bims-fibdiv 2026-02-22 papers

bims-fibdiv

Biomed News

on Fibroblast diversity

Issue of 2026–02–22
ten papers selected by
Emilio Ernesto Méndez Olivos, University of Calgary

Extracellular stiffness regulates cell fate determination and drives the emergence of evolutionary novelty in the teleost heart.
Androgen dysregulates the follicular extracellular matrix and increases pro-fibrotic gene expression in the mouse ovary.
Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.
Expression patterns of fibroblast activation protein and extra-domain B fibronectin in canine malignant tumors.
Actinotrichia-independent developmental mechanisms of spiny rays facilitate the morphological diversification of Acanthomorpha fish fins.
Cholinergic signaling modulates intestinal pathophysiology in a Drosophila model of cystic fibrosis.
Striking a nerve: Sensory neurons orchestrate ECM remodeling and immune exclusion in TNBC.
Sacubitril/valsartan as a modulator of pulmonary fibrosis: insights into Lnc-SNHG-16/miR-455 modulation and Notch/Smad-3 pathway inhibition.
Spatiotemporal cellular dynamics of the notochord shape intervertebral disc morphogenesis in the mouse embryo through apoptosis and proliferation.
Obese Adipocytes Induce Fibroblast-to-Myofibroblast Transition through TGF-β1 signaling: Implications in Asthma Pathogenesis.

Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2511871123

Extracellular stiffness regulates cell fate determination and drives the emergence of evolutionary novelty in the teleost heart.

Sho Matsuki, Yusei Inoue, Ryuta Watanabe, Toshiyuki Mitsui, Yuuta Moriyama.

  The diversification of life is driven by the acquisition of new phenotypic traits, known as evolutionary novelties. While some genetic mechanisms underlying such traits have been identified, the role of physical properties of cellular and extracellular components remains largely unexplored. Here, we show that the evolution and development of the bulbus arteriosus (BA)-a teleost-specific, smooth muscle-rich heart outflow tract-is regulated by the mechanical properties of its extracellular environment. Specifically, we demonstrate that the teleost-specific extracellular matrix gene elastin b confers the uniquely low stiffness of the BA. In contrast to the BA, the homologous organ in nonteleost actinopterygians, the conus arteriosus (CA), and the ventricle are predominantly composed of cardiomyocytes and exhibit higher extracellular stiffness. Loss of elastin b function by knockdown or knockout leads to ectopic cardiomyocyte formation in the BA, accompanied by increased extracellular stiffness comparable to that of the ventricle. Furthermore, artificial stiffening of the BA extracellular environment is sufficient to induce ectopic cardiomyocyte differentiation. Taken together, these findings demonstrate that extracellular stiffness governs cell fate determination and highlight its role in the emergence of evolutionary novelties in the teleost heart.

Keywords:  ECM; elastin; heart; stiffness

DOI:  https://doi.org/10.1073/pnas.2511871123
Sci Rep. 2026 Feb 18.

Androgen dysregulates the follicular extracellular matrix and increases pro-fibrotic gene expression in the mouse ovary.

Thomas I R Hopkins, Avigdor Lerner, Iain E Dunlop, Stephen Franks, Kate Hardy.

  The extracellular matrix (ECM) defines the biomechanical and biochemical microenvironment of tissues, directing cell behaviour and phenotype. In the ovary, ECM must dynamically remodel in each cycle under hormonal regulation to control follicle development and produce fertilizable oocytes. Dysregulation of this process may result in aberrant formation of ECM as seen in polycystic ovary syndrome (PCOS) whose pathology includes fibrosis of the ovary and which is a major cause of infertility. PCOS is characterised by hyperandrogenism and, here, we investigate the impact of androgens on fibrosis, cell-ECM interactions and mechanosensing. We report an altered network of gene expression related to the genesis of fibrosis. Preantral follicles from C57BL/6 mice (14-15 days postpartum) were stimulated with dihydrotestosterone (DHT, 10nM) in 24/72 hours culture. Expression of fibrosis-associated genes (Eln; Ctgf; Acta2; Plod2; Hpse) significantly increased with androgen (72 h), as did TGF-β signalling (Tgfb1; Tgfb3). We show a direct connection between androgen and mechanosensing within the ovary, with androgen upregulating the mechanosensitive Hippo pathway (Yap1; Lats1; Lats2; Stk3; Stk4; Frmd6) and downstream targets (Ctgf; Axl; Cyr61). Our results highlight hyperandrogenism as a probable driver of the fibrosis in the polycystic ovary, and emphasise the importance of ECM regulation in follicle development and fertility.

