bims-ecemfi 2025-06-22 papers

Proc Natl Acad Sci U S A. 2025 Jun 24. 122(25): e2309772122

Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices.

Kolade Adebowale, Cole Allan, Byunghang Ha, Aashrith Saraswathibhatla, Junqin Zhu, Dhiraj Indana, Medeea C Popescu, Sally Demirdjian, Hunter A Martinez, Alex Esclamado, Jin Yang, Michael C Bassik, Christian Franck, Paul L Bollyky, Ovijit Chaudhuri.

Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity impact the three-dimensional (3D) migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for 3D culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices.

Keywords: 3D migration; monocytes; stromal matrix; viscoelasticity

DOI: https://doi.org/10.1073/pnas.2309772122

Sci Adv. 2025 Jun 20. 11(25): eadt3352

Tuning collagen nonlinear mechanics with interpenetrating networks drives adaptive cellular phenotypes in three dimensions.

Marco A Enriquez Martinez, Zhao Wang, Yanina D Alvarez, Jade E O'Neill, Robert J Ju, Petri Turunen, Melanie D White, Jitendra Mata, Elliot P Gilbert, Jan Lauko, Alan E Rowan, Samantha J Stehbens.

In living tissues, collagen networks rarely exist alone because they are embedded within other biological matrices. When combined, collagen networks rigidify via synergistic mechanical interactions and stiffen only with higher mechanical loads. However, how cells respond to the nonlinear elasticity of collagen in hybrid networks remains largely unknown. Here, we demonstrate that when collagen rigidifies by the interpenetration of a second polymer, the amount of force that initially stiffens the network (onset of stiffening, σc) increases and is sufficient to stimulate an increase in intracellular tension. We investigated this effect by precisely controlling the nonlinear elasticity of collagen with the synthetic semiflexible polymer, polyisocyanopeptides. We find that small increases in σc induce a biphasic response in cell-matrix interactions, influencing how cells migrate, proliferate, and generate contractile force. Our results suggest that cells adaptively respond to changes in the nonlinear mechanics of collagen, which may be a mechanistic behavior used during tissue homeostasis or when collagen rigidifies during pathological conditions.

DOI: https://doi.org/10.1126/sciadv.adt3352

Sci Adv. 2025 Jun 20. 11(25): eadw0808

Why are soft collagenous tissues so tough?

Jingyuan Tang, Xi Chen, Fengkai Liu, Liangsong Zeng, Zhigang Suo, Jingda Tang.

Bovine pericardium is the tissue of choice for replacing heart valves of human patients in minimally invasive surgery. The tissue has an extraordinarily high toughness of ~100 kilojoules per square meter. Here, we investigate the origin of the toughness through mechanical tests and microscopic observations. In the tissue, crimped, long, strong collagen fibers are embedded in a soft matrix. As a crack grows in the matrix, the fibers decrimp, reorient, slip, and bridge the crack. These microscopic processes enable the fibers to transmit high tension over a long distance. Using two types of experiments, we measure the bridging traction as a function of crack separation, σ(δ). The peak traction is σ0 ~ 60 megapascals. The maximum separation is δ0 ~ 6 millimeters, two to four orders of magnitude higher than that of hard tissues. Both the high traction and large separation of the bovine pericardium contribute to its high toughness.

DOI: https://doi.org/10.1126/sciadv.adw0808

Nature. 2025 Jun 18.

Morphodynamics of human early brain organoid development.

Akanksha Jain, Gilles Gut, Fátima Sanchis-Calleja, Reto Tschannen, Zhisong He, Nicolas Luginbühl, Fides Zenk, Antonius Chrisnandy, Simon Streib, Christoph Harmel, Ryoko Okamoto, Malgorzata Santel, Makiko Seimiya, René Holtackers, Juliane K Rohland, Sophie Martina Johanna Jansen, Matthias P Lutolf, J Gray Camp, Barbara Treutlein.

Brain organoids enable the mechanistic study of human brain development and provide opportunities to explore self-organization in unconstrained developmental systems1-3. Here we establish long-term, live light-sheet microscopy on unguided brain organoids generated from fluorescently labelled human induced pluripotent stem cells, which enables tracking of tissue morphology, cell behaviours and subcellular features over weeks of organoid development4. We provide a novel dual-channel, multi-mosaic and multi-protein labelling strategy combined with a computational demultiplexing approach to enable simultaneous quantification of distinct subcellular features during organoid development. We track actin, tubulin, plasma membrane, nucleus and nuclear envelope dynamics, and quantify cell morphometric and alignment changes during tissue-state transitions including neuroepithelial induction, maturation, lumenization and brain regionalization. On the basis of imaging and single-cell transcriptome modalities, we find that lumenal expansion and cell morphotype composition within the developing neuroepithelium are associated with modulation of gene expression programs involving extracellular matrix pathway regulators and mechanosensing. We show that an extrinsically provided matrix enhances lumen expansion as well as telencephalon formation, and unguided organoids grown in the absence of an extrinsic matrix have altered morphologies with increased neural crest and caudalized tissue identity. Matrix-induced regional guidance and lumen morphogenesis are linked to the WNT and Hippo (YAP1) signalling pathways, including spatially restricted induction of the WNT ligand secretion mediator (WLS) that marks the earliest emergence of non-telencephalic brain regions. Together, our work provides an inroad into studying human brain morphodynamics and supports a view that matrix-linked mechanosensing dynamics have a central role during brain regionalization.

