bims-ecemfi 2026-05-03 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–05–03
fourteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Nuclear compression overrides matrix softness to regulate stem cell fate through actomyosin-driven YAP mechanotransduction.
Fiber-Based Hydrogels for Designing Viscoelastic Responses in Particle-Based Biomaterials That Support Embedded 3D Printing.
Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton.
Physiological Buffer Selection Alters the Mechanics of Hydrogels with Hydrazone Cross-Links.
Intercellular contact is sufficient to drive fibroblast-to-myofibroblast transitions.
Mechanical cues regulate in vitro implantation of mouse embryos.
Quantifying the Contribution of Intrachain Conformational Locking to Covalent Hydrogel Mechanics.
Engineering tough blood clots for rapid haemostasis and enhanced regeneration.
3D environment favors persistent changes in cell functions and altered morphology, wrinkling, and biomechanical signature of the nucleus.
Local-friction governs water mobility in hydrogels acting as extracellular mimics.
Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.
Co-evolving Biomaterials: Spatiotemporally Programmable Materials Steering Dynamic Macrophage State Transitions.
Microenvironment optimization enables kidney organoid longevity with epithelial-endothelial joint basement membrane formation.
Universal Persistent Brownian Motions in Confluent Tissues.

Acta Biomater. 2026 Apr 24. pii: S1742-7061(26)00261-8. [Epub ahead of print]

Nuclear compression overrides matrix softness to regulate stem cell fate through actomyosin-driven YAP mechanotransduction.

Ying Zhou, Yanru Wu, Dabing Ren, Qianchen Shao, Xinyi Wang, Chunwu Zhang, Min Bao.

  Mechanical cues play a pivotal role in regulating stem cell fate, yet how cells integrate compressive forces in compliant microenvironments remains poorly understood. Here, we show that nuclear compression overrides soft matrix cues to induce osteogenic differentiation in mesenchymal stem cells through an integrin/vinculin-independent, cytoskeleton-mediated mechanism. Using a microfabricated polydimethylsiloxane (PDMS) confiner, we applied defined vertical confinement (3 and 10 μm) to mesenchymal stem cells (MSCs) cultured on substrates of varying stiffness. On soft substrates, compression triggered a marked increase in cell spreading, actomyosin contractility and cortical stiffness, leading to YAP nuclear translocation and upregulation of osteogenic transcription factors such as Runx2. Surprisingly, this response occurred in the absence of canonical integrin-vinculin signaling, but was abolished by pharmacological inhibition of actin polymerization or myosin II activity. Prolonged intermittent confinement promoted robust osteogenesis on soft substrates, as demonstrated by alkaline phosphatase (ALP) staining and gene expression, and was suppressed by YAP inhibition. Our findings uncover a previously unrecognized nuclear mechanosensing axis, in which cells actively generate internal tension to counteract external compression and engage YAP-mediated transcriptional programs, providing a tunable strategy for directing stem cell fate in soft environments. STATEMENT OF SIGNIFICANCE: Mechanical control of stem cell fate is traditionally attributed to extracellular matrix stiffness. Here, we show that vertical nuclear confinement functions as a dominant mechanical cue that can override soft matrix signals to direct cell differentiation. Using a precisely controlled confinement system, we find that confinement induces a cytoskeletal reinforcement response that occurs largely independent of canonical integrin-vinculin adhesion signaling, leading to increased actomyosin contractility, cortical stiffening, and YAP nuclear localization. This tension-driven nuclear mechanosensing enables robust osteogenic commitment even in otherwise non-permissive soft environments. Our findings reveal a distinct mode of mechanotransduction in which cells elevate intracellular tension to counter external confinement, highlighting nuclear confinement as a key regulator of stem cell fate in confined microenvironments.

Keywords:  Cell confinement; MSC differentiation; Mechanotransduction; Nuclear deformation; Substrate stiffness

DOI:  https://doi.org/10.1016/j.actbio.2026.04.040
ACS Biomater Sci Eng. 2026 May 01.

Fiber-Based Hydrogels for Designing Viscoelastic Responses in Particle-Based Biomaterials That Support Embedded 3D Printing.

