Liang Hu

Mechanical signals contribute to tissue homeostasis and disease progression by regulating cell behavior and intercellular communication. Extracellular vesicles (EVs) can relay donor-cell responses to mechanical stimuli to recipient cells, linking the mechanical microenvironment to physiological and pathological changes. Drawing on 98 studies published between January 2015 and February 2026, this review examines the connections between mechanical stimulation, EV remodeling and biological outcomes. We outline the mechanisms linking cellular mechanosensing and mechanotransduction to EV biogenesis, release and molecular remodeling, alongside changes in EV abundance, size, cargo, and function. We then discuss how these changes shape EV activity under conditions of physiological homeostasis, adaptive stress and pathological loading. Mechanically remodeled EVs can support homeostasis and tissue repair or promote disease progression, depending on the stimulus characteristics and the environments of donor and recipient cells. Beyond their local and distant effects, EVs may also contribute to feedback regulation of mechanical responses. Such feedback may involve direct effects on donor cells or changes in the local microenvironment mediated by neighboring cells. These proposed mechanisms require further direct experimental support. By connecting mechanical inputs with EV remodeling and function, this Review offers a framework for understanding intercellular communication within the mechanical microenvironment. It also considers implications for optimizing therapeutic EV production and exploring interventions in disease.

Stem-cell-derived extracellular vesicles (EVs) that carry bioactive proteins and nucleic acids reflecting the parental cells offer a promising route for cell-free cardiac regenerative medicine. However, the origin, composition, and function of EVs derived from differentiating human induced pluripotent stem cells (iPSCs) during cardiomyocyte differentiation are largely unknown. We report a detailed, 4D label-free proteomic analysis of EVs at 17 consecutive time points and their parental cells at three crucial differentiation stages to investigate the origins and proteome dynamics of human iPSC-derived EVs along the temporal trajectory of cardiomyocyte differentiation. Our comprehensive proteomic profiling reveals dynamic oscillations in EV proteomes, reflecting alterations in protein expression in parental cells over the time course of the cardiomyocyte differentiation. Comparative proteomic analyses of EVs and their respective parental cells at three critical stages reveal that proteins associated with extracellular matrix organization and cell differentiation are preferentially sorted into EVs throughout differentiation, particularly at the postcardiac progenitor stage. However, proteins involved in gene expression and cellular metabolism are significantly retained in parental cells during differentiation, particularly at the precardiac progenitor stage. We investigated temporal proteomic changes between consecutive EVs, revealing regulatory proteomic dynamics during cardiomyocyte differentiation. Our study enhances our understanding of EV protein sorting during cardiomyocyte differentiation over time and the molecular mechanisms controlling each differentiation stage. It provides valuable insights for further studies exploring the functions of human iPSC-derived EVs isolated at different differentiation stages and their applications in advancing cell-free cardiac regeneration therapies.

Pupillary block in PACG impedes aqueous humor (AH) flow through the iris–lens channel (ILC), while existing models that simplify the ILC geometry fail to accurately capture this flow and its role in PACG pathophysiology. A computational model is developed to investigate AH flow in the anterior segment of the human eye, in which the ILC is represented as a porous medium with variable porosity to account for different ILC conditions. The ILC is modeled as an equivalent porous medium to represent effective flow resistance rather than a physiological porous structure. The governing flow and solid mechanics equations are solved to systematically examine the effects of pupillary block severity on AH flow, pressure distribution, iris deformation, and energy dissipation. The results demonstrate that ILC porosity plays a critical role in determining the severity of pupillary block and the extent of anterior chamber angle (ACA) closure. When the porosity decreases below 0.35, the posterior–anterior pressure difference increases sharply to 419.14 Pa, driving anterior iris displacement and subsequent contact with the trabecular meshwork, thereby inducing ACA closure and increasing flow resistance and energy dissipation. In contrast, for porosities above 0.35, iris deformation is reduced by up to 67%, the ACA remains open, and AH flows smoothly, indicating a significantly alleviated pupillary block condition. This study provides new insight into the role of the ILC in pupillary block and suggests a novel therapeutic strategy based on modulation of ILC porosity to improve AH dynamics in PACG.