Keywords:  Androgen; ECM; Fibrosis; Ovary; PCOS

DOI:  https://doi.org/10.1038/s41598-025-32927-6
iScience. 2026 Feb 20. 29(2): 114788

Cancer-associated fibroblasts as a critical driver in tumor metastasis: The mechanisms and future perspectives.

Lingyu Ding, Zhen Li, Jing Yue, Liqing Qiu, Zhifeng Tian, Hongfang Zhang.

  Tumor metastasis represents a lethal event for patients due to the lack of effective treatments. Compared with primary tumors, the components of the tumor microenvironment (TME) of metastatic tumors are different. Tumor cells alone are unable to metastasize. Cancer-associated fibroblasts (CAFs), as one major component of TME, drive tumor metastasis. In metastatic lesions, the proportion of CAFs is significantly higher and is spatially close to tumor cells with high metastatic potential. CAFs themselves are resistant to chemoradiotherapy and have strong invasive ability based on their major role in degrading the extracellular matrix (ECM). Furthermore, CAFs determined the organs to which tumor cells metastasize. By interaction with tumor cells, CAFs were activated, transdifferentiated, and in turn enhanced the invasive ability of tumor cells. Tumor cells also promoted the infiltration of CAFs in tumor tissues, allowing them to establish a pre-metastatic microenvironment. In this review, we have deeply analyzed the association of CAFs and tumor metastasis from the perspectives of exosomes, metabolic reprogramming, suppression of anti-tumor immunity, and epigenetic modification. We also discussed the future perspectives of CAFs-based anti-metastasis strategies. This information may deepen our understanding of CAFs-initiated tumor metastasis and shed novel insight into the development of anti-metastasis therapies.

Keywords:  Cancer; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2026.114788
Front Vet Sci. 2025 ;12 1719994

Expression patterns of fibroblast activation protein and extra-domain B fibronectin in canine malignant tumors.

Silvia Dell'Aere, Elisa Maria Gariboldi, Alessandra Ubiali, Roberta Ferrari, Luigi Auletta, Matilde Bocci, Andrea Galbiati, Ettore Gilardoni, Giulia Rotta, Valentina Balbi, Gaia Beatrice Maria Bianchi, Alessandra Verdi, Dario Neri, Samuele Cazzamalli, Damiano Stefanello, Paola Roccabianca.

   Introduction: Fibroblast activation protein (FAP) is involved in the extracellular matrix (ECM) remodeling and wound healing. Absent in most adult tissues, it is overexpressed by neoplastic cells and/or cancer-associated fibroblasts (CAFs) in several human malignancies. The extra Domain-B of fibronectin (EDB+FN) is a splice variant of fibronectin involved in angiogenesis and tissue remodeling, overexpressed by CAFs and cancer-associated vessels (CAVs) in many aggressive human tumors. This study aims to investigate FAP and EDB+FN expressions in canine tumors and assess their potential as druggable targets in animal patients.
Methods: FAP and EDB+FN expression was assessed by immunohistochemistry on 88 canine tumors, including Soft Tissue Sarcomas [STS], Osteosarcomas [OSA], Hemangiosarcomas [HSA], Apocrine Gland Anal Sac Adenocarcinomas [AGASAC], Mast Cell Tumors [MCT], Lymphomas, and Melanomas, using polyclonal and monoclonal anti-FAP and the L19 anti-EDB antibodies. Expression distribution and intensity were semi-quantitatively scored in neoplastic cells, CAFs, CAVs, and stroma.
Results: FAP was variably expressed in neoplastic cells (79/88), CAFs (79/88), and CAVs (82/88) across all tumor types, but mostly in AGASACs, STSs, and MCTs. The monoclonal antibody presented greater specificity. EDB+FN expression was less present across tumor types, mostly with a vascular staining pattern. Labelling was most intense and consistent in the neoplastic cells, CAFs, and CAVs of melanomas, and to a lesser extent in AGASAC and STS.
Discussion: STS, AGASAC, and MCT could be candidates for FAP-targeted strategies; melanomas are the most promising for EDB+FN-directed therapies. These results support FAP and EDB+FN as targets worth investigating for clinical applications in animal patients.

