bims-fibdiv 2026-01-25 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2026–01–25
twenty-one papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Collagen in Fibrotic Diseases.
Innovations in collagen-network remodeling and extracellular matrix mechanics: toward a new era in articular cartilage repair.
Immunomodulation by collagen VI across fibrotic and tumor microenvironmental contexts.
The role of free-fatty acid receptors FFA1 and FFA4 in organ fibrosis.
The Impact of Ageing on Fibrillar Collagens.
Metixene hydrochloride hydrate mitigates kidney tubulointerstitial fibrosis by inhibiting Smad3 phosphorylation.
Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma.
Versatile role of fibro-adipogenic progenitors in neuromuscular junction homeostasis and pathology.
Targeting TBK1 With GSK8612 Suppresses Kidney and Cardiac Inflammation and Fibrosis in DOCA/Salt Hypertension.
Engineered Perfusable Hepatic Fibrosis Model via Embedded Sacrificial Bioprinting Recapitulates Stiffness-Driven Fibrogenesis.
Peptide FK2 attenuates inflammation and pro-fibrotic cellular transitions via targeting the IKKβ/NF-κB/TGF-β1 axis in renal fibrosis.
Hepatocyte-hepatic stellate cell interactions in liver fibrosis: Mechanisms and therapeutic implications.
Bone sialoprotein: a multifunctional regulator of bone remodelling and tumour progression.
Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization.
Macrophage-Derived Ferritin Exacerbates Silica-Induced Pulmonary Fibrosis via PIK3R2-Mediated Fibroblast Differentiation.
Nintedanib Attenuates Epidural Fibrosis After Laminectomy in Rats.
The role of metformin in extracellular matrix-based three-dimensional cell culture Models: A mini-review on therapeutic potentials.
Deficiency of inducible nitric oxide synthase alleviates dermal fibrosis and inflammation in scleroderma.
Proprotein Convertase Subtilisin/Kexin Type 9 Induces Platelet-Derived Transforming Growth Factor-β to Promote Myocardial Fibrosis After Myocardial Infarction.
Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.
V-ATPase a3 Directs Secretory Lysosome Transport in Enamel Formation.

Subcell Biochem. 2026 ;113 343-375

Collagen in Fibrotic Diseases.

Andrzej Fertala.

  This chapter explores the role of fibrillar collagens, mainly collagen I, in developing fibrotic disorders associated with acute or chronic injuries. While collagen molecules' fundamental structure, composition, and intracellular biosynthesis steps remain similar in healthy and scar tissues, their extracellular architecture and physical properties significantly differ. These differences arise from the excessive production of collagen I and auxiliary proteins associated with collagen I folding and posttranslational modifications. As a result, the overaccumulation of collagen I-based fibrotic deposits creates a rigid mechanical environment that, through mechanotransduction, amplifies pro-fibrotic signaling in resident fibroblasts.In reviewing the literature, this chapter highlights key players that create, transmit, and sustain these signals, thereby perpetuating fibrosis. Given the growing recognition of mechanotransduction as a valid therapeutic target to limit fibrosis, this chapter also discusses strategies to inhibit different elements of this process. A significant challenge with these strategies is that both balanced and excessive scarring rely on the exact underlying mechanisms of scar tissue formation. Consequently, conventional anti-fibrotic agents may inadvertently impair the essential scarring needed to preserve tissue integrity after injury. Therefore, mechanotherapeutics that reduce collagen accumulation-driven scar stiffness represent a novel approach for developing more targeted anti-fibrotic therapies.

Keywords:  Collagen; Collagen fibril; Extracellular matrix; Fibrosis; Matrix stiffness; Mechanotransduction; Myofibroblasts; Procollagen; Scar

DOI:  https://doi.org/10.1007/978-3-032-05273-5_11
Front Bioeng Biotechnol. 2025 ;13 1740135

Innovations in collagen-network remodeling and extracellular matrix mechanics: toward a new era in articular cartilage repair.

Kai Huang, Yifan Hong, Haili Cai.

  Articular cartilage is a highly specialized connective tissue with a hierarchically organized extracellular matrix (ECM) that provides the mechanical resilience necessary for joint function. Central to this functionality is the depth-dependent architecture of collagen-primarily type II-interwoven with proteoglycans, enabling efficient resistance to compressive and shear stresses. This review synthesizes recent advances in ECM dynamics, emphasizing the interplay between collagen organization, viscoelastic microenvironments, and pericellular-matrix (PCM)-mediated mechanotransduction. Emerging evidence implicates type III collagen as a regulator of early cartilage remodeling and a putative biomarker of osteoarthritis (OA) progression. Additionally, we highlight cutting-edge studies on the synergistic effects of mechanical loading and enzymatic degradation on collagen integrity, providing novel insights into ECM deterioration in disease contexts. We evaluate next-generation biomaterials-including viscoelastic hydrogels, anisotropic scaffolds, and magnetic field-assisted fiber alignment-designed to recapitulate the native anisotropy and multiscale mechanics of cartilage. Together, these recent developments redefine the landscape of cartilage repair and delineate promising avenues for translational regenerative therapies.

Keywords:  articular cartilage; collagen fiber organization; extracellular matrix dynamics; mesenchymal stem cells; osteoarthritis; viscoelastic properties

DOI:  https://doi.org/10.3389/fbioe.2025.1740135
Histol Histopathol. 2026 Jan 19. 25034

Immunomodulation by collagen VI across fibrotic and tumor microenvironmental contexts.

