Cells in vivo are often subject to the challenge of spatial confinement from neighboring cells and extracellular matrix (ECM) that are usually adhesive and deformable. Here, we showed that confinement makes initially quiescent round cells on soft adhesive substrates spread and migrate, exhibiting a phenotype similar to that of cells on unconfined stiff substrates. Interestingly, the confinement-induced cell spreading and migration exist widely in many cell types, and depend on formins, cell contractility and endonuclear YAP-TEAD interaction. Finally, we demonstrated the nucleus is a mechanosensor independent of ECM rigidity, and its flattening alone is sufficient to trigger YAP nuclear translocation, assembly of focal adhesions and stress fibers, cell spreading and migration. Thus, our findings revealed a new inside-out mechanism through which the nucleus directly detects and responds to external mechanical confinement, and could have important implications for cell migration in crowded micro-environments during cancer metastasis, wound healing and embryonic development.

01 Jun 2025·STAR Protocols

Protocol for high-resolution optical mapping of ex vivo rat heart for electrophysiological studies

Article

Author: Tsai, Yuan Si ; Chang, Chu Ling ; Hu, Yu Feng ; Sung, Yen Ling

Cardiac optical mapping provides high-resolution spatiotemporal insights into cardiac electrophysiology. Here, we present a protocol for capturing electrical signals in rats using voltage-sensitive dyes and blebbistatin to inhibit muscle contractions. We describe steps for aortic cannulation, heart isolation, optical mapping, and detailed signal analysis. This staining strategy utilized in this protocol allows for precise signal recording while minimizing motion artifacts, thereby enhancing image quality on the cardiac surface. For complete details on the use and execution of this protocol, please refer to Hu et al.¹.

01 May 2025·Gastroenterology

In Obesity, Esophagogastric Junction Fat Impairs Esophageal Barrier Function and Dilates Intercellular Spaces via Hypoxia-Inducible Factor 2α

Article

Author: Ustaoglu, Ahsen ; Leeds, Steven ; Genta, Robert M ; Kale, Ishani ; Ekeanyanwu, Rebecca ; Nguyen, Anh D ; Davis, Daniel ; Spechler, Stuart Jon ; Wang, Xuan ; Ward, Marc ; Pan, Zui ; Zhang, Qiuyang ; Sifrim, Daniel ; Paris, Sheré ; Podgaetz, Eitan ; Chang, Yan ; Souza, Rhonda F ; Woodland, Philip J ; Zhang, Xi

BACKGROUND & AIMSDilated intercellular space in esophageal epithelium, a sign of impaired barrier function, is a characteristic finding of gastroesophageal reflux disease that is also found in obese patients without gastroesophageal reflux disease. We explored molecular mechanisms whereby adipose tissue products might impair esophageal barrier integrity.METHODSCultures of visceral fat obtained during foregut surgery from obese and nonobese patients were established. Monolayer and air-liquid interface cultures of human esophageal cells were grown with conditioned medium (CM) from fat cultures. RNA sequencing, enzyme-linked immunosorbent assay, western blot, immunostaining, histology, and analyses of barrier function were performed; inhibitors of hypoxia-inducible factor 2α (HIF-2α [PT2385]), caspase-1 (AC-YVAD-CHO), myosin light chain kinase (Dreverse PIK), and myosin light chain phosphatase (permeant inhibitor of phosphatase 250) were applied; blebbistatin was used to disrupt actin-myosin interactions; N-acetylcysteine was used to scavenge reactive oxygen species.RESULTSCM from esophagogastric junction fat of obese patients caused dilated intercellular space with impaired barrier function in esophageal air-liquid interface cultures; these effects were blocked by PT2385. CM from esophagogastric junction fat of obese patients induced reactive oxygen species production that activated HIF-2α in esophageal cells. RNA-sequencing analyses linked CM from esophagogastric junction fat of obese patient-induced HIF-2α increases with innate immune response pathways. Cross-talk between HIF-2α and caspase-1 in esophageal cells led to interleukin 1β secretion, and interleukin 1β/interleukin 1 receptor 1 signaling caused dilated intercellular space with impaired esophageal barrier function via actin-myosin interactions induced by myosin light chain phosphorylation.CONCLUSIONSWe have elucidated molecular mechanisms whereby visceral fat of obese patients can impair esophageal barrier integrity by secreting substances that generate reactive oxygen species, which activate HIF-2α in esophageal epithelial cells. These mechanisms could render the esophagus of obese individuals vulnerable to damage from acid and other noxious agents.

100 Deals associated with Blebbistatin

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Indication	Highest Phase	Country/Location	Organization	Date
Colitis	Preclinical	China	Tsinghua University	13 May 2015

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