Keywords:  EDB; FAP; canine tumor; extra domain B; fibroblast activation protein; fibronectin; melanoma; sarcoma

DOI:  https://doi.org/10.3389/fvets.2025.1719994
Nat Commun. 2026 Feb 14.

Actinotrichia-independent developmental mechanisms of spiny rays facilitate the morphological diversification of Acanthomorpha fish fins.

Kazuhide Miyamoto, Junpei Kuroda, Satomi Kamimura, Yasuyuki Sasano, Gembu Abe, Satoshi Ansai, Noriko Funayama, Masahiro Uesaka, Koji Tamura.

Skeletal forms in vertebrates have been regarded as good models of morphological diversification. Fish fins show great diversity in form, with their supporting skeletal structure being classified into soft rays and spiny rays. In fish evolution, spiny-ray morphologies are known to be sometimes extremely modified; however, it remains unknown how the developmental mechanisms of spiny rays have contributed to their morphological diversification. By using the rainbowfish Melanotaenia praecox for examination of the extracellular matrix (ECM) and cell dynamics of spiny-ray development, we demonstrate that spiny-ray development is independent of the actinotrichia (needle-shaped collagen polymers at the tip of fins), which are known as an important ECM in soft-ray morphogenesis. Furthermore, we found that in the thorny spiny ray of the filefish Stephanolepis cirrhifer, the lateral protrusions are associated with BMP-positive osteoblast condensation, as in the spiny-ray tips in M. praecox and S. cirrhifer. Taken together, our findings reveal that osteoblast distribution and signaling-molecule intensity would contribute to spiny-ray modification. In comparison to soft ray development, the independence from actinotrichia in spiny rays would facilitate growth direction change, leading to their morphological diversification. This suggests that variation in cell distribution and ECM usage may be important contributors to morphological diversification, not only in Acanthomorpha, but also in other animal taxa.

DOI: https://doi.org/10.1038/s41467-026-69180-y
PLoS Genet. 2026 Feb;22(2): e1012048

Cholinergic signaling modulates intestinal pathophysiology in a Drosophila model of cystic fibrosis.

Elizabeth A Lane, Afroditi Petsakou, Ying Liu, Weihang Chen, Mujeeb Qadiri, Yanhui Hu, Norbert Perrimon.

Cystic fibrosis (CF) is a monogenic genetic disease caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride/bicarbonate channel, which is expressed in certain epithelial cells. Current therapies focus on restoring CFTR function, but many gut-related pathologies persist, highlighting the need for complementary treatments to improve the quality of life of people with CF. In this study, we use Drosophila melanogaster as a model to investigate the gut-specific effects of Cftr loss. We demonstrate that enterocyte specific knockdown of Cftr in flies recapitulates several CF pathologies, including reduced intestinal motility, nutrient malabsorption, and decreased energy stores. Using single-nuclei RNA sequencing (snRNA-seq), we identify significant transcriptional changes in the CF model gut, including the upregulation of acetylcholine esterase (Ace, human AChE), which leads to reduced cholinergic signaling. Cholinergic signaling has been shown to affect CFTR function but this is the first time CFTR loss of function has been shown to alter cholinergic signaling. Functional assays confirm that cholinergic sensitivity is diminished in CF guts. Furthermore, restoring cholinergic signaling via Ace knockdown rescues multiple CF-associated phenotypes. Additionally, we identify the transcription factor Fork head (Fkh), the Drosophila homolog of human FOXA1/FOXA2, which is known to be a positive regulator of Cftr transcription in the intestine, as a positive regulator of Ace expression in CF guts. This study establishes the Drosophila gut as a powerful model to investigate CF pathogenesis, genetic modifiers, and identifies Ace and fkh as genetic modifiers. This work also suggests that enhancing cholinergic signaling may represent a viable therapeutic strategy for gastrointestinal manifestations of CF.