Jennifer H Hammel, Sharon Gerecht.

The extracellular matrix (ECM) plays fundamental roles in modulating tissue structure and function under normal and pathological conditions. ECM composition is an essential consideration for studying cellular microenvironments, as varied composition leads to changes in cell behavior and delivery of therapeutics. Collagen VI is a non-fibrillar collagen that is found in both fibrotic and tumor microenvironments, where it promotes disease progression and suppresses the immune system. In this review, we summarize the contributions of collagen VI to fibrosis and tumor progression, followed by a focus on its ability to modulate the immune system in these contexts. Finally, we explore whether collagen VI could be a suitable therapeutic target for future study. While many studies have demonstrated the importance of collagen VI in disease progression, further studies of its immunomodulation abilities are needed to fully realize its potential as a therapeutic target in fibrosis and the tumor microenvironment.

DOI: https://doi.org/10.14670/HH-25-034
Br J Pharmacol. 2026 Jan 19.

The role of free-fatty acid receptors FFA1 and FFA4 in organ fibrosis.

Priyanka F Karmokar, Nader H Moniri.

  Fibrosis, a consequence of dysregulated wound healing underlying chronic diseases such as metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel disease (IBD), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (PF) and systemic sclerosis (SSc), accounts for nearly 45% of deaths in developed countries. Fibrosis is driven by persistent epithelial injury and aberrant communication among epithelial, mesenchymal, and immune cells, leading to fibroblast activation, myofibroblast accumulation, and excessive extracellular matrix (ECM) deposition. Despite its clinical significance, antifibrotic therapy remains largely limited to pirfenidone and nintedanib for PF and resmetirom for MASH. The continued failure of many candidates in clinical development highlights the persistent unmet need for more effective antifibrotic approaches. FFA1 (GPR40) and FFA4 (GPR120) are free-fatty acid receptors (FFAR) that sense medium- and long-chain fatty acids, primarily coupling to Gαq/11 and β-arrestin signalling pathways to regulate diverse physiological processes. Although these FFAR have been extensively investigated in the context of metabolic disorders, emerging evidence indicates that FFA1 and FFA4 also play critical roles in the pathophysiology of fibrosis across multiple organs. This review highlights the roles of FFA1 and FFA4 in mitigating fibrosis, either directly or indirectly, across various organs, including the liver, kidney, lung, heart, and peritoneum, as well as in disorders associated with fibrosis-related injuries.

Keywords:  FFA1; FFA4; GPR120; GPR40; fibrosis; inflammation

DOI:  https://doi.org/10.1111/bph.70334
Subcell Biochem. 2026 ;113 377-412

The Impact of Ageing on Fibrillar Collagens.

Elizabeth G Canty-Laird, Himadri S Gupta, Helen L Birch.

  The world population is ageing rapidly. The over-60s now outnumber the under- 5s, and 1 in 6 people will be over 60 by 2030 (WHO). Collagen is a key structural component of many tissues and organs, and although a fraction of the collagenous component of tissues is remarkably long-lived, it progressively accumulates damage over a lifetime. The capacity for new collagen synthesis and post-translational modification is altered and dysregulated during ageing. The mature crosslinks that stabilise collagenous tissues can remain stable or increase with age, whereas age-related glycation end-products can increase and affect tissue biomechanics. At the fibrillar nanoscale, changes associated with ageing and disease influence fibril deformation and stress transfer in a tissue-specific manner. Age-related loss of collagen can be caused by proteolytic degradation, but normal collagen turnover is also affected by ageing and its dysregulation is detrimental to tissue homeostasis. Age-related accumulation of senescent cells may contribute to the aberrant turnover of collagen during ageing. Finally, collagen itself may hold the key to counteracting some of the detrimental effects of ageing, with ingested hydrolysed collagen peptides demonstrating beneficial effects on skin and the musculoskeletal system.

Keywords:  Ageing; Collagen; Crosslinking; Degradation; Nanomechanics; Nanostructure; Senescence; Supplements; Turnover

DOI:  https://doi.org/10.1007/978-3-032-05273-5_12
Exp Mol Pathol. 2026 Jan 16. pii: S0014-4800(26)00004-3. [Epub ahead of print]145 105025

Metixene hydrochloride hydrate mitigates kidney tubulointerstitial fibrosis by inhibiting Smad3 phosphorylation.

Kyeong-Min Lee, Yeo Jin Hwang.

  Chronic Kidney disease (CKD), in which renal fibrosis is the defining pathological feature, poses significant global health and economic challenges. Despite its high clinical prevalence, effective therapies to prevent or reverse renal fibrosis remain scarce. Metixene hydrochloride hydrate (MHH), an anticholinergic drug once used for Parkinson's disease, has not been evaluated for renal fibrosis. Here, we investigated whether MHH mitigates renal fibrosis in a unilateral ureteral obstruction (UUO) mouse model and evaluated its effects on transforming growth factor-β1 (TGF-β1) signaling in renal cells. MHH did not affect the cell viability of NRK-49F cells at concentrations ranging from 0.5 to 5 μM. In vitro, MHH effectively suppressed TGF-β1-induced PAI-1 expression (both mRNA and protein) and secretion in renal fibroblasts, as well as PAI-1 secretion and protein expression in renal glomerular endothelial cells. Furthermore, TGF-β1 stimulated the mRNA and protein expressions of key renal fibrotic factors, including collagen type I, fibronectin, and alpha-smooth muscle actin, in NRK-49F cells. MMH significantly inhibited the expression of these renal fibrotic factors in these cells. UUO kidneys exhibited markedly increased tubular atrophy and interstitial fibrosis, as well as increased expression of renal fibrotic markers. MHH treatment significantly mitigated these pathological parameters and expression of renal fibrotic markers. Mechanistically, MHH suppressed TGF-β1-induced Smad3 phosphorylation both in vitro and in vivo. Our findings indicate that MHH exerts potent antifibrotic effects by downregulating the TGF-β1/Smad3 signaling pathway and suppressing the expression of fibrotic factors in renal cells and obstructed kidneys. Therefore, MHH could be repositioned as a therapeutic agent for renal fibrosis in various kidney diseases.

