bims-ecemfi 2026-04-19 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–04–19
nine papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Mechanical memory primes cells for confined migration.
Guidance of cellular nematic elastomers into shape-programmable living surfaces.
Mechanical confinement balances ECM remodeling in chondrocytes via MAPK and Hedgehog signaling.
Partial EMT Drives Persistent Collective Migration via Collision Guidance in Heterogeneous Populations.
Bottom-Up Programming of Cell States in Cancer Organoids with Defined Synthetic Adhesion Cues.
Time-dependent memory of hypoxia exposure influences tumor invasion dynamics.
Cardiac fibroblast anisotropy is determined by YAP-dependent cellular contractility and ECM production.
Programmable Steric Control of Collagen Peptide-to-Fiber Assembly.
Organized Randomness: How Hierarchical Coupling of an Excitable System and a Bistable Switch Shape Spontaneous Cell Migration.

Cell Rep. 2026 Apr 16. pii: S2211-1247(26)00345-1. [Epub ahead of print]45(4): 117267

Mechanical memory primes cells for confined migration.

Jia Wen Nicole Lee, Yeji Chang, Malhar S Chitnis, Yixuan Li, Xu Gao, Avery Rui Sun, Jin Zhu, Jennifer L Young, Andrew W Holle.

  When migratory cells move between stiffness niches in vivo, they encounter confined spaces imposed by extracellular matrix (ECM) networks. Cells from one niche possess mechanosensitive adaptations that influence their response to new environments, a concept known as mechanical memory. How this memory is acquired and how it influences migratory potential in confinement remain poorly understood. Here, we combine stiffness priming using polyacrylamide hydrogels with a confinement platform to screen memory across healthy and transformed cells. Using a dose-and-passage approach, we find that cells primed on soft substrates navigate confinement more efficiently. Bulk RNA sequencing identifies NFATC2 as a transcription factor mediating mechanical memory through genetic reprogramming. Inhibition of NFATC2 confirms that it is required for memory acquisition and enhanced confined migration. Highly invasive cancer cells fail to retain mechanically induced phenotypes following cue removal, suggesting differential adaptation strategies. These findings establish mechanical memory as a cell-intrinsic regulator of confined migration.

Keywords:  CP: cell biology; NFATC2; cell migration; confined migration; mechanical memory; mechanotransduction; substrate stiffness; transcriptional regulation

DOI:  https://doi.org/10.1016/j.celrep.2026.117267
Science. 2026 Apr 16. 392(6795): 317-323

Guidance of cellular nematic elastomers into shape-programmable living surfaces.

Pau Guillamat, Waleed Mirza, Pradeep K Bal, Manuel Gómez-González, Pere Roca-Cusachs, Marino Arroyo, Xavier Trepat.

Engineering living materials that autonomously morph into predetermined shapes holds potential for synthetic morphogenesis and soft robotics. Harnessing cellular tissues to self-organize and generate forces offers a promising route toward this goal. However, controlling tissue mechanics to direct morphogenesis remains challenging. We introduce a strategy to program tissue-shape transformations through nematic organization of cellular forces. By controlling nematic order and topological defects, we generate tissues programmed with specific stress fields. Using a theoretical framework coupling contractile nematics with thin-sheet mechanics, we show that nematically guided active stresses can drive morphogenesis through Gaussian morphing. Experimentally, detachment of nematic tissues triggers out-of-plane deformations, generating reproducible three-dimensional shapes. Integrating contractility and nematic patterning, our approach establishes a framework for designing shape-programmable living surfaces.

DOI: https://doi.org/10.1126/science.adz9174
Biomaterials. 2026 Mar 27. pii: S0142-9612(26)00195-X. [Epub ahead of print]333 124171

Mechanical confinement balances ECM remodeling in chondrocytes via MAPK and Hedgehog signaling.

Mu H Yuan, Suzette T Lust, Daniele Marciano, Julien E Gautrot, Cécile A Dreiss, Francesco Dell'Accio, Suzanne E Eldridge, Agamemnon E Grigoriadis, Chunling Tang, Eileen Gentleman.

  Mechanical cues from the extracellular matrix (ECM) are critical regulators of chondrocyte behavior and cartilage homeostasis. Mechanical confinement, determined by the stress relaxation properties of the surrounding matrix, can drive anabolic ECM production or catabolic activity. However, the intracellular signaling pathways linking confinement to ECM remodeling remain poorly defined. Here, alginate hydrogels with tunable stress relaxation properties were used to investigate how confinement regulates signaling and matrix production. Low-confinement, fast-relaxing matrices promoted ECM deposition, whereas high-confinement, slow-relaxing matrices increased inflammatory and catabolic gene expression. Kinase activity profiling identified mitogen-activated protein kinase (MAPK) signaling as a key pathway modulated by confinement, with subsequent activation of Hedgehog (Hh) signaling. Pharmacological activation of Hh signaling enhanced matrix deposition and restored chondrogenic morphology in low-confinement conditions. ECM formation negatively correlated with primary cilia length, and confinement-mediated changes in chondrocyte volume occurred even without primary cilia. These findings support a model in which confinement regulates matrix production via MAPK and Hh signaling to maintain homeostasis, with alterations in confinement, such as those in osteoarthritis or aging, linked to changes in chondrocyte phenotype. This work positions confinement as a central regulator of cartilage mechanobiology and provides design principles for viscoelastic biomaterials supporting balanced ECM remodeling.

