xiaoxing Yin, Xiaoling Liu, Bingzheng Dong, Jianyun Wang.

  Tubulointerstitial fibrosis composed of epithelial-mesenchymal transition (EMT) and the resulting extracellular matrix (ECM) accumulation is the primary feature of diabetic nephropathy (DN), but its mechanism remained unclear. In the present study, sirtuin 5 (SIRT5) was screened for the key pathogenic factor by proteomics analysis in DN mice. Then SIRT5 was overexpressed and knocked down in the kidney of mice and in renal tubular epithelial cells. It was found that the elevation of SIRT5 in renal tubular epithelial cells exacerbated EMT, ECM accumulation and worsened the renal function of mice. Using real-time PCR, co-immunoprecipitation, and cycloheximide tracking assay, we found that SIRT5 increased the desuccinylation, the ubiquitination of kidney type glutaminase (GLS1), which thereby caused an increase in GLS1 protein. Meanwhile, when GLS1 protein maintained at some level, changes in SIRT5 do not impact the EMT process and the subsequent ECM accumulation. Furthermore, we found that SIRT5 was increased in kidneys of DN patients, it was also up-regulated in the urine of DN patients and had correlations with renal function of patients. Collectively, SIRT5 induces tubulointerstitial fibrosis via GLS1 in DN, which renders it a promising therapeutic target for DN.

Keywords:  Diabetic nephropathy; EMT; Fibrosis; GLS1; SIRT5

DOI:  https://doi.org/10.1016/j.ejphar.2026.178589
FEBS J. 2026 Feb 03.

ADAMTS proteases in extracellular vesicles: emerging mediators of extracellular matrix dynamics and disease progression.

Carlos Peris-Torres, Juan Carlos Rodríguez-Manzaneque.

  Recent advances highlight extracellular vesicles (EVs) as key mediators of intercellular communication, carrying a complex cargo that includes extracellular matrix (ECM) components and associated modulators. Among them, ADAMTS proteases are emerging as pivotal regulators due to their ability to orchestrate precise ECM remodeling events and influence cellular behavior in pathological contexts such as cancer, vascular diseases, and tissue regeneration. Notably, the identification of specific ADAMTS family members within EV populations suggests that EVs may serve as vehicles for paracrine delivery and localized proteolytic activity, enabling spatially and temporally restricted ECM modulation. This review synthesizes current knowledge on the association between EVs and ADAMTS proteases, including their known substrates, and highlights their converging roles in shaping the extracellular landscape. We also discuss key knowledge gaps, especially concerning the diversity of ADAMTS-EV interactions, their functional impact in different physiological and pathological settings, and some reflections regarding their potential translational opportunities.

Keywords:  ADAMTS proteases; EV corona; extracellular matrix; extracellular vesicles; inflammation; intercellular communication

DOI:  https://doi.org/10.1111/febs.70433
Invest Ophthalmol Vis Sci. 2026 Feb 02. 67(2): 18

The Molecular Mechanisms and Therapeutic Potentials of Engrailed-1 in Fibrotic Scar Formation Post Glaucoma Filtration Surgery.

Yi Lin, Wangdu Luo, Xiaomin Zhu, Julong Yu, Xiangji Li, Lin Xie.

Purpose: Conjunctival scarring is a major cause of glaucoma filtration surgery (GFS) failure, necessitating effective antifibrotic strategies. This study investigated the role of engrailed-1 (EN1) in conjunctival fibrosis and evaluated the therapeutic potential of EN1-targeted biomaterials for antiscarring in post-GFS patients.
Methods: Fibrotic models were developed using TGF-β2-induced human Tenon fibroblasts (HTFs) and a rat GFS model. EN1 was identified as a key therapeutic target using RNA interference, transcriptome sequencing, chromatin immunoprecipitation-qPCR, and dual-luciferase assays. Exosomes (Exos) loaded with EN1 small interfering RNA were encapsulated in a GelMA hydrogel to form the Gel-Exo-siEN1 composite material.
Results: EN1 expression was significantly elevated in TGF-β2-stimulated HTFs and conjunctival scar tissue post GFS. Inhibition of EN1 reduced TGF-β2-induced proliferation and migration in HTFs and decreased fibrosis-related gene expression. These effects may be mediated through the Yes-related protein/transcriptional co-activator PDZ-binding motif and SMAD3 pathways. Assays confirmed that EN1 inhibition suppressed proliferation and migration and downregulated fibrosis markers like fibronectin, collagen I, and α-smooth muscle actin. Western blot analysis showed increased Yes-related protein/transcriptional co-activator PDZ-binding motif expression after TGF-β2 induction, which was reduced by verteporfin. Chromatin immunoprecipitation-PCR confirmed that SMAD3 binds to the EN1 promoter, regulating its expression. Exo analysis showed Exo-siEN1 maintained stability and effectively delivered siEN1, leading to significant EN1 knockdown and reduced fibrosis in rat Tenon's fibroblasts. Gel-Exo-siEN1 treatment significantly increased functional bleb area, reduced IOP, and decreased collagen deposition and inflammatory cell infiltration in the conjunctiva after GFS.
Conclusions: Gel-Exo-siEN1 is a promising strategy for preventing postsurgical scarring and improving the outcomes of glaucoma surgery.