Keywords:  Chronic kidney disease; Metixene; Renal fibrosis; Smad3; Transforming growth factors; Unilateral ureteral obstruction

DOI:  https://doi.org/10.1016/j.yexmp.2026.105025
Sci Adv. 2026 Jan 23. 12(4): eady0550

Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma.

Emma D Wrenn, Jacob C Harris, April A Apfelbaum, Jonah R Valenti, Patricia A Lipson, Stephanie I Walter, Nicolas M Garcia, Aya Miyaki, Steven C Chen, Jim M Olson, Jason P Price, Kelly M Bailey, Elizabeth R Lawlor.

Subpopulations of cancer-associated fibroblast (CAF)-like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a transforming growth factor-β (TGFβ) signaling positive feedback loop. Hybrid cells derepress TGFBR2 and up-regulate expression and secretion of TGFβ2 to sustain pathway activation and ECM deposition. Although TGFβ ligands can potently induce growth arrest in cells of epithelial origin, we show that TGFβ1 and TGFβ2 promote cell invasion of EwS cells without affecting proliferation. Thus, stroma-derived and tumor-derived TGFβ ligands induce and maintain hybrid EwS cells to promote pro-metastatic cell phenotypes.

DOI: https://doi.org/10.1126/sciadv.ady0550
Biochem Biophys Res Commun. 2026 Jan 12. pii: S0006-291X(26)00049-5. [Epub ahead of print]800 153286

Versatile role of fibro-adipogenic progenitors in neuromuscular junction homeostasis and pathology.

Ruizhi Li, Jingtao Li, Shujuan Zou, Xing Yin.

  The neuromuscular junction (NMJ) is a specialized synapse that enables reciprocal signaling between motor nerves and muscle fibers. NMJ integrity is essential for muscle homeostasis, while retrograde signals from muscle also modulate nerve axon physiology. Nerve injury or neuromuscular diseases often result in functional deficits and histological changes. Fibro-adipogenic progenitors (FAPs) are muscle-resident multipotent mesenchymal cells, and a large body of research illustrated their role in muscle mass maintenance and regeneration. Recently, FAPs have been suggested to be responsive to NMJ perturbations. However, many questions remain, including how FAPs sense nerve injury and neuropathology; what factors drive their fate determination; and what effectors mediate their responses to NMJ impairments. In this review, we first provide a brief overview of NMJ structure and formation, then discuss the role of FAPs in NMJ homeostasis, nerve injury, and neuromuscular diseases. FAPs regulate NMJ development and regeneration via paracrine factor secretion, extracellular matrix modulation, and cellular interaction. Aberrantly activated FAPs drive pathological muscle fibrosis, fatty-infiltration, and ectopic bone formation. This comprehensive perspective of FAP-NMJ interactions will shed a new light on NMJ regeneration mechanisms and neuromuscular disease control.

Keywords:  Acetylcholine receptor; Extracellular matrix; Fibro-adipogenic progenitors; Nerve injury; Neuromuscular diseases; Neuromuscular junctions

DOI:  https://doi.org/10.1016/j.bbrc.2026.153286
Nephrology (Carlton). 2026 Jan;31(1): e70166

Targeting TBK1 With GSK8612 Suppresses Kidney and Cardiac Inflammation and Fibrosis in DOCA/Salt Hypertension.

Jiamin Huang, Wei Rong, Ling Li, Wenqiang Yu, Shuangquan Chen, Haihui Xie, Hua Liang.

   AIM: To investigate the therapeutic potential of GSK8612, a selective TBK1 inhibitor, against the inflammatory and fibrotic pathological remodeling in the heart and kidneys induced by DOCA/salt hypertension in mice.
METHODS: A salt-sensitive hypertension model was established in male C57BL/6 mice via uninephrectomy followed by DOCA/salt treatment. Hypertensive mice were administered the selective TBK1 inhibitor GSK8612 (1.5 mg/kg, i.p., once every two days) or vehicle for 21 days. Blood pressure was monitored weekly. Renal and cardiac injury were assessed by histopathology, including Hematoxylin and Eosin, Sirius Red, and Masson's trichrome staining. Extracellular matrix deposition was evaluated via Western blot and immunofluorescence. Macrophage-to-myofibroblast transition was determined by F4/80 and α-SMA co-staining. Inflammatory cell infiltration was evaluated by immunohistochemistry, while cytokine mRNA levels were quantified by RT-qPCR.
RESULTS: While GSK8612 treatment showed no significant effect on blood pressure in DOCA/salt-challenged mice, it significantly improved kidney function and attenuated kidney injury compared to DOCA/salt-treated controls. GSK8612 treatment significantly inhibited myofibroblast accumulation and extracellular matrix deposition in the kidneys and reduced infiltration of inflammatory cells. Furthermore, it effectively inhibited macrophage-to-myofibroblast transition in hypertensive nephropathy. Notably, GSK8612 administration also ameliorated DOCA/salt-induced cardiac inflammation and fibrosis, as evidenced by reduced infiltration of F4/80+ macrophages and decreased fibroblast activation.
CONCLUSION: Pharmacological inhibition of TBK1 with GSK8612 confers dual organ protection, attenuating both kidney and heart inflammation and fibrosis in a murine model of salt-sensitive hypertension.