Keywords:  Cartilage tissue engineering; ECM remodeling; Mechanical confinement; Primary cilium; Viscoelastic hydrogels

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124171
bioRxiv. 2026 Apr 09. pii: 2026.04.07.714519. [Epub ahead of print]

Partial EMT Drives Persistent Collective Migration via Collision Guidance in Heterogeneous Populations.

Hyuntae Jeong, Jiwon Kim, Jea-Yun Sim, Susan E Leggett, Ian Y Wong.

The epithelial-mesenchymal transition (EMT) alters cell-cell interactions to facilitate collective or individual migration during embryonic development, wound repair, or tumor invasion. Epithelial cells are typically cohesive and stationary while mesenchymal cells are individually dispersed and motile. Additional "partial" EMT states are thought to occur with distinct adhesive and migratory behaviors, but these functional phenotypes are poorly understood. Here, we show that cells treated with moderate TGF- β concentration exhibit collective migration that is fast and directionally persistent despite heterogeneity in epithelial, partial, and mesenchymal states. We find cells coordinate their motility by reorienting in similar directions after transient contacts, a distinct "collision guidance" mechanism that differs from epithelial arrest or mesenchymal repulsion. Moreover, partial EMT cells sustain collision guidance when interacting with epithelial or mesenchymal cells, which otherwise have increased tendency to repel. We corroborate these experimental observations with a computational model using self-propelled interacting particles that align their motion or repel upon contact. Finally, we show that partial EMT enables tissue monolayer fronts to overwhelm and displace monolayers of other cell types after collision. Overall, these results reveal that partial EMT promotes coherent and emergent behaviors that bridge from cell to tissue length scales, with potential implications for shaping epithelial tissue formation, regeneration, or disorganization.

DOI: https://doi.org/10.64898/2026.04.07.714519
Adv Mater. 2026 Apr 14. e17390

Bottom-Up Programming of Cell States in Cancer Organoids with Defined Synthetic Adhesion Cues.

Ali Nadernezhad, Verena J Kast, Dagmar Pette, Franziska Baenke, Daniel E Stange, Carsten Werner, Daniela Loessner.

  Despite advances in defined culture systems, current organoid models lack programmable control of transcriptomic states beyond fixed genetic constraints or broadly specific microenvironmental conditions. Here, a bottom-up biomaterial-based platform is introduced to program cell state changes in pancreatic cancer organoids by tuning minimal adhesion cues within a synthetic matrix. A Design of Experiments framework is used to systematically model the patient-specific transcriptome-wide impact of matrix-presented adhesion cues. Focusing on epithelial-mesenchymal transition (EMT) as a proof-of-concept cellular program, a multiobjective optimization approach is applied to identify patient-specific matrix compositions that enrich EMT-associated transcriptional programs. Organoids cultured in these optimized matrices exhibit transcriptomic signatures consistent with EMT enrichment and coordinated shift in EMT-associated regulatory signatures. Secretome profiling further reveals changes in cytokines previously linked to EMT-associated inflammatory, hypoxia, and TGF-β signaling. Together, these findings demonstrate that quantitative and targeted modulation of defined adhesion cues enables programmable control of transcriptomic states in pancreatic cancer organoids.

Keywords:  computational biomaterials design; organoid microenvironment engineering; patient‐derived cancer organoids; synthetic extracellular matrix; transcriptomic state programming

DOI:  https://doi.org/10.1002/adma.202517390
bioRxiv. 2026 Apr 09. pii: 2026.04.07.716866. [Epub ahead of print]

Time-dependent memory of hypoxia exposure influences tumor invasion dynamics.

Gopinath Sadhu, Paras Jain, Ritesh Kumar Meena, Jason Thomas George, Mohit Kumar Jolly.

Cancer cells in hypoxic environments often proliferate less but exhibit enhanced migration relative to their normoxic counterparts. Recent in vitro and in silico studies have characterized the role of hypoxic memory - the ability of cancer cells to retain their hypoxic phenotype even when reoxygenated - in tumor invasion. However, the observations have been limited either to exposing cancer cells to hypoxia for a fixed duration or by assuming a fixed-time persistence of the hypoxic state upon reoxygenation independent of the duration of hypoxia exposure. Thus, time-dependent cell-state changes during hypoxia and their impact on hypoxic memory remains unclear. Here, we first analyze transcriptomic data from breast cancer samples to show that the genes upregulated at transcriptional level and hypomethylated at epigenetic level are enriched in cell invasion, indicating hypoxic memory-driven process of tumor invasion. Next, we used a computational model to investigate how the spatial-temporal dynamics of oxygen levels in a tumor drive time-dependent changes in hypoxic memory and influence tumor invasion dynamics. Our simulation results show that such dynamic hypoxic memory can drive enhanced tumor invasion over a fixed hypoxic memory by a) enriching hypoxic cell density at the tumor front, b) reducing sensitivity of hypoxic cell state to fluctuations in oxygen supply, and c) enhancing effective diffusion of hypoxic cells. Our results highlight the crucial role of dynamic hypoxic memory in shaping tumor invasion dynamics, underscoring the need to elucidate its underlying mechanisms in future studies.