M Gregory Grewal, Emily Ferrarese, Lauren Porter, Georgia T Helein, Christopher B Highley.

  Viscoelastic biomaterials that exhibit biomimetic responses to applied stresses are important in studying physiology and designing biomaterial scaffolds. Particle-based hydrogels offer potential for engineering viscoelasticity through the design of both the component microparticles and their processing into bulk particle-based materials. When particles are not cross-linked to one another, particle movements in response to strain can potentially relieve applied stresses and facilitate the material's use in dynamic processes like bioprinting. In particle-based hydrogels based on spherical hydrogel microparticles (HMPs), particle movement is restricted by contact with immediately adjacent HMPs. In comparison, fiber-based hydrogel systems leverage high-aspect-ratio microfiber components with long-range interactions. Here, microfibers with aspect ratios of ∼15:1 length/diameter are used to form particle-based hydrogels to compare how interparticle interactions at increased length scales alter properties compared to particle-based hydrogels based on spherical HMPs. Like particle-based hydrogels formed from spherical HMPs, those formed from fiber HMPs exhibit viscoelasticity with shear-thinning and self-healing behaviors. But fiber-based materials allow enhanced control over bulk stress relaxation times (T1/2 ∼ 1-100+ s) across a range of applied strains (σ ∼ 2.5%-50%) in a packing density-dependent fashion. Fiber-based systems relaxed stresses continuously and to a greater degree at low strains in comparison to HMP systems. Dynamic interfiber interactions in fiber-based hydrogels also supported embedded printing, where perfusable channels can be printed into fiber-based hydrogels stabilized by physical interfiber interactions. Taken together, fiber-based hydrogels offer opportunities for designing complex biomaterial scaffolds, including allowing control over viscoelastic properties through hydrogel design and control over heterogeneous 3D structures through embedded printing.

Keywords:  dynamic materials; embedded printing; granular hydrogels; microfibers; particle-based hydrogels; stress relaxation

DOI:  https://doi.org/10.1021/acsbiomaterials.5c01432
Nat Mater. 2026 Apr 29.

Fibrillar adhesion dynamics govern the timescales of nuclear mechano-response via the vimentin cytoskeleton.

Amy E M Beedle, Vivek Sharma, Jorge Oliver-De La Cruz, Anuja Jaganathan, Aina Albajar-Sigalés, F Max Yavitt, Kaustav Bera, Ion Andreu, Ignasi Granero-Moya, Dobryna Zalvidea, Zanetta Kechagia, Gerhard Wiche, Xavier Trepat, Johanna Ivaska, Kristi S Anseth, Vivek B Shenoy, Pere Roca-Cusachs.

The cell nucleus is continuously exposed to external signals, of both chemical and mechanical nature. To ensure proper cellular response, cells need to regulate the transmission, timing and duration of these signals. Although such timescale regulation is well described for chemical signals, whether and how it applies to mechanical signals reaching the nucleus is still not fully understood. Here we demonstrate that the formation of fibrillar adhesions locks the nucleus in a mechanically deformed conformation, setting the mechano-response timescale to that of fibrillar adhesion remodelling (~1 h). This process encompasses both mechanical deformation and associated mechanotransduction (such as via YAP), in response to both increased and decreased mechanical stimulation. The underlying mechanism is the anchoring of the vimentin cytoskeleton to fibrillar adhesions and the extracellular matrix through plectin 1f, which maintains nuclear deformation. Our results reveal a mechanism to regulate the timescale of mechanical adaptation, effectively setting a low-pass filter to mechanotransduction.

DOI: https://doi.org/10.1038/s41563-026-02590-x
Biomacromolecules. 2026 Apr 28.

Physiological Buffer Selection Alters the Mechanics of Hydrogels with Hydrazone Cross-Links.

Daiyao Zhang, Neil J Baugh, Narelli de Paiva Narciso, Sarah C Heilshorn.