Keywords:  TBK1; cardiac; fibrosis; hypertension; inflammation; kidney

DOI:  https://doi.org/10.1111/nep.70166
Adv Mater. 2026 Jan 22. e13401

Engineered Perfusable Hepatic Fibrosis Model via Embedded Sacrificial Bioprinting Recapitulates Stiffness-Driven Fibrogenesis.

Weikang Lv, Tuya Naren, Abdellah Aazmi, Haoran Yu, Yujun Wang, Jie Ying Lee, Mengfei Yu, Junjun Jia, Xiuxiu Jiang, Huayong Yang, Liang Ma.

  Hepatic fibrosis, as the common pathological endpoint of chronic liver diseases, is characterized by a self-perpetuating vicious cycle comprising extracellular matrix (ECM) driven liver tissue stiffening and sustained hepatic stellate cell (HSC) activation. Although existing studies have simulated fibrotic microenvironments using 2D models with tunable matrix stiffness or static 3D cultures, these models lack engineered hepatic sinusoidal vasculature and dynamic mechanical stimulation within 3D ECM contexts. This study employed embedded sacrificial bioprinting to construct functional liver sinusoid-mimetic vascular networks within hydrogel matrix of precisely tunable elastic modulus, establishing a dynamically perfused in vitro liver fibrosis model. Experimental validation demonstrated that matrix stiffness directly drives HSC activation, inducing marked myofibroblastic transdifferentiation. Furthermore, compared to static models, 3D dynamic perfusion significantly enhanced hepatocyte sensitivity to high-stiffness matrix, more accurately replicating the functional decline of hepatocytes in fibrotic microenvironments observed in vivo. More critically, the biomimetic in vitro platform established in this study presents a potential avenue for evaluating pharmacotherapeutic interventions against liver fibrosis. Through targeted inhibition of key signaling hubs, we achieved partial reversal of HSC activation on stiff matrix and partial recovery of liver tissue function. Overall, by simultaneously integrating matrix stiffness modulation, 3D multicellular interactions, and hemodynamic stimulation, this work effectively addresses the insufficient responsiveness of hepatocytes to mechanical cues in conventional models due to inadequate mechanical stimulation. This approach provides a robust framework for faithfully recapitulating the pathophysiological progression of liver fibrosis in vitro through precise tuning of ECM mechanical properties, thereby offering a promising platform for future drug screening and therapeutic assessment.

Keywords:  dynamic mechanical force stimulation; embedded sacrificial printing; hepatic sinusoids; liver fibrosis model

DOI:  https://doi.org/10.1002/adma.202513401
Eur J Pharmacol. 2026 Jan 19. pii: S0014-2999(26)00049-X. [Epub ahead of print] 178567

Peptide FK2 attenuates inflammation and pro-fibrotic cellular transitions via targeting the IKKβ/NF-κB/TGF-β1 axis in renal fibrosis.

Runling Yang, Xiaocui Feng, Jianfeng Zhang, Tianyi Chen, Wenqian Wang, Yangrui Liu, Wanru Chen, Jingya Bai, Bangzhi Zhang.

  Chronic kidney disease (CKD) refers to a pathological change characterized by the progressive and irreversible loss of renal function. Renal fibrosis is the final pathological outcome of CKD without effective treatment. Persistent inflammation is one of the most important factors in the occurrence and development of fibrosis. FK2, a 9-amino-acid-residue peptide originating from the silk of Zea mays L., was reported to have anti-inflammatory effects on mice. In this study, we verified for the first time that FK2 has an inhibitory effect on the process of renal fibrosis both in vivo and in vitro. Mechanistically, we identified IKKβ as a direct target of FK2. By binding to IKKβ, FK2 concurrently suppresses the IKKβ/NF-κB and TGF-β1/Smad2/3 signaling axes, thereby effectively mitigating the associated inflammatory response and key cellular processes including macrophage-to-myofibroblast transition (MMT) and epithelial-mesenchymal transition (EMT). Our research provides a promising candidate molecule for the development of anti-renal fibrosis drugs, and targeting IKKβ presents a viable strategy for treating kidney fibrosis.

Keywords:  EMT; FK2; IKKβ/NF-κB; MMT; inflammation; renal fibrosis

DOI:  https://doi.org/10.1016/j.ejphar.2026.178567
Hepatol Commun. 2026 Feb 01. pii: e0893. [Epub ahead of print]10(2):

Hepatocyte-hepatic stellate cell interactions in liver fibrosis: Mechanisms and therapeutic implications.

Zihan Wang, Zixuan Cao, Yunsheng Dong, Yi Hong, Li Zuo, Hua Wang.