DOI: https://doi.org/10.64898/2026.04.07.716866
Biomaterials. 2026 Apr 07. pii: S0142-9612(26)00229-2. [Epub ahead of print]333 124205

Cardiac fibroblast anisotropy is determined by YAP-dependent cellular contractility and ECM production.

Daniel Pereira-Sousa, Pau Guillamat, Francesco Niro, Vladimír Vinarský, Soraia Fernandes, Marco Cassani, Stefania Pagliari, Xavier Trepat, Marco Rasponi, Jorge Oliver-De La Cruz, Giancarlo Forte.

  Cardiac fibroblasts (CFbs) determine the topological arrangement and the anisotropy of the heart tissue which maintains tissue integrity and function through the production and remodeling of the extracellular matrix (ECM). Under pathological conditions, CFbs can activate into myofibroblasts and promote maladaptive ECM remodeling that may lead to heart failure. Yes-Associated Protein (YAP) - a key player in cardiac fibrosis onset - has been implicated in CFb activation but its role in coordinating the supracellular organization of CFbs and in shaping the instructive properties of the ECM remains poorly understood. We addressed these questions by generating CFbs from wild-type (WT) and YAP knockout (KO) human embryonic stem cells. YAP depletion reduced the expression of cardiogenic markers and altered the transcriptomic profile of ECM- and contractility-related genes. We further demonstrated that YAP expression is required for CFbs monolayer alignment, and its absence resulted in reduced ECM deposition, decreased anisotropy, and diminished force generation. Pharmacological inhibition of cell contractility closely mirrored YAP KO phenotype, suggesting that YAP regulates both monolayer organization and ECM structure through its control over contractility. ECM cross-seeding experiments confirmed the role of ECM as a structural guide for cellular alignment. Moreover, cardiomyocytes cultured on KO CFb-derived ECM exhibited impaired sarcomere organization and altered calcium dynamics. Together, these findings demonstrate that YAP activity in CFbs governs the structural and functional properties of the ECM, influencing both fibroblast alignment and cardiomyocyte activity. Moreover, they underscore the critical role of YAP in maintaining the supracellular organization and mechanical integrity of cardiac tissue.

Keywords:  Cardiac fibroblasts; Cardiomyocyte function; Cell contractility; Extracellular matrix anisotropy; Nematic order; YAP

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124205
J Am Chem Soc. 2026 Apr 16.

Programmable Steric Control of Collagen Peptide-to-Fiber Assembly.

Pengfei Jin, David M Chenoweth.

Peptide-based collagen-mimetic materials have drawn growing interest as fibrillar collagen surrogates due to their accessibility and versatility. However, an efficient strategy for assembling collagen peptides into well-defined collagen filaments remains elusive, owing to the nonspecific intermolecular interactions in collagen triple-helix formation. Here, we develop a new strategy for designing peptides that form triple-helical collagen-mimicking filaments using a single-residue side-chain modification. By organizing the intermolecular steric interactions in a "bump-gap" design, the peptides self-assemble into interlocked, endlessly growing triple-helical filaments with exceptional specificity. The peptide filaments exhibit high aspect ratios with micrometer lengths and are capable of forming networked structures that build hydrogels. These collagen-mimicking hydrogels, triggered by pH-dependent self-assembly, demonstrate superior stiffness over natural collagen with remarkable shear-thinning properties.

DOI: https://doi.org/10.1021/jacs.6c00833
Cold Spring Harb Perspect Biol. 2026 Apr 13. pii: a041750. [Epub ahead of print]

Organized Randomness: How Hierarchical Coupling of an Excitable System and a Bistable Switch Shape Spontaneous Cell Migration.

Masahiro Ueda, Hiroaki Takagi, Satomi Matsuoka.

In various eukaryotic organisms, amoeboid cells undergoing spontaneous migration generate membrane protrusions and establish front-rear polarity in an autonomous manner through signal transduction networks that couple excitable Ras dynamics to downstream bistable modules. Recent genetic and live-cell imaging studies in Dictyostelium cells have identified Ras GTPase and the newly characterized guanine nucleotide exchange factor RasGEFX as core drivers of this excitability, amplifying stochastic basal Ras activity into discrete signaling patches and propagating waves. These excitatory events initiate pseudopod formation even in the absence of external guidance cues and engage the bistable PIP3-PTEN switch to stabilize cell polarity. The same Ras excitable network also drives constitutive macropinocytosis, revealing a shared mechanism for membrane protrusion and fluid uptake. This hierarchical excitable-bistable architecture, coupled with motile machinery, converts intrinsic molecular noise into structured, non-Brownian exploratory behavior, representing an adaptive strategy that enables cells to exploit stochasticity for navigation in complex natural environments.

DOI: https://doi.org/10.1101/cshperspect.a041750