DOI: https://doi.org/10.1371/journal.pgen.1012048
Cell. 2026 Feb 19. pii: S0092-8674(26)00107-8. [Epub ahead of print]189(4): 993-994

Striking a nerve: Sensory neurons orchestrate ECM remodeling and immune exclusion in TNBC.

Debra Barki, Neta Eilat, Ruth Scherz-Shouval.

The tumor microenvironment drives cancer progression, yet neural contributions remain underexplored. Zhang et al. unravel a signaling circuit involving cancer cells, sensory neurons, and cancer-associated fibroblasts that promotes desmoplasia and excludes cytotoxic T cells, positioning the neuron-fibroblast axis as a therapeutic vulnerability and potential predictor of immunotherapy response.

DOI: https://doi.org/10.1016/j.cell.2026.01.020
Naunyn Schmiedebergs Arch Pharmacol. 2026 Feb 18.

Sacubitril/valsartan as a modulator of pulmonary fibrosis: insights into Lnc-SNHG-16/miR-455 modulation and Notch/Smad-3 pathway inhibition.

Zeinab M Abdel-Nasser, Mai A Zaafan.

  Pulmonary fibrosis is a progressive and life-threatening interstitial lung disease marked by excessive extracellular matrix accumulation and declining pulmonary function. Despite available therapies, clinical outcomes remain suboptimal, necessitating the exploration of novel therapeutic approaches. Sacubitril/valsartan, a dual-acting agent combining a neprilysin inhibitor and angiotensin II receptor blocker, has recently emerged as a candidate with potential anti-fibrotic properties. This study investigates the therapeutic efficacy of sacubitril/valsartan in a bleomycin-induced rat model of pulmonary fibrosis. The compound was administered orally once daily, beginning on the first day of fibrosis induction and continued for 21 days. Fibrotic progression was evaluated through biochemical and histological assessments, including quantification of hydroxyproline content, α-smooth muscle actin (α-SMA) expression, collagen deposition percentage, and histopathological examination of lung tissue. Molecular analyses revealed that sacubitril/valsartan significantly downregulated the expression of long non-coding RNA SNHG-16 and concurrently upregulated miR-455 levels. These changes were associated with suppression of the Notch-2/Smad-3 signaling pathway. Additionally, sacubitril/valsartan treatment resulted in a notable reduction in pulmonary levels of transforming growth factor-β (TGF-β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), indicating attenuation of both fibrotic and inflammatory responses. Collectively, these findings suggest that sacubitril/valsartan mitigates pulmonary fibrosis through modulation of the SNHG-16/miR-455 axis and inhibition of the Notch-2/Smad-3/TGF-β signaling cascade, highlighting its potential as a promising therapeutic strategy for the management of pulmonary fibrosis.

Keywords:  Notch-2/Smad-3; Pulmonary fibrosis; SNHG-16/miR-455; Sacubitril/valsartan; TGF-β

DOI:  https://doi.org/10.1007/s00210-026-05034-0
Dev Dyn. 2026 Feb 17.

Spatiotemporal cellular dynamics of the notochord shape intervertebral disc morphogenesis in the mouse embryo through apoptosis and proliferation.