DOI: https://doi.org/10.1167/iovs.67.2.18
Commun Biol. 2026 Jan 31. 9(1): 147

Mesenchymal stem cell-derived extracellular matrix for musculoskeletal tissue regeneration.

Shuqing Lv, Jia Wang, Jianan Chen, Yunyuan Yu, Xinying Huang, Gang Zhao, Xinfeng Zhou, Yong Xu.

Mesenchymal stem cell-derived extracellular matrix (mECM) is increasingly recognized in tissue regeneration due to its high biocompatibility, controllability, and customizability. In musculoskeletal diseases, mECM provides a 3D scaffold mimicking the natural cellular environment and contains bioactive components regulating cell behavior and fate to promote tissue regeneration and repair. This review summarizes the preparation methods and composition of mECM, its effects on regulating cell behavior, and its applications in bone, cartilage, muscle, nerve, and blood vessel repair. It also analyzes the potential mechanisms of mECM's effects and identifies key challenges to be addressed prior to clinical translation, outlining future development directions.

DOI: https://doi.org/10.1038/s42003-026-09638-3
bioRxiv. 2026 Jan 13. pii: 2026.01.12.699153. [Epub ahead of print]

Multiomics reveals epigenetic control of fibroblast activity after myocardial infarction and a key role for RUNX transcription factors.

Yuxia Li, Xujia Zhang, Kishan Ghimire, Nishan Khatri, Leshan Wang, Qianglin Liu, Mohammad Shiri, Rayyan Shakoori, Sachin Upadhayaya, Boyu Li, Joseph Francis, Constantine A Simintiras, Rui Li, Jiangwen Sun, Xing Fu.

Background: After myocardial infarction (MI), cardiac fibroblasts proliferate and undergo a sequential differentiation process. They first transition into cardiac myofibroblasts, a transient and highly contractile state, and ultimately into matrifibrocytes, a more stable state that partially resembles chondrocytes. These dynamic transitions are essential for infarct healing and scar formation. While insufficient fibroblast activation can compromise infarct integrity, excessive activation promotes pathological fibrosis that impairs cardiac function. Despite its clinical importance, the transcriptional and epigenetic regulation of these transitions remain poorly understood. Elucidating underlying mechanisms is critical for developing strategies to fine-tune fibroblast activity during cardiac repair.
Methods: We performed bulk RNAseq, ATACseq, CUT&Tag, CUT&RUN, EMseq, and Hi-C on cardiac fibroblasts from uninjured and post-MI mouse hearts. In parallel, we conducted single-nucleus multiomic (snRNAseq and snATACseq) profiling across multiple time points after MI. Subsequent integrated analysis explored epigenetic mechanisms regulating cardiac fibroblast gene expression and activity. Using an improved computational strategy, we constructed gene regulatory networks to identify key transcription factors and biological processes regulated by these transcription factors. To assess the role of Runx1 specifically, we used tamoxifen-inducible, fibroblast-specific Runx1 knockout mice to evaluate transcriptional, epigenetic, and functional outcomes with the same genomic tools and additional complementary assays.
Results: Cardiac fibroblasts undergo extensive chromatin remodeling after MI, which is highly correlated with changes in transcriptomic profiles. In contrast, the role of DNA methylation is relatively minor. Gene regulatory network analysis identified Runx1 as a central regulator of cardiac fibroblast proliferation and matrifibrocyte differentiation. In vitro and in vivo validation confirmed Runx1 as a key modulator of transcriptional and epigenetic changes in cardiac fibroblasts. Runx1 KO reduced cardiac fibroblast proliferation, disrupted the myofibroblast-to-matrifibrocyte transition, and affected macrophage cytokine expression through altered cardiac fibroblast-macrophage communication. Fibroblast-specific Runx1 knockout mice showed improved post-MI survival and reduced cardiac dilatation, especially in males. Simultaneous Runx2 deletion further enhanced the effects of Runx1 knockout.
Conclusions: Cardiac fibroblast activation and differentiation after MI are regulated by dynamic epigenetic changes. Runx1 plays a pivotal role in modulating cardiac fibroblast activities, and its deletion improves cardiac repair by mitigating maladaptive fibroblast responses. By illuminating the centrality of Runx1 in post-MI repair, this study identifies an actionable pathway for therapeutically steering fibroblast responses.