Hydrogels are used for a wide range of biomedical applications. While mechanical characterization of hydrogels is frequently performed in isotonic saline, the chemical identity of these solutions may vary widely from the ionic environments encountered during their use. To explore this idea, we test the mechanical properties of a hydrogel cross-linked with dynamic covalent chemistry (DCC) in several physiologically relevant ionic solutions that mimic different biological conditions. Specifically, we evaluate rheological properties of a hydrazone-cross-linked hydrogel composed of recombinant, chemically modified hyaluronan and elastin-like protein (ELP). Our results show that the shear moduli and stress relaxation properties of DCC hydrogels can vary significantly in different ionic environments. We identify the thermoresponsive nature of ELP and changes in hydrazone bond kinetics as the primary reasons for the observed differences in mechanical properties. Taken together, this work elucidates mechanisms underpinning changes in hydrogel mechanics in different physiological solutions.

DOI: https://doi.org/10.1021/acs.biomac.5c02684
J Appl Physiol (1985). 2026 Apr 29.

Intercellular contact is sufficient to drive fibroblast-to-myofibroblast transitions.

Vasuretha Chandar, Benjamin M Goykadosh, Harikrishnan Parameswaran.

  Fibroblast cells play a key role in maintaining the extracellular matrix. During wound healing, fibroblasts differentiate into highly contractile myofibroblasts, which secrete extracellular matrix proteins like collagen to facilitate tissue repair. Under normal conditions, myofibroblasts undergo programmed cell death after healing to prevent excessive scar formation. However, in diseases like fibrosis, the myofibroblasts remain active even after the wound is closed, resulting in excessive collagen buildup and a stiff, fibrotic matrix. The reasons for the persistence of myofibroblasts in fibrosis are not well understood. Here, we show the existence of a mechanism where direct physical contact between a fibroblast and a myofibroblast is sufficient for fibroblasts to transition into myofibroblasts. We demonstrate that the fibroblast-myofibroblast transition can occur even in the absence of known biochemical cues, such as growth factor activation or mechanical cues from a stiff, fibrotic matrix. Furthermore, we demonstrate that contact-based fibroblast-myofibroblast activation can be inhibited by the Gαq/11/14 inhibitor FR900359, which prevents the formation of myofibroblasts. These findings provide new insights into the persistence of the myofibroblast phenotype and highlight potential approaches to regulate the fibroblast-to-myofibroblast transition.

Keywords:  Cytoskeletal tension; Fibroblast-Myofibroblast transitions; Mechanobiology; Mechanotransduction; PLC activation

DOI:  https://doi.org/10.1152/japplphysiol.00382.2025
Mater Today Bio. 2026 Jun;38 103105

Mechanical cues regulate in vitro implantation of mouse embryos.

Qian Liu, Kai Chen, Shaoshan Pan, Tao Zhang, Qian Wang, Jiaying Zhu, Jin Zhang, Xiaohua Jiang, Haiying Jia, Shengxia Zheng, Tianzhi Luo.

  Uterine mechanical properties, particularly tissue stiffness, are dynamically regulated during the embryo implantation window to ensure optimal mechanocompatibility. However, maternal aging and fibrotic pathologies, such as adenomyosis and intrauterine adhesions, disrupt this balance, leading to increased stromal stiffness due to abnormal extracellular matrix (ECM) deposition and crosslinking. In this study, we simulated various uterine environments in vitro by adjusting the mechanical cues, aiming to exploring embryonic mechanosensing and invasive capabilities during implantation. Our observations revealed that embryos cultured on softer substrates demonstrated enhanced developmental efficiency and exhibited distinct assembly morphologies compared to those on stiffer substrates. Using traction force microscopy (TFM), we quantified the traction forces exerted by embryos on soft substrates, noting a gradual increase in these forces before they stabilized within a specific range and displayed sustained fluctuations that were closely linked to cytoskeletal remodeling. We further identified that the traction force provided a real-time assessment of the developmental status of the embryo during implantation. Additionally, given that the mechanosensitive Yes-associated protein (YAP) differentially responds to substrate stiffness, we further investigated its pivotal role during early embryogenesis by RNA-seq. This research offers insights into mechanics-based interventions that could potentially enhance the outcomes in assisted reproductive technologies.

Keywords:  Actin cytoskeleton; Embryo implantation; Hydrogel; Substrate stiffness; Traction force

DOI:  https://doi.org/10.1016/j.mtbio.2026.103105
Langmuir. 2026 Apr 27.