DOI: https://doi.org/10.1038/s41586-025-09151-3

Adv Sci (Weinh). 2025 Jun 19. e04778

Highly Oriented Bio-Mimetic Hydrogels by Calendering.

Zhanqi Liu, Yuqing Wang, Haidi Wu, Huamin Li, Longcheng Tang, Guo Wang, Daxin Zhang, Jianping Yin, Yinggang Miao, Yongqian Shi, Pingan Song, An Xie, Xuewu Huang, Wancheng Gu, Yiu Wing Mai, Jiefeng Gao.

Anisotropic hydrogels are promising candidates as load-bearing materials for tissue engineering, while huge challenges remain in exploring effective and scalable methods for the preparation of anisotropic hydrogels with simultaneous high tensile strength, large toughness, good fracture strain, excellent fatigue and swelling resistances. Inspired by the brick-and-mortar layered structure of nacre and the hierarchical fibril strucure of soft tissues (e.g., tendon and ligament), a facile organogel-assissted calendering strategy is reported to design anisotropic hydrogels with a highly oriented and dense fiber lamellar strucure. The synergy of shearing and annealing promotes macromolecular chain alignment and crystallinity along the calendering direction while forming a nacre-like lamellar morphology in the thickness direction. The tensile strength, elastic modulus, toughness and fracture energy of the anisotropic hydrogels can reach as high as 41.0 ± 6.4 MPa, 67.0 ± 5.1 MPa, 46.2 ± 3.3 MJ m-3, and 62.20 ± 8.55 kJ m-2, respectively. More importantly, the hydrogels show excellent crack growth and swelling resistances with the fatigue threshold increased to 2170 J m-2. This study provides a promising approach for fabrication of large-sized biomimetic anisotropic hydrogels with outstanding mechanical properties for biomedical and engineering applications.

Keywords: anisotropic hydrogels; calendering; fatigue resistance; mechanical properties

DOI: https://doi.org/10.1002/advs.202504778

Matrix Biol. 2025 Jun 12. pii: S0945-053X(25)00050-2. [Epub ahead of print]

Mechanical control of breast cancer malignancy by promotion of mevalonate pathway enzyme synthesis.

Sara Göransson, Helene Olofsson, Henrik J Johansson, Feifei Yan, Christos Vogiatzakis, Shuo Liang, Hermano Martins Bellato, Laia Masvidal, Inci Aksoylu, Johan Hartman, Glaucia N M Hajj, Ola Larsson, Janne Lehtiö, Staffan Strömblad.

In breast cancer, mechanotransduction from stiffened extracellular matrix (ECM) drives proliferation and invasion. Here, we use a model of matrix stiffening mimicking progression of breast ductal carcinoma in situ to invasive ductal carcinoma. Quantitative mass spectrometry identified enrichment of ECM-stiffness upregulated mevalonate pathway enzymes, indicating sterol/isoprenoid metabolism reprogramming. Consistently, the first committed mevalonate pathway enzyme, Hydroxymethylglutaryl-CoA Synthase (HMGCS1), was upregulated in human breast cancer specimens and spatially correlated with cross-linked ECM. ECM-stiffness promoted HMGCS1 protein synthesis without corresponding mRNA level alterations, indicating post-transcriptional regulation of mevalonate biosynthesis via microenvironmental mechanical cues to impose rapid metabolic alterations. Moreover, HMGCS1-RNAi blocked the stiffness-driven breast cancer proliferative and invasive phenotype. Mechanistically, mechanotransduction signaling, through integrin and Rac1 to promote HMGCS1 protein expression, drives the breast cancer malignant phenotype. Intriguingly, the Rac1-P29S cancer mutant promoted a malignant phenotype without stiff ECM in a mevalonate-dependent manner. In summary, we define a mechano-responsive pathway controlling mevalonate pathway enzyme synthesis that drives breast cancer malignant behaviors.

Keywords: Rac; cell signaling; cell-matrix adhesion; ductal carcinoma in situ (DCIS); mechanobiology; mechanotransduction; small GTPases

DOI: https://doi.org/10.1016/j.matbio.2025.05.005