Julie Warin, Estelle Balissat, Pauline Colombier, Lily Paillat, Maeva Dutilleul, Anne Camus.

   BACKGROUND: The notochord is a midline structure essential for vertebrate embryogenesis, contributing to the development of the nervous system, digestive tract, and vertebral column. In particular, notochord signaling is indispensable for proper patterning and coordinated development of alternating vertebrae and intervertebral discs (IVDs). Later, notochordal cells (NCs) mature and adopt a characteristic vacuolated morphology before giving rise to the core of the forming IVD, the nucleus pulposus (NP). Postnatally, NCs play a pivotal role in maintaining disc integrity through the secretion of specific factors and extracellular matrix (ECM). Despite its importance in disc formation and homeostasis, the morphogenetic mechanisms underlying the notochord's transformation into the NP are insufficiently characterized.
RESULTS: We conducted a comprehensive histological and immunohistochemical analysis to investigate the cellular events governing NP formation in the mouse developing spine. Temporal analysis of intracytoplasmic vacuole formation using Lamp-1 marker revealed that vacuolation contributed to NP growth, while cell density progressively decreased. In addition, quantitative analyses demonstrated a notable proliferative capacity within notochordal cells coupled with region-specific apoptotic activity in sclerotome, at future disc sites.
CONCLUSIONS: This study highlights the intricate balance of cellular proliferation, programmed cell death, matrix remodeling, and vacuolation dynamics as key determinants in shaping the NP along the rostro-caudal axis.

Keywords:  axial skeleton development; intervertebral disc; morphogenesis; mouse embryos; notochord; nucleus pulposus formation; sclerotome

DOI:  https://doi.org/10.1002/dvdy.70119
Am J Physiol Lung Cell Mol Physiol. 2026 Feb 21.

Obese Adipocytes Induce Fibroblast-to-Myofibroblast Transition through TGF-β1 signaling: Implications in Asthma Pathogenesis.

Nour Jalaleddine, Mahmood Hachim, Alexander Giddey, Mellissa Gaudet, Qutayba Hamid, Mohammed Uddin, Saba Al Heialy.

  Obesity, a key risk factor for severe asthma, is associated with worsening symptoms and poor responses to conventional therapies. Recent studies have highlighted the presence of adipocytes within airway walls, which correlates positively with body mass index (BMI). However, the role of adipocytes in asthma pathogenesis remains largely unknown. This study aims to explore their potential contribution to airway fibrosis, a progressive form of the disease, through fibroblast-to-myofibroblast transition (FMT). In vitro co-culture models were developed to investigate the interactions between adipocytes (derived from patients with and without obesity) and fibroblasts (from patients with and without asthma) on FMT. Proteomic and multiplex analyses were used to identify potential mediators of adipocyte-induced FMT. Our data revealed a significant increase in fibrogenic markers, such as alpha-smooth muscle actin and vimentin, in fibroblasts co-cultured with obese (Ob) adipocytes. Notably, this transition was more pronounced in asthmatic fibroblasts compared to healthy fibroblasts. Proteomic profiling of co-cultured Ob-adipocytes and asthmatic fibroblasts identified several significantly upregulated proteins linked to the regulation of the transforming growth factor-beta (TGF-β)signalling pathway, including inhibin A, latent TGF-β binding protein 1, thrombospondin 1 , and follistatin. The role of TGF-β was further substantiated by multiplex assays, which demonstrated a significant increase in TGF-β and leptin production by Ob-adipocytes following co-culture. These findings suggest that Ob-adipocytes may promote FMT in fibroblasts, especially asthmatic fibroblasts, by activating the TGF-β signalling pathway. This highlights a potential mechanism by which obesity exacerbates asthma severity and fibrosis, providing new avenues for therapeutic intervention.

Keywords:  adipocytes; asthma; fibroblast-to-myofibroblast transition; lung fibrosis; obesity

DOI:  https://doi.org/10.1152/ajplung.00208.2025