Quantifying the Contribution of Intrachain Conformational Locking to Covalent Hydrogel Mechanics.

Tianfu Zheng, Chongling Cheng, Dayang Wang.

In covalently cross-linked hydrogel networks, physical associations and interchain entanglements are commonly treated as noncovalent cross-links contributing to network mechanics. Here, we propose that, beyond these interchain effects, a mechanically relevant contribution may arise from conformational locking within polymer strands between adjacent chemical cross-linking points. Using a solvent-exchange strategy in chemically cross-linked poly(acrylic acid) hydrogels, we selectively suppress weak interactions without altering the covalent network topology, enabling isolation of these local intrachain constraints. Weak interactions can stabilize locally folded conformations within cross-link-to-cross-link segments, temporarily sequestering portions of load-bearing strands and reducing their mechanical participation under small deformation. This effect is termed intrachain conformational locking (InCL). Although the fraction of InCL is small, their systematic modulation can lead to measurable changes in macroscopic mechanical responses. An Ω-chain model is introduced to rationalize how the release of InCL-associated hidden length contributes to network deformation.

DOI: https://doi.org/10.1021/acs.langmuir.6c01111
Nature. 2026 Apr 29.

Engineering tough blood clots for rapid haemostasis and enhanced regeneration.

Shuaibing Jiang, Guangyu Bao, Zhen Yang, Jing Wu, Xingwei Yang, Joo Eun June Kim, Roselyn Jiang, Ying Zhan, Alexander Nottegar, Yin Liu, Zu-Hua Gao, Andrew Beckett, Anastasia Nijnik, Rong Long, Christian Kastrup, Jianyu Li.

Blood clots are pivotal for haemostasis and regeneration1, but they are mechanically weak and form slowly2, posing risks for life-threatening haemorrhage and limiting broader applications3-5. These limitations are attributed to complex coagulation cascades, abundant mechanically ineffective cells and little structural polymers. Strategies that strengthen polymer networks are inapplicable to these highly cellularized materials. Here we report a strategy that rapidly crosslinks red blood cells into tough cytogels and integrates them within blood clots. The resulting engineered blood clots (EBCs) form within seconds and exhibit a 13-fold increase in fracture toughness, and a 4-fold improvement in adhesion energy compared with native clots. Experiments and modelling identify the rupture of mechanically integrated cells as a key toughening mechanism. In vivo studies demonstrate that EBCs can rapidly halt haemorrhage, promote tissue regeneration, mitigate inflammation and foreign body reactions, and prevent postoperative adhesion. The safety and efficacy of both autologous and allogeneic EBCs were also validated. Our strategy is applicable to a range of cells and polymers. This work may motivate the development and translation of highly cellularized materials for bleeding control, wound management, tissue repair and regenerative medicine.

DOI: https://doi.org/10.1038/s41586-026-10412-y
Cell Rep Phys Sci. 2026 Feb 18. 7(2): 103116

3D environment favors persistent changes in cell functions and altered morphology, wrinkling, and biomechanical signature of the nucleus.

Raquel González-Novo, Héctor Zamora-Carreras, Marina Armesto, Ana de Lope-Planelles, Horacio López-Menéndez, Pedro Roda-Navarro, Francisco Monroy, Lin Wang, Christopher P Toseland, Javier Redondo-Muñoz.

  The interplay between cells and their surrounding microenvironment drives multiple cellular functions, including migration, proliferation, and cell fate transitions. The nucleus is a mechanosensitive organelle; however, the morphological and functional changes of the nucleus induced by a three-dimensional (3D) extracellular environment remain unclear. Here, we report that leukemia Jurkat cells selected after 3D growth conditions retain persistent nuclear changes even after being released from confinement. These altered cells showed aberrant nuclear wrinkling, visualized by the lamin B1 distribution and mediated by disrupted actin dynamics and protein kinase C (PKC)β signaling. Moreover, these cells presented changes in chromatin compaction, transcription, apoptosis, and in vivo dissemination. By combining biomechanical techniques and single-nucleus analysis, we have determined that these cells exhibit a distinct nuclear mechanical behavior and biophysical signature compared with control cells. Together, these findings demonstrate that 3D microenvironments alter leukemia cell biology by promoting persistent changes in chromatin organization, morphology, and mechanical response of the nucleus.