DOI: https://doi.org/10.64898/2026.01.12.699153
Int Immunopharmacol. 2026 Feb 02. pii: S1567-5769(26)00163-3. [Epub ahead of print]173 116319

Fibroblast-derived CCL2 driven by MIF promotes joint capsule fibrosis via macrophage polarization regulation.

Yuxin Zhang, Jiling Ye, Yuxiang He, Yijia Wang, Minghui Lin, Zhigang Wu.

  Post-traumatic joint contracture (PTJC) is driven by persistent joint capsule inflammation and subsequent fibrosis. CC motif chemokine ligand 2 (CCL2) is recognized as a key regulator of sustained inflammation. However, the relevant regulatory mechanism involved in CCL2 production in PTJC has not been fully elucidated. In this study, we investigated whether MIF can facilitate CCL2 production from fibroblasts and regulate joint capsule fibrosis following PTJC. Our data demonstrated that PTJC-induced elevation of CCL2 levels was synchronous with MIF. Administration of MIF inhibitor 4-IPP at the lesion sites significantly reduced the expression of CCL2. An in vitro study revealed that MIF potently facilitated the production of CCL2 in joint capsule fibroblasts through interaction with CD74 receptor and subsequent activation of JNK/CREB signaling. Interestingly, fibroblast-derived CCL2 promoted macrophage excessive polarization toward M2 phenotype through the CC motif chemokine receptor 2 (CCR2), thereby amplifying chronic inflammation and fibrosis. The inhibition of MIF activity prevented the pro-fibrotic process by decreasing CCL2. Our results provide insights into the new functions of MIF-mediated CCL2 production in fibroblasts, which exacerbates the pathological microenvironment by tuning joint capsule inflammation and fibrosis during PTJC. The present study may provide a new therapeutic strategy for other inflammation- and fibrosis-associated diseases.

Keywords:  C-C motif chemokine ligand 2; Chronic inflammation; Fibroblast; Fibrosis; Macrophage; Macrophage migration inhibitory factor

DOI:  https://doi.org/10.1016/j.intimp.2026.116319
Acta Neuropathol Commun. 2026 Jan 30.

From origins to nomenclature: illuminating the landscape of CNS fibroblasts and fibroblast-like cells.

Jianing Lin, Kuo Liao, Sebastian A Lewandowski.

  Fibroblasts are a group of stromal cells that contribute to the scarring process in many neurological conditions in the central nervous system (CNS). Recently, single-cell sequencing efforts allowed an in-depth understanding of their cell origins and subpopulation profiles. Meanwhile, vascular leptomeningeal cells and the "type A pericytes" were also proposed as CNS fibroblast-like cells in the last decade by histological, functional and transcriptomic analysis. While these cells share overlapping features with CNS fibroblasts, the inconsistent use of nomenclature and partially overlapping cell-type markers is likely to cause confusion within the growing field of neurobiology. In this review, we will delineate the current knowledge of subtypes and functions of CNS fibroblasts, with special focus on the source of PVFs during development and the nomenclature origins of other similar cell types. We aim to provide comprehensive insights into these cells with similar functions or transcriptomic profiles.

Keywords:  Central nervous system; Fibroblasts; Perivascular fibroblasts; Type A pericytes; Vascular leptomeningeal cells

DOI:  https://doi.org/10.1186/s40478-026-02236-8
Am J Physiol Renal Physiol. 2026 Feb 03.

The Transcription Factor TCF21 is Necessary for Adoption of Cell Fates by Foxd1+ Stromal Progenitors during Kidney Development.