  Hepatic fibrosis, driven by chronic liver injury, results from complex interactions between hepatocytes and hepatic stellate cells (HSCs). In response to hepatocyte damage, activated HSCs undergo transdifferentiation into myofibroblast-like cells, contributing to the accumulation of extracellular matrix (ECM) components and the progression of fibrosis. This review explores the intricate bidirectional crosstalk between hepatocytes and HSCs, focusing on the molecular mechanisms underlying their interactions during liver fibrosis. Hepatocytes, upon injury, release inflammatory mediators, reactive oxygen species (ROS), and exosomes, which activate HSCs and promote fibrotic progression. Conversely, activated HSCs exacerbate hepatocyte dysfunction through cytokine release, ECM remodeling, and mechanical stress. Key signaling pathways, including transforming growth factor-beta (TGF-β), platelet-derived growth factor (PDGF), and oxidative stress mechanisms, are central to these processes. The review also discusses current challenges in targeting hepatic fibrosis and proposes future research directions, including the use of multi-omics technologies to unravel the dynamic spatiotemporal interactions between hepatocytes and HSCs. Understanding this intricate regulatory network will be crucial for the development of novel therapeutic strategies to reverse liver fibrosis and improve patient outcomes.

Keywords:  cell crosstalk; hepatic stellate cells; hepatocytes; liver fibrosis

DOI:  https://doi.org/10.1097/HC9.0000000000000893
Bone Res. 2026 Jan 19. 14(1): 11

Bone sialoprotein: a multifunctional regulator of bone remodelling and tumour progression.

Valentina Kottmann, Philipp Drees, Erol Gercek, Ulrike Ritz.

Bone sialoprotein (BSP) is a major non-collagenous protein of the bone extracellular matrix and an important regulator of bone formation and resorption. BSP is produced by bone cells and chondrocytes and present in the bone matrix, cells, dentin and cartilage. However, its aberrant expression in primary tumour tissues and the sera of cancer patients with metastases implicates BSP in tumour biology and progression. The Arg-Gly-Asp (RGD) motif of BSP may be crucial not only for the attachment of metastasising cells to the bone surface but also for tumour growth, survival and activity. This review examines the structure and functions of BSP, including its roles in angiogenesis, bone formation, osteoclast differentiation and activity and cancer cell proliferation, survival, complement evasion, adhesion, migration and invasion. Growing evidence highlights BSP as a key mediator of tumour pathophysiology, skeletal metastasis development and associated bone remodelling. These processes are driven through RGD-integrin binding, the integrin/BSP/matrix metalloproteinase axis, integrin-independent signalling pathways, epithelial-to-mesenchymal transition and potentially post-translational modifications. A deeper understanding of BSP's role in tumour progression may reinforce its potential as a prognostic and diagnostic tumour biomarker and aid the development of anti-BSP antibodies or targeted inhibitors for skeletal metastases and bone diseases.

DOI: https://doi.org/10.1038/s41413-025-00490-5
Bone Res. 2026 Jan 19. 14(1): 10

Thrombospondin 1 and 2 regulate mesenchymal progenitor cell fate and matrix organization.

Madysen K Hunter, Sneha Korlakunta, Neda Vishlaghi, Monisha Mittal, Kyle Cragg, Conan Juan, Chase A Pagani, Yuxiao Sun, Lindsey Lammlin, Karen Kessell, Dylan Feist, Ji Hae Choi, Meng-Lun Hsieh, Jahnu Saikia, Craig L Duvall, Heeseog Kang, Andrea I Alford, Kurt D Hankenson, Robert J Tower, Tristan Maerz, Benjamin Levi.

Thrombospondin 1 and 2 (TSP1 and TSP2) are critical regulators of extracellular matrix (ECM) interactions, influencing cell differentiation and tissue repair. Recent discoveries from our laboratory and others highlight the importance of altered ECM alignment in influencing aberrant mesenchymal progenitor cell (MPC) differentiation and subsequent ectopic bone formation in trauma-induced heterotopic ossification (HO). However, the key regulators of this MPC to ECM interaction have yet to be elucidated. This study uncovers the role of matricellular TSP1 and TSP2 in MPC/ECM interaction as well as HO formation and progression. Using single-cell RNA sequencing, spatial transcriptomics, and in vivo models, we found that TSP1 is upregulated in tissue remodeling macrophages and MPCs at the injury site, while TSP2 is restricted to MPCs surrounding the HO anlagen. TSP1/2 double knockout (DKO) mice exhibited significantly reduced HO volume and disrupted ECM alignment. These findings highlight the crucial roles of TSP1 and TSP2 in musculoskeletal injury repair as well as HO formation and progression, supporting the potential to therapeutically target TSP1 and TSP2 to prevent HO.

DOI: https://doi.org/10.1038/s41413-025-00493-2
Adv Sci (Weinh). 2026 Jan 21. e19191

Macrophage-Derived Ferritin Exacerbates Silica-Induced Pulmonary Fibrosis via PIK3R2-Mediated Fibroblast Differentiation.

Liqun Wang, Xuxi Chen, Hongying Quan, Rui Qian, Shuyu Gong, Qiurong He, Ying Gao, Ajia Axi, Manyu Zhao, Qin Zhang, Ling Zhang, Lijun Peng, Xin Sun, Ben Zhang, Yuqin Yao.