Keywords:  3D microenvironment; biophysics; cell-matrix interactions; extracellular matrix; mechanical adaptation; mechanobiology; mechanotransduction; nuclear deformability; tumor plasticity

DOI:  https://doi.org/10.1016/j.xcrp.2026.103116
Phys Chem Chem Phys. 2026 Apr 28.

Local-friction governs water mobility in hydrogels acting as extracellular mimics.

Monojit Das, Jayanta Mondal, Naglaa Atif Alhadi Rahma, Gourab Ghosh, Nivedita Pan, Lopamudra Roy, Ria Ghosh, Susmita Mondal, Muhammad Munir, Anjan Kumar Das, Niko Hildebrandt, Ranjan Das, Ranjit Biswas, Samir Kumar Pal.

The extracellular matrix (ECM) controls essential cellular processes, including migration, proliferation, and regeneration. Recent counterintuitive studies demonstrate improved cell motility in hyper-viscous settings, raising basic questions about the functionality of the extracellular matrix (ECM) despite the usual expectation that a uniform-viscous ECM is ideal for its function. In this study, we propose that "local friction or micro-viscosity" - rather than bulk viscosity - more accurately governs molecular dynamics within ECM-like environments. Building on our previous findings, in which nanoparticle-embedded chitosan hydrogels showed scar-free wound healing, we have investigated the water dynamic behaviour across varying viscosities using a methylcellulose solution (mimicking cell viscosity) and pH-dependent chitosan hydrogels. By employing dielectric relaxation and ultrafast solvation spectroscopy, we characterize distinct water populations, namely free water, loosely bound water (biological water), and structurally ordered water inside the ECM matrix, and highlight their independent contributions related to the micro-viscosity. Our results suggest that the relative abundance and dynamics of these water types are related to viscoelasticity, which underlie the exceptional therapeutic behaviour of ECM-mimetic materials, offering a new paradigm for understanding cellular microenvironments. This work advances the concept of "functional water dynamics" as a complementary mechanism in cell-matrix interaction models.

DOI: https://doi.org/10.1039/d6cp00469e
Sci Adv. 2026 May;12(18): eaec3773

Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.

Yuan Shen, Wang Xi, René-Marc Mège, Walter Kob, Benoit Ladoux.

Epithelial tissues maintain organ integrity while continuously remodeling during morphogenesis, repair, and disease. At high cell densities, these tissues often appear mechanically arrested in a disordered, solid-like state, raising the question of how they retain the ability to reorganize. Here, we show that, unlike thermal glasses, dense epithelial tissues do not exhibit caging behavior but instead behave as a complex fluid. Cells display subdiffusive creep together with Fickian yet non-Gaussian dynamics and compressed exponential relaxation, hallmarks of stress-driven fluidity. This fluidity arises from the tissue's structural and mechanical organization rather than from cell division or extrusion, which only transiently enhance local dynamics. Fast-moving cells organize into collective, anisotropic clusters whose spatial heterogeneity correlates with local structural entropy and soft vibrational modes. Together, these findings reveal a hidden fluidity in densely packed epithelia that supports mechanical stability while preserving the capacity for remodeling during development, wound healing, and early tumor invasion.

DOI: https://doi.org/10.1126/sciadv.aec3773
Acta Biomater. 2026 Apr 29. pii: S1742-7061(26)00276-X. [Epub ahead of print]

Co-evolving Biomaterials: Spatiotemporally Programmable Materials Steering Dynamic Macrophage State Transitions.

Minhao Li, Ziyi Feng, Song Zeng, Meiqi Jin, Shiming Chen, Huazhe Yang, Ying Huang.

