bims-ecemfi 2025-04-27 papers

Acta Biomater. 2025 Apr 18. pii: S1742-7061(25)00288-0. [Epub ahead of print]

Hydrogels with multiple RGD presentations increase cell adhesion and spreading.

Abolfazl Salehi Moghaddam, Katelyn Dunne, Wendy Breyer, Yingjie Wu, E Thomas Pashuck.

A key challenge in hydrogel design for cell culture is replicating the cell-matrix interactions found in tissues. Cells use integrins to bind their local matrix and form adhesions in which integrins dynamically move on the cell membrane while applying significant forces to the local matrix. Identifying important biomaterial features for these interactions is challenging because it is difficult to independently adjust variables such as matrix stiffness, stress relaxation, the mobility of adhesion ligands, and the ability of these ligands to support cellular forces. In this work, we designed a hydrogel platform consisting of interpenetrating polymer networks of covalently crosslinked poly(ethylene glycol) (PEG) and self-assembled peptide amphiphiles (PA). We can tune the viscoelasticity of the hydrogel by modulating the composition of both networks. Ligand mobility can be adjusted independently of the matrix mechanical properties by attaching the arginine-glycine-aspartic acid (RGD) cell adhesion ligand to either the covalent PEG network, the dynamic PA network, or both networks at once. We find that endothelial cell adhesion formation and spreading is maximized in soft gels in which adhesion ligands are present on both the covalent and non-covalent networks. The dynamic nature of adhesion domains, coupled with their ability to exert substantial forces on the matrix, suggests that having different presentations of RGD ligands which are either mobile or capable of withstanding significant forces is needed to mimic different aspects of complex cell-matrix adhesions. These results will contribute to the design of hydrogels that better recapitulate physiological cell-matrix interactions. STATEMENT OF SIGNIFICANCE: Creating artificial environments that accurately mimic how cells interact with their surrounding matrix in natural tissues remains a fundamental challenge in biomaterials science. This study introduces a dual-network hydrogel platform that independently controls mechanical properties and adhesion ligand mobility by combining stable and dynamic polymer networks. A significant body of work has shown that matrix viscoelasticity and adhesion ligand mobility are important for cell adhesion and spreading. Our work builds on this by showing that endothelial cells function optimally when they can simultaneously engage with both mobile adhesion sites and force-resistant anchoring points, independent of matrix viscoelasticity. These insights will guide the design of more physiologically relevant hydrogels for tissue engineering applications and disease modeling.

Keywords: Cell adhesion; ECM; biomaterials; hydrogel

DOI: https://doi.org/10.1016/j.actbio.2025.04.037

Am J Physiol Cell Physiol. 2025 Apr 24.

Mechano-metabolism: Recent Findings on the Intersection of Cell Adhesion, Cell Migration, and Metabolism.

Emily D Fabiano, Jenna M Poole, Cynthia A Reinhart-King.

Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.

Keywords: Extracellular Matrix; Focal Adhesions; Integrins; Metabolism; Migration

DOI: https://doi.org/10.1152/ajpcell.00892.2024

Nat Commun. 2025 Apr 23. 16(1): 3811

Frictiotaxis underlies focal adhesion-independent durotaxis.

Adam Shellard, Kai Weißenbruch, Peter A E Hampshire, Namid R Stillman, Christina L Dix, Richard Thorogate, Albane Imbert, Guillaume Charras, Ricard Alert, Roberto Mayor.

Cells move directionally along gradients of substrate stiffness - a process called durotaxis. In the situations studied so far, durotaxis relies on cell-substrate focal adhesions to sense stiffness and transmit forces that drive directed motion. However, whether and how durotaxis can take place in the absence of focal adhesions remains unclear. Here, we show that confined cells can perform durotaxis despite lacking focal adhesions. This durotactic migration depends on an asymmetric myosin distribution and actomyosin retrograde flow. We propose that the mechanism of this focal adhesion-independent durotaxis is that stiffer substrates offer higher friction. We put forward a physical model that predicts that non-adherent cells polarise and migrate towards regions of higher friction - a process that we call frictiotaxis. We demonstrate frictiotaxis in experiments by showing that cells migrate up a friction gradient even when stiffness is uniform. Our results broaden the potential of durotaxis to guide any cell that contacts a substrate, and they reveal a mode of directed migration based on friction. These findings have implications for cell migration during development, immune response and cancer progression, which usually takes place in confined environments that favour adhesion-independent amoeboid migration.

