bims-ecemfi 2026-09-06 papers

Sci Adv. 2026 Sep 04. 12(36): eaee3256

Mechanical cues of an interpenetrating polysaccharide matrix regulate self-assembly of collagen fibers.

Fatemeh Tavakoli Joorabi, Nicholas J Derr, Zecheng Li, Bryan A Nerger, Chris H Rycroft, David J Mooney, Kyle H Vining.

Collagen molecules self-assemble into supramolecular fibers within a molecularly crowded, polysaccharide-rich extracellular matrix (ECM) that has fluid-like, viscoelastic properties. Here, we determine that the viscoelasticity of alginate networks regulates the assembly of type I collagen fibers. The viscoelasticity and shear moduli of the alginate network were tuned by the polymer weight percentage and degree of cooperative ionic and covalent norbornene-tetrazine cross-linking. Stepwise shear strain applied to covalently cross-linked hydrogels generated higher stress than in ionic hydrogels. Hydrogels with reduced viscoelasticity also showed reduced water permeability. Second-harmonic generation confocal imaging revealed that decreasing viscoelasticity significantly suppressed collagen fiber self-assembly. Simulations demonstrated mechanical coupling between the hydrogel network and the aggregate size of collagen molecules, which was consistent with experimental results showing impaired rate and magnitude of self-assembly in covalently cross-linked networks. These results provide a framework for understanding how ECM mechanical properties can influence the assembly and organization of fibrillar macromolecules.

DOI: https://doi.org/10.1126/sciadv.aee3256

Acta Biomater. 2026 Sep 03. pii: S1742-7061(26)00591-X. [Epub ahead of print]

Transient Calcium Signaling Reprograms YAP Mechanosensitivity through Actin Remodeling.

Julian M Jimenez, Badri Narayanan Narasimhan, Zihou Ye, Kun-Che Peng, Stephanie I Fraley.

YAP is a central regulator of cell fate, proliferation, and tissue homeostasis that integrates physical cues from the extracellular matrix (ECM). While stiff environments canonically drive YAP nuclear localization and soft environments promote cytoplasmic sequestration, the logic by which cells integrate mechanical inputs with transient biochemical signals remains poorly defined. Here, we examine how intracellular calcium transients interact with substrate compliance to regulate YAP dynamics and transcriptional outputs across epithelial, myoblast, and fibroblast lineages. Using collagen-coated polyacrylamide hydrogels with tunable mechanics, we show that substrate compliance shapes the kinetics of calcium signaling, calcium-mediated actin remodeling, and YAP nuclear shuttling. We demonstrate that calcium signaling can transiently relax baseline mechanical constraints on YAP activity, triggering nuclear translocation and transcriptional activation even on compliant or non-adhesive substrates where YAP is classically suppressed. We identify substrate compliance as a biophysical regulator that filters the transduction of calcium transients into gene-specific programs. Targets such as CYR61 are induced across all mechanical contexts tested, whereas targets like CTGF and AREG require permissive mechanical conditions. These results suggest a preliminary model in which the mechanical state of the cell tunes the activation barrier for YAP-dependent transcription, enabling context-dependent responses to universal biochemical triggers. We show that destabilizing the F-actin cytoskeleton by promoting depolymerization or sequestering actin monomers results in attenuation of the calcium-mediated YAP activity, while stabilizing F-actin results in amplification YAP activity in response to calcium stimulation. This work reveals a fundamental mechanism by which transient signals integrate with matrix mechanics to produce distinct YAP-dependent outcomes, suggesting new strategies for controlling cell fate in regenerative medicine and engineered tissues. STATEMENT OF SIGNIFICANCE: Although YAP regulation by steady-state mechanical cues is well established, how these cues interact with dynamic biochemical signals such as calcium transients to control gene-specific transcription remains unclear. We show that intracellular calcium transients act as rapid, tunable inputs that promote YAP nuclear localization and target gene expression, even on soft substrates that normally suppress YAP activity. Low-threshold gene targets are activated broadly, whereas high-threshold targets require stiffer environments, positioning substrate mechanics as a biophysical gate that shapes the magnitude, kinetics, and gene specificity of calcium-mediated YAP responses. These findings provide insights into how cells integrate transient calcium signals with steady-state matrix mechanics to regulate proliferation, differentiation, and tissue behavior, and provide a framework for guiding cell fate in engineered tissues, organoids, and regenerative medicine.