Gal Finer, George S Yacu, Mohammad Daud Khan, Yalu Zhou, Gaurav Gadhvi, Sarah E Ward, Mohammed Sayed, R Ariel Gomez, Maria Luisa S Sequeira-Lopez, Joo-Seop Park, Hee-Woong Lim, Susan E Quaggin, Deborah R Winter.

  The stromal compartment of the developing kidney arises from Foxd1-expressing progenitors and gives rise to diverse cell types essential for nephrogenesis, including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms guiding their fate specification remain incompletely defined. Here, we identify the basic helix-loop-helix transcription factor Tcf21 as a critical determinant of stromal cell identity during kidney development. We performed single-cell RNA sequencing (scRNA-seq) on Foxd1-lineage cells isolated from embryonic day 14.5 (E14.5) Tcf21 conditional knockout (Tcf21-cKO) Foxd1Cre/+;Rosa26mTmG;Tcf21f/f and control kidneys, revealing seven transcriptionally distinct stromal subpopulations. Loss of Tcf21 resulted in marked depletion of Medullary/Perivascular stroma, Collecting duct associated stroma, Proliferating stroma, and Nephrogenic zone associated subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces. Additionally, we identified a novel cluster unique to Tcf21-cKO kidneys, characterized by high expression of Endomucin (Emcn). These cells spanned pseudotime trajectories and were distributed broadly across the mutant kidney. These findings were corroborated by E14.5 single-cell ATAC sequencing (scATAC-seq), which confirmed altered chromatin accessibility in Tcf21-deficient stroma. To assess the persistence and downstream impact of these defects, we performed bulk and scRNA-seq at E18.5, revealing sustained expansion of Emcn+ cells with pro-fibrotic and perivascular transcriptional programs. Histological analyses at 2 months demonstrated lasting architectural disruption, interstitial fibrosis, and impaired renal function in Tcf21-cKO mice. Our results identify Tcf21 as a key regulator of stromal progenitor fate and establish a developmental origin for fibrotic remodeling and kidney dysfunction.

Keywords:  Foxd1; Tcf21; kidney; single-cell-RNA-sequencing; stroma

DOI:  https://doi.org/10.1152/ajprenal.00345.2025
Bone Res. 2026 Feb 05. 14(1): 17

Single cell atlas decodes the molecular dynamics of scar repair after human rotator cuff tear.

Yiming Qin, Guang Yang, Tao Zhang, Yuying Yang, Liyang Wan, Tao Zhang, Linfeng Wang, Zhiyu Hu, Zhu Dai, Hongkang Zhou, Chengjun Li, Jianzhong Hu, Hongbin Lu.

Irreversible fibrotic scarring after rotator cuff tear (RCT) compromises the mechanical properties of the healing tendon, yet the underlying mechanisms remain poorly understood. Here, we analyzed the histological features of human RCT scars, characterized by disruption of tendon architecture, disorganized collagen fibrils, and imbalance in type I/III collagen ratios and fibril diameters. Using single-cell RNA sequencing of tendon stumps from patients with RCT, we deconvolved the cellular and molecular landscape of the fibrotic scarring microenvironment. Heterogenous pro-fibrotic subclusters were identified and validated to participate into scar formation, including tendon stem cell, senescent tenocyte, SOX9-driven pro-fibrotic macrophage, and pro-fibrotic endothelial cells undergoing endothelial-mesenchymal transition (EndoMT). Furthermore, we found that osteopontin and TGF-β signaling were key drivers of extracellular matrix deposition, and their blockade ameliorated fibrotic scarring after RCT. Collectively, our study dissected the dynamic scarring microenvironment in human RCT and highlights potential therapeutic targets for preventing pathological scar formation.

DOI: https://doi.org/10.1038/s41413-025-00501-5
Development. 2026 Feb 01. pii: dev204784. [Epub ahead of print]153(3):

Analysis of Eya1 and Tbx1 mutants highlights interactions between the muscle and developing cartilage during external ear formation.

Juan M Fons, Ying Sun, Roman H Khonsari, Abigail S Tucker.