DOI: https://doi.org/10.1038/s41467-025-58912-1

Acta Biomater. 2025 Apr 22. pii: S1742-7061(25)00147-3. [Epub ahead of print]

Macromolecular crowding-based biofabrication utilizing unmodified extracellular matrix bioinks.

Seyma Nayir Jordan, Xianmu Li, Alejandro Rossello-Martinez, Zixie Liang, Xiangyu Gong, Hugh Xiao, Michael Mak.

The extracellular matrix (ECM) is the body's natural cell-scaffolding material, and its structure and content are often imitated for applications in tissue engineering and regenerative medicine to promote biocompatibility. One approach toward biomimicking natural ECMs is to utilize decellularized extracellular matrices (dECMs), which involve removing cellular components from native tissues to preserve natural components. Solubilizing dECMs to produce bioinks therefore holds high potential for 3D biofabrication and bioprinting of bioactive scaffolds and tissues. However, solubilized ECMs have low printability owing to their slow gelation times, which necessitates additional artificial modifications (e.g. crosslinking) to facilitate biofabrication applications. In this study, we demonstrate a method utilizing macromolecular crowding (MMC) to confer printability, via rapid gelation, to solubilized unmodified dECMs from a variety of tissue types - heart, muscle, liver, small intestine, and large intestine. We show cell spreading and contractility in cell-laden dECM gels fabricated through MMC, highlighting biocompatibility with our method. Finally, we demonstrate successful extrusion bioprinting of complex 3D structures using unmodified dECM solutions as bioinks, revealing the potential of our MMC-based fabrication method for layer-by-layer building of user-designed bioinks made from wide-ranging fully physiological tissues. STATEMENT OF SIGNIFICANCE: Decellularized extracellular matrix (dECM) bioinks are among the most promising materials for simulating native organ-specific extracellular matrices. However, standard methods for gelling solubilized dECMs are slow and result in poor mechanical and structural characteristics, reducing printability. dECM solutions are typically supplemented with additional crosslinkers for the formation of robust hydrogels. The crosslinkers may be toxic to cells, and they often need UV light for activation. Here, we present a method that allows wide-ranging dECMs to be easily patternable and 3D printable in their unmodified forms. We demonstrate cell spreading and contractility in cell-laden unmodified dECM gels created demonstrating cell viability and bioactivity. We also demonstrated successful extrusion bioprinting of complex 3D structures utilizing low concentration unmodified dECM bioinks and normal healthy lung fibroblasts.

Keywords: Bioprinting; Decellularized extracellular matrix; Macromolecular crowding; PEG

DOI: https://doi.org/10.1016/j.actbio.2025.02.052

Cell Biomater. 2025 Apr 22. pii: 100046. [Epub ahead of print]1(3):

Engineered epithelial curvature controls Paneth cell localization in intestinal organoids.

F Max Yavitt, Alex Khang, Kaustav Bera, Delaney L McNally, Michael R Blatchley, Aaron P Gallagher, Ophir D Klein, David Castillo-Azofeifa, Peter J Dempsey, Kristi S Anseth.

The cellular organization within organoid models is important to regulate tissue specific function, yet few engineering approaches can control or direct cellular organization. Here, a photodegradable hydrogel is used to create softened regions that direct crypt formation within intestinal organoids, where the dimensions of the photosoftened regions generate predictable and defined crypt architectures. Guided by in vivo metrics of crypt morphology, this photopatterning method is used to control the width and length of in vitro organoid crypts, which ultimately defines the curvature of the epithelium. By tracking expression of differentiated Paneth cell markers in real-time, we show that epithelial curvature directs the localization of Paneth cells within engineered crypts, providing user-directed control over organoid functionality. We anticipate that our improved control over organoid architecture and thus Paneth cell localization will lead to more consistent in vitro organoid models for both mechanistic studies and translational applications.

DOI: https://doi.org/10.1016/j.celbio.2025.100046