  Macrophages are highly plastic innate immune cells that integrate metabolic, inflammatory, and stromal cues to coordinate immune responses and tissue repair. In biomaterial-associated microenvironments, these signals act together over time and shape macrophage trajectories through ongoing interactions with surrounding tissues. Most currently available immunomodulatory biomaterials are understood as static, stimulus-responsive, or partially adaptive systems, rather than systems that fully operate in a closed-loop manner. Against this background, this review organizes macrophage-material interactions within a stage responsive framework. We relate the biological determinants of macrophage state transitions, including immunometabolism, regulated cell death and efferocytosis, and epigenetic remodeling, to three key dimensions of biomaterial design: timing, spatial control, and dose or sequence. In this review, co-evolving is used to describe a reciprocal, time-dependent process in which biomaterials influence macrophage behavior, while changes in the local microenvironment driven by macrophages in turn affect material behavior in vivo and shape downstream tissue outcomes. On this basis, we distinguish static, stimulus-responsive, and feedback-informed forms of immunomodulation, and discuss how future biomaterials may move toward more genuinely feedback-controlled interactions. STATEMENT OF SIGNIFICANCE: This review reframes immunomodulatory biomaterials through macrophage state transitions rather than fixed polarization labels. It proposes a stage-responsive framework linking key drivers of macrophage behavior, including immunometabolism, regulated cell death and efferocytosis, epigenetic remodeling, and tissue-niche crosstalk, to three design dimensions: timing, spatial control, and dose or sequence. Current strategies are classified as static, stage-programmed, stimulus-responsive, or feedback-informed, clarifying what existing materials can achieve and where true adaptive control remains limited. By integrating evidence from repair and disease contexts, the review provides a practical basis for designing biomaterials that better match macrophage transition kinetics and move toward stage-aware immune engineering.

Keywords:  Drug delivery; Dynamic immunotherapy; Efferocytosis; Immunometabolism; Macrophage plasticity; Programmable biomaterials

DOI:  https://doi.org/10.1016/j.actbio.2026.04.055
bioRxiv. 2026 Apr 13. pii: 2026.04.09.717566. [Epub ahead of print]

Microenvironment optimization enables kidney organoid longevity with epithelial-endothelial joint basement membrane formation.

Sophie M Blackburn, Benjamin A Juliar, Arjun Sen, Mary C Regier, Benjamin S Freedman.

Kidney organoids degrade in long-term culture and lack joint basement membranes between epithelial and endothelial cells characteristic of renal tissue. Here we show that these limitations can be overcome in static cultures simply by optimizing the microenvironment. Supplementing standard media with tubular-enhancing factors (TEFs) dramatically improves organoid yield and longevity, while vascular-enhancing factors (VEFs) and replating increases endothelial cell yield and invasiveness. A transcriptomic and imaging atlas demonstrates maintenance of nephron structures for six months with increased metabolism, signaling, differentiation, and aging-related pathways. In addition to adherent cultures, these media also enable organoid differentiation and vascularization in suspension cultures and hydrogels. Remarkably, addition of TEFs and VEFs to organoids in suspension induces self-assembly of joint basement membranes between endothelial cells and podocytes or tubules, a major feature of renal tissue. Microenvironment optimization thus enables longitudinal stabilization and higher-order vascularization of kidney organoids, offering a diverse resource for long-term studies and tissue engineering applications.

DOI: https://doi.org/10.64898/2026.04.09.717566
Phys Rev Lett. 2026 Apr 17. 136(15): 158401

Universal Persistent Brownian Motions in Confluent Tissues.

Alessandro Rizzi, Sangwoo Kim.

Biological tissues are active materials whose nonequilibrium dynamics emerge from distinct cellular force-generating mechanisms. Using a two-dimensional active foam model, we compare the effects of traction forces and junctional tension fluctuations on confluent tissue dynamics. While these two modes of activity produce qualitatively different cell shapes, rearrangement statistics, and spatiotemporal correlations in fluid states, we find that the long-time cellular motion universally converges to persistent Brownian dynamics. This universal feature contrasts with the nonuniversal correlations between cell geometry, rearrangement rate, and fluidity, which depend sensitively on the underlying modes of active force. Our results demonstrate that persistent Brownian motion provides a minimal framework for describing tissue dynamics, while distinct active forces leave identifiable structural and dynamical signatures, thereby enabling inference of the dominant active force in fluid state tissues.

DOI: https://doi.org/10.1103/g6l8-wbt1