  Silicosis is a progressive and life-threatening fibrotic lung disease caused by crystalline silica. However, targeted therapies remain unavailable due to its incompletely understood pathogenic mechanisms. Here, we identify ferritin as a pivotal mediator of silica-induced pulmonary fibrosis by integrating clinical exploration with experimental validation. We detected persistently elevated ferritin levels in lung tissues and serum from silicosis patients and silica-exposed mice, and demonstrated that exogenous ferritin administration exacerbates fibrosis in vivo. Multi-omics profiling and co-culture experiments revealed that macrophage-secreted ferritin promotes fibroblast-to-myofibroblast differentiation and pathological extracellular matrix (ECM) deposition via the PIK3R2/SMAD signaling axis. Importantly, genetic knockdown of ferritin in macrophages significantly suppressed myofibroblast differentiation and collagen accumulation both in vivo and in vitro. These findings underscore that ferritin functions not only as a potential clinical biomarker for silicosis surveillance but also as a pathogenic driver through macrophage-fibroblast crosstalk, and provide a theoretical foundation for developing integrated diagnostic and therapeutic strategies against silicosis.

Keywords:  ferritin; fibroblast; macrophages; phosphoinositide‐3‐kinase regulatory subunit 2; silicosis

DOI:  https://doi.org/10.1002/advs.202519191
J Korean Neurosurg Soc. 2026 Jan 21.

Nintedanib Attenuates Epidural Fibrosis After Laminectomy in Rats.

Kadri Kulualp, Meltem Kumaş Kulualp, Ziya Yurtal, Sefa Kizildağ, Beste Balbal Kandemir.

   Objective: Epidural fibrosis (EF) is a major contributor to postoperative morbidity following laminectomy. This study investigated the antifibrotic, anti-inflammatory, and anti-angiogenic effects of nintedanib (NIN), a multi-tyrosine kinase inhibitor, in a rat model of post-laminectomy EF.
Methods: Twenty-one male Wistar albino rats were assigned to three groups: Control, Laminectomy (LAM), and Laminectomy + Nintedanib (NIN). The laminectomy procedure was performed at the L3 level. NIN administration, following laminectomy, was administered orally at a dose of 50 mg/kg/day for 28 days. Histopathological evaluations included hematoxylin-eosin staining for dura mater thickness and fibroblast density, and Masson's trichrome staining for collagen deposition and adhesion grading. α-smooth muscle actin (α-SMA) expression was evaluated using immunohistochemistry and RT-qPCR. Gene expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor (PDGFR), and transforming growth factor-β1 (TGF-β1) was quantified to characterize inflammatory, angiogenic, and fibrogenic responses. Statistical comparisons were conducted using one-way ANOVA or Kruskal-Wallis tests with appropriate post hoc analyses.
Results: The LAM group exhibited marked post-laminectomy changes, including increased dura mater thickness (8.20 ± 0.23 µm vs. 3.93 ± 0.08 µm in controls, p < 0.0001), elevated fibroblast density (p = 0.0006), severe collagen deposition, and high-grade epidural adhesions (Grade 3, p = 0.0006). NIN treatment attenuated these alterations, reducing dura mater thickness (4.80 ± 0.20 µm, p < 0.0001 vs. LAM), fibroblast density (p < 0.01), and adhesion grade (Grade 1, p = 0.0012). α-SMA immunoreactivity was high in LAM (Grade 3, p < 0.0001), whereas NIN significantly suppressed myofibroblast activation (Grade 1, p = 0.0012). NIN also significantly downregulated inflammatory mediators TNF-α (p < 0.001) and IL-1β (p < 0.001), as well as angiogenic markers VEGF (p < 0.001) and PDGF (p < 0.001), and fibrogenic mediators TGF-β1 (p < 0.001) and α-SMA (p < 0.01). These findings indicate that NIN suppresses fibroblast activation, extracellular matrix accumulation, and myofibroblast differentiation, thereby limiting epidural adhesion and scar maturation.
Conclusion: Nintedanib effectively mitigated epidural fibrosis after laminectomy through combined antifibrotic, anti-inflammatory, and anti-angiogenic actions. By improving the dural structure and reducing key molecules that contribute to scar formation, NIN shows significant promise as a treatment to prevent postoperative epidural adhesions. Future studies with extended follow-up may help clarify its clinical relevance.

Keywords:  Epidural fibrosis; Laminectomy; Nintedanib; Rat model; Treatment

DOI:  https://doi.org/10.3340/jkns.2025.0245
Biochem Biophys Rep. 2026 Mar;45 102424

The role of metformin in extracellular matrix-based three-dimensional cell culture Models: A mini-review on therapeutic potentials.

Mahshid Zamani, Nepton Soltani.