Keywords: Calcium dynamics; YAP/TAZ signaling; actin cytoskeleton; mechanotransduction; substrate stiffness

DOI: https://doi.org/10.1016/j.actbio.2026.09.002

ACS Biomater Sci Eng. 2026 Sep 04.

Biomimetic Hydrogels with Nucleus Pulposus-like Viscoelasticity and ECM Peptides for Discogenic Differentiation of Stem Cells.

Yin Liu, Yixun Cheng, Evan Johnston, Shuaibing Jiang, Hosni Cherif, David Juncker, Nicole Y K Li-Jessen, Lisbet Haglund, Jianyu Li.

Intervertebral disc (IVD) degeneration is a leading cause of low back pain (LBP), primarily originating in the nucleus pulposus (NP). Regenerative strategies combining mesenchymal stem cells (MSCs) with biomaterials offer great potential for NP repair by replenishing cells and restoring extracellular matrix (ECM). However, key translational challenges remain, including limited stem cell differentiation, poor cell survival in the harsh degenerative niche, and insufficient biomaterial support. While matrix viscoelasticity has been shown to influence adipose-derived stem cell (ASC) discogenic differentiation, its interplay with cell-adhesive ligands for IVD regeneration remains unclear. Moreover, most current hydrogels fail to replicate the ultrafast stress relaxation properties of native non-degenerative human NP tissue. Here, we developed viscoelastic ECM peptide-functionalized hydrogels (VEPH), specifically designed to mimic healthy human NP biomechanics and promote ASC differentiation for NP regeneration. We biochemically conjugated NP ECM-derived adhesive peptides (IKVAV, hA5G26, CHAD) through maleimide-thiol click chemistry, achieving hydrogels with significantly faster stress relaxation (∼25 s) compared to conventional viscoelastic alginate hydrogels (>100 s). Our results demonstrated that VEPH supported >95% ASC viability and robust metabolic activity over 21 days in 3D culture. Notably, the IKVAV-functionalized hydrogel significantly enhanced ASC cell-matrix interactions, upregulated NP marker expression (KRT18, HIF-1α, ITGA3, and CD24), and promoted type-II collagen secretion, indicating an NP-committed cell fate. Our findings highlight the synergistic roles of matrix viscoelasticity and NP-specific biochemical cues in directing ASC discogenic differentiation and advancing novel biomaterial design for IVD regeneration.

Keywords: cell-adhesive peptides; cell-matrix interaction; hydrogels; intervertebral disc regeneration; stem cells

DOI: https://doi.org/10.1021/acsbiomaterials.5c02074

Methods Mol Biol. 2026 ;3022 179-196

Triple Helical-Peptides: Collagen-Mimicking Tools for Tissue Engineering.

Audrey Ziverec, Jean-Daniel Malcor.

Reproducing the biological cues naturally provided by collagen is a promising yet challenging approach to influence cell behavior in the field of tissue engineering. To mimic collagen, biomimetic peptides that self-assemble into the characteristic triple helix structure of collagen have been functionalized to biomaterials designed for tissue repair. These triple-helical peptides (THPs) contain recognition motifs for collagen-binding proteins (receptors expressed on the cell surface or secreted proteins), thus replicating the collagen interactions occurring in native tissues and triggering specific cellular responses. Here, we describe how THPs are synthesized, characterized, and covalently grafted into hydrogels commonly used in tissue engineering through two different approaches: maleimide conjugation and coupling using carbodiimides. This approach has led to significant improvements in cell adhesion, differentiation, function, and extracellular matrix deposition in biomaterials manufactured for regenerative medicine applications.

Keywords: Biomaterials functionalization; Biomimetic peptides; Cell/collagen interactions; Collagen-binding receptors; Tissue engineering; Triple-helical peptides

DOI: https://doi.org/10.1007/978-1-0716-5194-0_11