  Microtia is a common feature of several human syndromes affecting the external ear (pinna), yet the cellular and molecular mechanisms remain poorly understood. Using human embryos and mouse models of branchio-oto-renal (BOR) and 22q11.2 deletion syndromes, we show that the syndromic genes Eya1 and Tbx1 are expressed in mesoderm-derived auricular muscle. In Eya1 mutant mice, auricular muscles failed to form and pinna morphogenesis was disrupted, with comparable defects observed in mesoderm-specific Tbx1 mutants. Both mutant pinnae exhibited impaired cartilage differentiation, suggesting that auricular muscle provides signals to the neural crest-derived mesenchyme to regulate cartilage differentiation. In contrast, defects in cartilage development alone or loss of muscle contraction did not affect early pinna morphogenesis. Auricular myocytes expressed Fgfs, while the surrounding mesenchyme expressed Fgfr1, Fgfr2 and ERM proteins. Disrupted Fgf signalling was observed in mutant cartilage and muscle. In ex vivo cultures, inhibition of Fgf or Bmp signalling recapitulated cartilage defects, whereas BMP4 restored Sox9 expression. These findings identify the mesoderm as essential for pinna initiation and morphogenesis, and reveal signalling mechanisms underlying microtia in BOR and 22q11.2 deletion syndromes.

Keywords:  22q11 deletion syndrome; Auricle; BMP; Branchio-oto-renal syndrome; FGF; Microtia; Pinna

DOI:  https://doi.org/10.1242/dev.204784
EBioMedicine. 2026 Jan 30. pii: S2352-3964(26)00023-X. [Epub ahead of print]124 106142

Microenvironmental niches dictate divergent fibroblast fates in reversible versus progressive lung fibrosis.

Licheng Song, Yi Yang, Yifan Fu, Yaru Liu, Qi Li, Mengli Zheng, Chen Yao, Dingyun Song, Ruofan Su, Wen Chen, Jingyu Chen, Huaiyong Chen, Lixin Xie.

   BACKGROUND: Fibroblast behaviour is a key determinant of outcomes in interstitial lung diseases (ILDs), yet mechanisms governing the switch between reversible repair and progressive fibrosis remain unclear. How disease-specific cellular niches shape fibroblast fate across ILD phenotypes has not been compared in situ.
METHODS: We profiled peripheral lung tissues from controls, organising pneumonia (OP), connective tissue disease-associated ILD (CTD-ILD), and idiopathic pulmonary fibrosis (IPF) using High-Definition Visium spatial transcriptomics. A matched single-cell RNA-seq atlas was integrated via robust cell-type deconvolution to map cellular neighbourhoods. Differential expression and pathway activity were validated by immunofluorescence. Predicted ligand-receptor mechanisms and fibroblast responses were tested in vitro under glucocorticoid (GC), TGF-β1, and B-cell/MIF perturbations with receptor blockade.
FINDINGS: Disease-specific niches were tightly coupled to fibroblast states. OP exhibited B-cell-AT2-myofibroblast-enriched niches with high GC responsiveness and apoptosis. IPF was dominated by bronchiolised epithelium, alongside myofibroblasts exhibiting glucocorticoid resistance and strong matrix programmes. CTD-ILD exhibited macrophage-rich niches with multinucleated giant cells. In vitro, GC induced NR3C1-mediated apoptosis in fibroblasts, whereas TGF-β1 drove a senescent, GC-resistant phenotype. IgD + B-cell-derived MIF enhanced fibroblast migration via CD74, an effect blunted by TGF-β1. Thus, niche composition dictates fibroblast fate, distinguishing GC-sensitive resolution from apoptosis-resistant fibrosis.
INTERPRETATION: A GC-sensitive, apoptosis-prone myofibroblast niche in OP may underpin reversibility, whereas CTD-ILD and IPF follow distinct trajectories driven by immune dysregulation and epithelial-stromal maladaptation. These spatial microenvironmental signatures nominate therapeutic targets and may inform precision therapy for fibrotic lung disease.
FUNDING: The National Natural Science Foundation of China (82172109 to L.X., 82570001 to H.C.), the Ministry of Science and Technology of the People's Republic of China (2023YFC3502605, 2024YFA1108906) (H.C.), the Natural Science Foundation of Tianjin, China (25JCZDJC01260) (H.C.); the Key Laboratory of Medical Rescue Key Technology and Equipment, Ministry of Emergency Management (Open Fund Project No. YJBKFKT202410).

Keywords:  Connective tissue disease-associated interstitial lung disease; Glucocorticoid; Idiopathic pulmonary fibrosis; Organising pneumonia; Spatial transcriptomics

DOI:  https://doi.org/10.1016/j.ebiom.2026.106142
DNA Cell Biol. 2026 Feb 05. 10445498261417437

The Significance of the Piezo1-Mediated Mechanotransduction Pathway in Normal Morphogenesis.