Accurately predicting the temporal and spatial distribution of intraocular drugs to enhance anti-glaucoma treatment efficacy remains a significant challenge in clinical ophthalmology. Developing more precise numerical models of intraocular drug transport holds substantial clinical value. This study establishes a model of intraocular drug transport, which includes the trabecular meshwork (TM), collector channels (CC), and uveoscleral outflow pathway, and analyzes the parameters affecting aqueous humor (AH) outflow and the impact of the uveoscleral pathway on drug transport. Results indicate that the uveoscleral pathway influences AH outflow, with its porous media significantly impeding drug clearance, leading to drug accumulation in the anterior chamber and higher concentrations in the TM. A reduction in TM porosity or the number of CC hinders drug transport to varying extents, increasing peak drug concentration at TM targets by 11.27% and 12.8%, respectively. Furthermore, neglecting the uveoscleral pathway may result in an 10.93% underestimation of TM drug concentration. This study provides insight into the pathways involved in anti-glaucoma drug transport, contributing to the optimization of drug design for improved therapeutic outcomes.

Scalable approaches for enhancing therapeutic small extracellular vesicles (sEVs) production can facilitate the transition of sEVs from bench to bedside and beyond. Here, we present a user-friendly method to manipulate the extracellular mechanical microenvironment of umbilical cord-derived mesenchymal stem cells (MSCs), a promising cell type for generating sEVs with therapeutic benefits, to boost sEV secretion and regenerative bioactivity. The bioreactor system, called the programmable controlled rotating platform (PRP), is designed to apply normal stress on cell surface through centrifugal rotation culture. Experimental analyses suggested that the PRP can promote a 4-fold sEV secretion increase without affecting cell viability and sEV size when compared to the traditional static culture condition. More importantly, PRP-induced MSC-sEVs can significantly promote epithelial cell migration in vitro and accelerate corneal wound healing in a murine model, with suppressed inflammatory responses in wound bed tissue. Further mechanistic investigations revealed that this process involves the activation of cellular transcriptional signals implicated in sEV biogenesis. Concurrently, sEV cargo undergoes remodeling to enrich regenerative and immunoregulatory functions. These findings demonstrate the efficacy of our established platform in advancing sEV production and improving clinical performance, providing a novel sEV-based mechanism for ocular treatments, including corneal epithelialization and even retinal neural regeneration.

An implantable collamer lens (ICL) is a biocompatible artificial lens specifically designed to correct refractive errors in myopic patients with high precision and stability, but postoperative complications are observed after ICL implantation surgery. A novel ICL with drain channels is designed to improve the beneficial aqueous humor (AH) flow postoperatively and reduce the risk of visual impairment. This study analyzes the effects of conventional ICL, ICL with a central hole (Hole-ICL), and ICL with a drain channel (scICL) on AH flow. The impact of the geometric parameters of the drain channel in scICL on AH velocity and pupil flow rate is investigated. Additionally, a double-channel ICL (dcICL) is designed to analyze the impact of drain channel symmetry on AH flow. The results indicate the maximum velocities on the posterior chamber (PC) circle line are 2.24×10−6, 2.46×10−6, and 1.23×10−5 m/s for conventional ICL, Hole-ICL, and scICL in an up-facing eye, respectively. In both up-facing and horizontally facing eyes, the pupil flow rate in the scICL increase by 21% and 5.5%, respectively. The AH flow velocity reaches its maximum when the drain channel width is approximately 38% of the total scICL width and a concomitant proximity to the scICL thickness. When the width ratio and depth ratio of the dcICL are equal to zero (analogous to the scICL), the AH flow velocity and pupil flow rate reach their maximum. The scICL presented in this study improves the AH flow, reducing postoperative complications associated with ICL implantation and providing guidance for the clinical myopia treatment.

Discovering the secrets of diseases from tear extracellular vesicles (EVs) is well-recognized and appreciated. However, a precise understanding of the interaction network between EV populations and their biogenesis from our body requires more in-depth and systematic analysis. Here, we report the biological profiles of different-size tear EV subsets from healthy individuals and the origins of EV proteins. We have identified about 1800 proteins and revealed the preferential differences in the biogenesis among distinct subsets. We observe that eye-related proteins that maintain retinal homeostasis and regulate inflammation are preferentially enriched in medium-size EVs (100 to 200 nm) fractions. Using universal analysis in combination with the Human Protein Atlas consensus dataset, we found the genesis of tear EV proteins with 37 tissues and 79 cell types. The proteins related to retinal neuronal cells, glial cells, and blood and immune cells are selectively enriched among EV subsets. Our studies in heterogeneous tear EVs provide building blocks for future transformative precision molecular diagnostics and therapeutics.

Early diagnosis of diabetic kidney disease (DKD) has long been a complex problem. This study aimed to analyze the metabolomic characteristics of plasma extracellular vesicles (EVs) at different sta...