Rxiv mechanobio2d ago
📰 "SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis"
https://www.biorxiv.org/content/10.64898/2026.03.19.712957v1?rss=1 #Mechanotransduction #Mechanosensing #Extracellular
SUN2 mediates epigenetic remodeling to drive mechanotransduction during skin fibrosis

Fibrosis involves sustained changes in fibroblast gene expression, leading to excessive extracellular matrix (ECM) deposition and progressive tissue stiffening. Although matrix stiffness is a potent regulator of cell fate and transcription, how nuclear mechanosensing contributes to fibrosis remains unclear. Here, we define a central role for SUN2, a component of linker of nucleoskeleton and cytoskeleton (LINC) complexes, as a mediator of stiffness-dependent nuclear and chromatin responses during skin fibrosis. SUN2 transcripts are upregulated in dermal fibroblasts of patients with systemic sclerosis and Sun2 protein is elevated in fibrotic mouse skin. Nuclear size, A-type lamins and Sun2 are elevated in dermal fibroblasts plated on stiff substrates. Loss of Sun2 protects against bleomycin-induced skin fibrosis in vivo and abolishes stiffness-induced changes in nuclear size and fibrotic gene expression in vitro. Mechanistically, we identify three Sun2-dependent mechanosensitive chromatin states and show that mechanical induction of the histone methyltransferase Ezh2 requires Sun2. These findings define SUN2 as a nuclear mechanosensor that couples matrix stiffness to chromatin regulation and transcriptional programs that drive fibrosis, identifying it as a potential therapeutic target pathway in fibrotic disease. ### Competing Interest Statement The authors receive research funding from Boehringer-Ingelheim Pharmaceutical, Inc. National Institute of Arthritis and Musculoskeletal and Skin Diseases, https://ror.org/006zn3t30, AR076938, AR0695505, AR084558, AR085488 National Institute of General Medical Sciences, https://ror.org/04q48ey07, GM153474 LEO Foundation, https://ror.org/02rgsr590 Boehringer Ingelheim (Germany), https://ror.org/00q32j219

bioRxiv
Rxiv mechanobio2d ago
📰 "FraCeMM - A Framework for Cell-Matrix Mechanotransduction"
https://www.biorxiv.org/content/10.64898/2026.03.16.712065v1?rss=1 #Mechanotransduction #Mechanical #Cell
FraCeMM - A Framework for Cell-Matrix Mechanotransduction

Cells sense and respond to the mechanical properties of their environment, yet the minimal physical principles sufficient to reproduce mechanotransduction and durotaxis remain debated. This work introduces FraCeMM, a physics-first mechanochemical simulation framework coupling stochastic ligand-integrin-talin binding to a deformable soft-body cell model on an elastic substrate. Without imposed polarity, directional cues, or migration rules, the model reproduces hallmark mechanobiological behaviors including stiffness-dependent spreading, traction reinforcement, focal adhesion asymmetry, and directed durotaxis. A finite pool of adhesion molecules, mechanically coupled through elastic linkages, drives emergent force asymmetry and polarization via self-consistent feedback between stochastic binding, molecular availability, and substrate stiffness. Despite minimal assumptions and a coarse-grained molecular representation, resulting traction forces, adhesion loads, and migration speeds fall within experimentally reported ranges. These results support the view that local force balance, limited adhesion resources, and mechanically binding are sufficient to generate adaptive mechanosensing and directed migration, establishing a transparent and extensible foundation for computational mechanobiology. ### Competing Interest Statement The authors have declared no competing interest.

bioRxiv
Rxiv mechanobio4d ago
📰 "Cryo-EM reveals a right-handed double-helix dimer architecture of PCDH15 critical for mechanotransduction"
https://doi.org/doi:10.64898/2026.03.02.709101
https://pubmed.ncbi.nlm.nih.gov/41846998/
#Mechanotransduction #Cadherin #Force
Cryo-EM reveals a right-handed double-helix dimer architecture of PCDH15 critical for mechanotransduction

Tip links connect the stereocilia of mechanosensory hair cells in the inner ear and transmit force onto mechanotransduction (MET) channels. Tip links consist of protocadherin 15 (PCDH15) and cadherin 23 (CDH23), which assemble into an extracellular filament approximately 150 nm in length. Rare freeze-etched electron microscopy (EM) images have suggested that tip links could be right-handed double helices in vivo, but direct structural evidence has been lacking. Using cryo-EM we determined the structure of a large part of the extracellular PCDH15 domain. Two PCDH15 molecules form a parallel cis dimer stabilized by several dimerization interfaces, including two strand crossovers and two parallel contacts, yielding a right-handed double helix. Functional studies show that mutations in PCDH15 dimerization-domains impair MET. Our results establish the molecular foundation for how PCDH15 forms a right-handed double helix to enable mechanical sensing. ### Competing Interest Statement The authors have declared no competing interest. NIDCD, DC005965 NIGMS, GM154904, GM157915 Searle Scholars Award

bioRxiv
Rxiv mechanobioMar 15
📰 "Biochemical and Mechanical Signal Differentially Contribute to Survival in Surface-Modified Cell Model"
https://doi.org/doi:10.1007/s13770-026-00800-w
https://pubmed.ncbi.nlm.nih.gov/41831120/
#Mechanotransduction #Mechanical #Actin #Cell
Rxiv mechanobioMar 14
📰 "Mechanotransduction-Induced Gene Expression Reveals Activation of TGFβ/SKIL/TAZ Axis and Supports Invasive Phenotype in Triple-Negative Breast Cancer"
https://doi.org/doi:10.3390/ijms27052456
https://pubmed.ncbi.nlm.nih.gov/41828672/
#Mechanotransduction #Matrix
Rxiv mechanobioMar 13
📰 "iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept"
https://www.biorxiv.org/content/10.64898/2026.03.12.711267v1?rss=1 #Mechanotransduction #Cell
iPSC modeling of pulmonary arterial hypertension to uncover pathomechanisms and unrecognized modes of action of sotatercept