Reza Rezaei, Yaser Mohammadi, Zohreh Rezaei, Farzad Sadri.

  Mechanical forces are fundamental drivers of morphogenesis, yet the molecular mechanisms that convert these physical cues into transcriptional responses remain incompletely understood. This review synthesizes current evidence identifying the mechanosensitive ion channel Piezo1 as a master regulator of developmental processes. The structural and biophysical principles underlying Piezo1 function are highlighted, focusing on its trimeric architecture and force-from-lipids gating mechanism that directly couples membrane tension to Ca2+ influx. Its spatiotemporal expression during embryogenesis is reviewed, and the downstream pathways it activates are examined, including mitogen-activated protein kinase (MAPK) and yes-associated protein/transcriptional co-activator with PDZ-binding moti (YAP/TAZ), alongside crucial crosstalk with canonical morphogen signaling cascades such as Notch, Wntwingless/integrated signaling pathway (Wnt)/beta-catenin (β-catenin), and bone morphogenetic protein/transforming growth factor-beta (BMP/TGF-β). Functional studies across diverse model systems demonstrate that Piezo1 orchestrates conserved morphogenetic events, including vascular and lymphatic patterning, neurogenesis, epithelial morphogenesis, myoblast fusion, and osteogenesis. Human genetic data further underscore its nonredundant role, linking gain-of-function mutations to dehydrated hereditary stomatocytosis and loss-of-function mutations to primary lymphatic dysplasia. Collectively, these findings establish Piezo1 as an essential integrator of mechanical and biochemical signals, central to tissue patterning and organ formation. The review concludes by emphasizing Piezo1's therapeutic potential in regenerative medicine and developmental disorders, while also underscoring the challenges of targeting such a broadly influential mechanosensor.

Keywords:  Piezo1; mechanotransduction; molecular signaling; morphogenesis

DOI:  https://doi.org/10.1177/10445498261417437
Poult Sci. 2026 Feb 02. pii: S0032-5791(26)00211-7. [Epub ahead of print]105(4): 106584

Stage-specific transcriptional atlas of goose satellite cells uncovers molecular dynamics driving embryonic skeletal muscle development.

Cui Wang, Yunzhou Yang, Yi Liu, Jiuli Dai, Shufang Chen, Huiying Wang, Daqian He.

  Muscle development in goose embryos is a complex and highly coordinated process involving dynamic morphological and transcriptional changes. Skeletal muscle satellite cells (SMSCs) play essential roles in postnatal muscle growth, regeneration, and meat quality, yet the molecular mechanisms regulating SMSC behavior during embryonic development in geese remain incompletely characterized. In this study, we integrated histology, immunofluorescence, and transcriptomics to investigate leg muscle development and SMSC dynamics in female Zhedong White (ZW) geese at embryonic days 15, 18, and 23 (E15F, E18F, and E23F). Histological examination revealed progressive myofiber hypertrophy and alignment from E15F to E23F. Concurrently, the proportion of Pax7⁺ SMSCs progressively decreased, indicating the establishment of a quiescent satellite cell pool. RNA sequencing of SMSCs identified numerous differentially expressed genes across developmental stages. Transcriptomic profiling indicated a clear developmental transition: early stages (E15F) were enriched in genes related to structural and contractile proteins (e.g., MYL1, ACTC1, TNNT2), while later stages (E23F) were associated with upregulation of genes involved in lipid metabolism (e.g., PPARG, PLIN2, ACSL1), extracellular matrix remodeling (e.g., MMP2, SPP1), and signal transduction (e.g., FGF10, IGFBP5). Functional enrichment analysis further supported a shift from active myogenesis toward metabolic maturation and tissue reorganization. Protein-protein interaction network analysis identified a core regulatory module involving MEF2C, MEF2D, MYOD1, and MSTN. Key gene expression trends were confirmed by quantitative PCR. Together, these findings provide a comprehensive transcriptomic resource that delineates the stage-specific molecular programs guiding SMSC differentiation and functional maturation during embryonic myogenesis in geese.

Keywords:  Differential expression; Embryonic development; Goose; SMSCs; Transcriptome

DOI:  https://doi.org/10.1016/j.psj.2026.106584