  Metformin, a widely used antidiabetic agent, exhibits pleiotropic effects extending beyond glycemic control, including the modulation of the extracellular matrix (ECM). Although traditional two-dimensional (2D) cell cultures have provided foundational insights, they inadequately replicate the complex tissue microenvironment in which metformin exerts its therapeutic actions. Emerging evidence underscores the pivotal role of ECM composition, stiffness, and cellular context in determining metformin's efficacy-particularly in cancer, fibrosis, and metabolic diseases. However, a comprehensive synthesis of its actions within physiologically relevant three-dimensional (3D) models remains lacking. This mini-review addresses this gap by systematically analyzing the interplay between metformin and the ECM in advanced 3D cell culture systems. We focus on metformin's ability to reprogram stromal cells, modulate mechanotransduction pathways (e.g., AMPK/mTOR), and influence cell-ECM dynamics within specific disease contexts. Furthermore, we discuss the integration of metformin-loaded biomaterials with 3D platforms, highlighting their dual function as drug delivery vehicles and active components of disease models. By synthesizing recent findings, this review emphasizes the bidirectional relationship between metformin and the ECM, positioning 3D culture models as indispensable tools for elucidating context-dependent drug responses. We also identify key challenges, including the lack of standardized ECM-based systems and the underrepresentation of immune and vascular components, and propose future directions for translating these models into personalized therapeutic strategies. This work underscores the necessity of moving beyond conventional 2D paradigms to fully harness metformin's therapeutic potential through the adoption of 3D ECM-based systems.

Keywords:  3D cell culture models; Drug delivery; Extracellular matrix; Metformin; Tissue engineering; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrep.2025.102424
Int Immunopharmacol. 2026 Jan 16. pii: S1567-5769(26)00009-3. [Epub ahead of print]172 116166

Deficiency of inducible nitric oxide synthase alleviates dermal fibrosis and inflammation in scleroderma.

Jing Luo, Mingwei Li, Di Zhao, Hong Chen, Junkai Huang, Mengke Sun, Qianyu Zhu, Qi Guo, Sicheng Song, Qianshu Yuan, Hui Li, Fengtong Li, Yingxi Li, Bingxin Zhang, Long Su, Weibin Xing, Lizhi Hu.

  Scleroderma is a connective tissue disorder marked by chronic inflammation and progressive skin fibrosis. Abnormal activation of fibroblasts (FBs) and deposition of collagen in the extracellular matrix (ECM) are the key to the progression of scleroderma. While FBs activation has been attributed to the dysfunction of keratinocytes (KCs) and immune cells, the crosstalk among these cells is considered critical for scleroderma progression. Recent evidence indicates that inducible nitric oxide synthase (iNOS) is highly expressed in scleroderma lesions, and iNOS contributes to the progression of dermatoses. Nevertheless, the specific role of iNOS in scleroderma remains to be fully elucidated. We utilized a bleomycin (BLM)-induced scleroderma model in wildtype (WT) and iNOS knockout (iNOS KO) mice to investigate the function of iNOS in scleroderma. We demonstrated that iNOS deficiency alleviated scleroderma progression, inhibiting inflammatory factor expression in KCs and neutrophils (Neus) infiltration. Subsequently, we stimulated FBs with TNF-α and IL-1β, which are mainly expressed by KCs and Neus, and confirmed that iNOS deletion attenuated FBs activation. We also revealed that iNOS inhibitors significantly attenuated the severity of scleroderma lesions. Our study collectively unveils a pivotal role of iNOS in scleroderma, highlighting its potential as a therapeutic target.

Keywords:  Fibroblasts; Inducible nitric oxide synthase; Intercellular crosstalk; Keratinocytes; Neutrophils; Scleroderma

DOI:  https://doi.org/10.1016/j.intimp.2026.116166
Hum Mutat. 2026 ;2026 4574795

Proprotein Convertase Subtilisin/Kexin Type 9 Induces Platelet-Derived Transforming Growth Factor-β to Promote Myocardial Fibrosis After Myocardial Infarction.

Qianyun Wang, Wenxiang Huang, Dianmin Xia, Feifei Wang, Sujit Nair.

   Aims: The recovery of cardiac function after acute myocardial infarction is crucial for the prognosis of patients with myocardial infarction. Proprotein convertase subtilisin/Kexin Type 9 (PCSK9) inhibitors are widely used in patients with acute myocardial infarction due to their potent low-density lipoprotein-lowering effects. Recent studies have shown that elevated levels of circulating PCSK9 are associated with increased platelet reactivity and thrombosis; however, the effect and mechanism of PCSK9 on cardiac repair after myocardial infarction through the induction of platelet activation remain unclear. Therefore, the objective of this study was to investigate and clarify the specific effect of PCSK9 on cardiac repair processes following myocardial infarction. The detailed molecular and cellular mechanisms through which PCSK9 regulates cardiac repair after myocardial infarction by inducing platelet activation were observed.
Methods and Results: Hearts from wild-type (WT) C57BL/6J mice and PCSK9 knockout (PCSK9-/-) mice were subjected to left coronary artery (LAD) ligation to establish a myocardial infarction model. Six weeks postoperation, echocardiographic analysis and Masson staining revealed that inhibiting the increase in PCSK9 expression after myocardial infarction significantly reduced myocardial fibrosis. Transcriptome sequencing of mouse myocardial tissue suggested that PCSK9 suppresses immune regulation and adhesion pathways and that the platelet marker integrin subunit alpha 2b (Itga2b) is a potential key molecule. Subsequent in vivo and in vitro experiments demonstrated that PCSK9 promotes platelet activation and induces the fibrogenic phenotypic transformation of fibroblasts by transforming growth factor-β (TGF-β). In further studies, coculture experiments of fibroblasts and platelets revealed that PCSK9 promotes the conversion of fibroblasts to myofibroblasts by inducing platelet-derived TGF-β secretion.
Conclusion: PCSK9 promotes platelet activation, induces the secretion of platelet-derived TGF-β, and thereby accelerates myocardial fibrosis after myocardial infarction.