Pulmonary arterial hypertension (PAH) is a potentially fatal disease characterized by obliterative remodeling of distal pulmonary arteries, commonly associated with bone morphogenetic receptor type 2 (BMPR2) gene mutations. In patients with PAH, sotatercept, an activin signaling inhibitor, improves hemodynamics and outcomes, but clinical responses vary and sometimes occur within weeks, suggesting additional mechanisms beyond its anti-proliferative, pro-apoptotic and anti-remodeling effects. Using patient-specific induced pluripotent stem cell-derived smooth muscle cells (iSMCs) with BMPR2 extracellular- or kinase-domain mutations, we were able to reproduce Activin A-driven PAH traits, including hyperproliferation, reduced apoptosis, enhanced contraction and excessive matrix production. We identified smooth muscle cell-to-myofibroblast transition as a previously unknown contributor to pulmonary vascular remodeling and demonstrate that it is blocked by sotatercept. Beyond its established effects, sotatercept rapidly reduced contractility, collagen-integrin mechanotransduction and TGF-beta receptor expression, disrupting a pathological positive feedback loop, reflected by lower levels of circulating TGF-beta 1 in patients on sotatercept. Taken together, our patient-derived iSMC platform links mutation-dependent mechanisms of pulmonary vascular remodeling to variable drug responsiveness and reveals previously unrecognized, potentially rapid-acting modes of sotatercept in PAH. ### Competing Interest Statement The authors have declared no competing interest. German Center for Lung Research, 82DZL002C1 German Research Foundation OL, 653/2-1 Lower Saxony (Nachhaltigkeitsfinanzierung Exzellenzcluster REBIRTH), ZN3440 German Research Foundation DFG KFO311, MA 2331/18-1, MA 2331/18-2

bioRxiv
Rxiv mechanobioMar 6
📰 "Mechanical stiffness of membrane-anchored backpacks modulates innate immune function in dendritic cells and macrophages"
https://doi.org/doi:10.1016/j.jconrel.2026.114753
https://pubmed.ncbi.nlm.nih.gov/41786045/
#Mechanotransduction #Mechanical #Cell
Rxiv mechanobioMar 2
📰 "A Modular Bioinstructive Platform Reveals Mechanistic Insights into Additive-Free, Topography-Driven Osteogenesis"
https://doi.org/doi:10.1002/adhm.202504865
https://pubmed.ncbi.nlm.nih.gov/41766211/
#Mechanotransduction #Cell
Rxiv mechanobioFeb 27
📰 "Gear-like MOF microrobots for single cell mechanotransduction of microvilli"
https://doi.org/doi:10.1038/s41467-026-70052-8
https://pubmed.ncbi.nlm.nih.gov/41748583/
#Mechanotransduction #Cell
Rxiv mechanobioFeb 26
📰 "Nucleoli as drivers of nuclear remodelling in cardiomyocytes during Heart Failure"
https://www.biorxiv.org/content/10.64898/2026.02.24.707499v1?rss=1 #Mechanotransduction #Cytoskeleton
Nucleoli as drivers of nuclear remodelling in cardiomyocytes during Heart Failure

Cardiomyocyte mechanotransduction has traditionally focused on the sarcomere and cytoskeleton, yet emerging evidence highlights the nucleus as an active mechanical responder. To adapt to the dynamic mechanical environment, the nucleus forms nuclear invaginations (NIs), double-membrane folds that provide structural support to chromatin and incorporate nuclear pore complexes to facilitate nucleo-cytoplasmic transport, including Ca2+ transport. However, how these structures are formed is not yet understood. We leveraged advances in high-resolution microscopy, mechanical stimulation, rat models and human samples, to study the formation, function and remodelling of cardiac NIs in Heart Failure (HF). Here, we demonstrate that the formation of NI in cardiomyocytes is regulated by both, cytoskeleton such as actin and detyrosinated microtubules as well as intranuclear nucleolar interactions with NI disruption resulting in elevated baseline nuclear Ca2+. In a 16-week post-Myocardial Infarction (MI) end-stage HF rat model, as well as in human Dilated Cardiomyopathy samples, a marked reduction in NIs is observed. Importantly, NI loss is already evident at 8 weeks post-MI, preceding detectable cytoskeletal stiffening. At this earlier stage, we observe increased DNA damage in the peri-nucleolar region, accompanied by nucleolar remodelling and a shift in nucleolar biomechanical properties. In conclusion, nucleolar maintenance emerges as a potential target for intervention. ### Competing Interest Statement The authors have declared no competing interest. The authors would like to acknowledge the Cellular Mechanosensing and Functional Microscopy Centre at Imperial College London for access to equipment. British Heart Foundation Imperial Centre of Research Excellence Award, RE/18/4/34215 EU-METAHEART Cost Action CA22169 British Heart Foundation, PG/20/6/34835; SP/F/23/150045 Austrian Science Fund, 10.55776/PAT9036624 and 10.55776/STA194 Molecular Medicine PhD Program at the Medical University of Graz UKRI Engineering and Physical Sciences Research Council, EP/X036049/1 Add-on Fellowship of the Joachim Herz Foundation

bioRxiv