Keywords:  PCSK9; myocardial fibrosis; platelet-derived TGF-β

DOI:  https://doi.org/10.1155/humu/4574795
Pharmacol Rep. 2026 Jan 20.

Dysregulation of store-operated calcium entry in fibroblast lines from adult and juvenile-onset Huntington's disease patients.

Samuel Oluwafemi Egbuwalo, Ewelina Latoszek, Hana Hansíková, Jiří Klempíř, Alžbeta Mühlbäck, Georg Bernhard Landwehrmeyer, Jacek Kuźnicki, Magdalena Czeredys.

   BACKGROUND: The pathology of Huntington's disease (HD) is marked by the aggregation of mutant huntingtin protein (mHTT), which results from expanded polyglutamine (polyQ) residues encoded by CAG repeats in the HTT gene. These repeats are differentially elongated in adult- and juvenile-onset HD. In striatal neurons, the mHTT disrupts cellular mechanisms such as store-operated calcium entry (SOCE), a process in which endoplasmic reticulum Ca²⁺ depletion triggers extracellular Ca²⁺ influx; however, this process can also be affected in peripheral cells. The aim of this study was to evaluate SOCE in fibroblasts derived from both HD onset patients and age-related controls.
METHODS: We conducted SOCE analysis in dermal fibroblasts from 12 HD patients (including adult- and juvenile-onset subtypes) and age-related healthy controls using Fura-2 AM ratiometric imaging paired with EGTA-based extracellular calcium chelation protocols. To evaluate SOCE response, we administered two SOC channel inhibitors, 6-bromo-N-(2-phenylethyl)-2,3,4,9-tetrahydro-1 H-carbazol-1-amine hydrochloride (C20H22BrClN2) and EVP4593, in premanifest HD fibroblasts.
RESULTS: In healthy human fibroblast lines, a decline in SOCE was observed between juvenile and adult individuals. In fibroblast lines from adult-onset HD patients (premanifest, early manifest, and manifest stages), we observed increased SOC channel activity. Conversely, juvenile-onset HD fibroblast lines exhibited reduced SOC channel activity compared to controls. Notably, SOCE dysregulation was independent of CAG repeat length in HD lines. Both SOC channel inhibitors attenuated SOCE in adult-onset HD lines.
CONCLUSION: The mHTT upregulates SOCE in adult-onset HD fibroblasts and downregulates it in juvenile-onset HD fibroblast lines; however, SOCE levels do not correlate with the length of CAG repeats encoding mHTT. Despite opposing trends compared to age-related controls, similar levels of SOCE in both HD-onset fibroblasts were detected. Both C20H22BrClN2 and EVP4593 show potential for stabilizing SOCE in adult-onset HD. These findings suggest that dysregulated SOCE could be investigated as a peripheral target for studying pathological processes potentially associated with Huntington's disease.

Keywords:  Fibroblasts; Huntingtin; Huntington’s disease; SOCE

DOI:  https://doi.org/10.1007/s43440-025-00820-8
J Dent Res. 2026 Jan 21. 220345251401512

V-ATPase a3 Directs Secretory Lysosome Transport in Enamel Formation.

K Otsu, S Ikezaki, N Goto-Matsumoto, A Ikarashi, H Sano, H Ida-Yonemochi, H Ohshima, G-H Sun-Wada, Y Wada, M Nakanishi-Matsui, H Harada.

  Enamel mineralization critically depends on maturation-stage ameloblasts (M-ABs) regulating pH, protein secretion, and cell-matrix adhesion. However, the molecular mechanisms underlying these processes remain poorly understood. This study identifies the vacuolar-type H+-ATPase (V-ATPase) a3 subunit as a key regulator of enamel formation via its role in secretory lysosome trafficking. In a3 knockout (a3KO) mice and cultured ameloblasts, a3 is required for both lysosomal acidification and the directional transport of odontogenic ameloblast-associated protein (ODAM)-containing secretory lysosomes to the ruffled border membrane of M-ABs. At this site, ODAM is crucial for mediating ameloblast adhesion to the enamel matrix. Loss of a3 caused severe enamel hypomineralization, characterized by reduced matrix acidification, cystic enamel defects, abnormal ruffled border morphology, and ameloblast detachment from the mineralizing surface. In vitro, a3-deficient ameloblasts exhibited significantly impaired adhesion to hydroxyapatite, decreased ODAM expression, and suppressed lysosomal acidification, indicating a3 is functionally required for maintaining ameloblast function and polarity. Mechanistically, Rab27A served as an important adaptor linking a3-positive secretory lysosomes to the microtubule network, enabling their polarized movement toward the distal plasma membrane. Disruption of this a3-Rab27A axis in a3KO cells mislocalized secretory lysosomes and defective ODAM delivery into the enamel matrix, compromising enamel mineralization. These findings reveal a new mechanism by which a3 orchestrates lysosomal positioning and ODAM secretion in enamel-forming cells. By integrating proton transport with vesicular trafficking and adhesion protein delivery, a3 functions as a key regulator of enamel mineralization. This study provides new insights into the pathogenesis of enamel hypomineralization and identifies a3 and its associated pathways as potential therapeutic targets for treating developmental enamel defects.

Keywords:  a3 knockout mice; enamel mineralization; hypomineralization; maturation-stage ameloblasts; odontogenic ameloblast-associated protein; vacuolar-type H+-ATPase

DOI:  https://doi.org/10.1177/00220345251401512