Assessment of air pollutant O3 pulmonary exposure using a bronchus-on-chip model coupling with atmospheric simulation chamber

Journal of Hazardous Materials, Journal Year: 2025, Volume and Issue: 486, P. 137106 - 137106

Published: Jan. 5, 2025

Language: Английский

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Engineering Organ-on-a-Chip Systems for Vascular Diseases

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2023, Volume and Issue: 43(12), P. 2241 - 2255

Published: Oct. 12, 2023

Vascular diseases, such as atherosclerosis and thrombosis, are major causes of morbidity mortality worldwide. Traditional in vitro models for studying vascular diseases have limitations, they do not fully recapitulate the complexity vivo microenvironment. Organ-on-a-chip systems emerged a promising approach modeling by incorporating multiple cell types, mechanical biochemical cues, fluid flow microscale platform. This review provides an overview recent advancements engineering organ-on-a-chip including use microfluidic channels, ECM (extracellular matrix) scaffolds, patient-specific cells. We also discuss limitations future perspectives diseases.

Language: Английский

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Dysfunctional mechanotransduction regulates the progression of PIK3CA-driven vascular malformations

APL Bioengineering, Journal Year: 2025, Volume and Issue: 9(1)

Published: Feb. 5, 2025

Somatic activating mutations in PIK3CA are common drivers of vascular and lymphatic malformations. Despite biophysical signatures tissues susceptible to lesion formation, including compliant extracellular matrix low rates perfusion, lesions vary clinical presentation from localized cystic dilatation diffuse infiltrative dysplasia. The mechanisms driving the differences disease severity variability role microenvironment potentiating progression poorly understood. Here, we investigate hemodynamic forces pathophysiology malformations (VMs), identify shear stress defective endothelial cell mechanotransduction as key regulators progression. We found that constitutive PI3K activation impaired flow-mediated alignment barrier function. show sensing PIK3CAE542K cells is associated with reduced myosin light chain phosphorylation, junctional instability, recruitment vinculin cell–cell junctions. Using three dimensional (3D) microfluidic models vasculature, demonstrate microvessels apply traction unaffected by flow interruption. further draining transmural resulted increased sprouting invasion responses microvessels. Mechanistically, decreased cellular nuclear elasticity resulting tensional homeostasis which may underlie dilation, tissue hyperplasia, hypersprouting PIK3CA-driven venous Together, these results suggest mechanics, mechanotransduction, maladaptive contribute development

Language: Английский

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Embryological cellular origins and hypoxia-mediated mechanisms in PIK3CA-driven refractory vascular malformations

EMBO Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Congenital vascular malformations, affecting 0.5% of the population, often occur in head and neck, complicating treatment due to critical functions these regions. Our previous research identified distinct developmental origins for blood lymphatic vessels areas, tracing them cardiopharyngeal mesoderm (CPM), which contributes development head, cardiovascular system both mouse human embryos. In this study, we investigated pathogenesis malformations by expressing Pik3ca H1047R CPM. Mice CPM developed abnormalities restricted neck. Single-cell RNA sequencing revealed that upregulates Vegf-a expression endothelial cells through HIF-mediated hypoxia signaling. Human samples supported findings, showing elevated HIF-1α VEGF-A malformed vessels. Notably, inhibition model significantly reduced abnormal vasculature. These results highlight role embryonic hypoxia-driven mechanisms providing a foundation therapies targeting difficult-to-treat conditions.

Language: Английский

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Human Cell‐Derived Matrix Composite Hydrogels with Diverse Composition for Use in Vasculature‐on‐chip Models

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(19)

Published: March 23, 2024

Microphysiological and organ-on-chip platforms seek to address critical gaps in human disease models drug development that underlie poor rates of clinical success for novel interventions. While the fabrication technology model cells used synthesize organs-on-chip have advanced considerably, most rely on animal-derived or synthetic extracellular matrix as a cell substrate, limiting mimicry physiology precluding use modeling diseases which dynamics play role pathogenesis. Here, cell-derived (hCDM) composite hydrogels 3D microphysiologic vasculature is reported. hCDM are derived from donor fibroblasts maintain complex milieu basement membrane, proteoglycans, nonfibrillar components. The 2D culture substrates demonstrated, patterned form engineered microvessels. Interestingly, enriched proteins associated with vascular morphogenesis determined by mass spectrometry, functional analysis demonstrates proangiogenic signatures endothelial cultured these hydrogels. In conclusion, this study suggests donor-derived could technical serve promote vascularization.

Language: Английский

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Vascular microphysiological systems

Current Opinion in Hematology, Journal Year: 2024, Volume and Issue: 31(3), P. 155 - 161

Published: Jan. 18, 2024

Purpose of review This summarizes innovations in vascular microphysiological systems (MPS) and discusses the themes that have emerged from recent works. Recent findings Vascular MPS are increasing complexity ability to replicate tissue. Many labs use study transport phenomena such as analyzing endothelial barrier function. Beyond permeability, these models also being used for pharmacological studies, including drug distribution toxicity modeling. In part, studies made possible due exciting advances organ-specific models. Inflammatory processes been modeled by incorporating immune cells, with explore both cell migration Finally, methods generating flourish, many researchers turned their attention flow more closely recapitulate vivo conditions. Summary These represent different types tissue disease states. Some devices relatively simple geometry few types, while others complex, multicompartmental microfluidics integrate several origins. 3D enable us observe model evolution real time perform a plethora functional assays not using traditional culture methods.

Language: Английский

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RAC1 inhibition ameliorates IBSP-induced bone metastasis in lung adenocarcinoma

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114528 - 114528

Published: July 24, 2024

Macrophage-to-osteoclast differentiation (osteoclastogenesis) plays an essential role in tumor osteolytic bone metastasis (BM), while its specific mechanisms remain largely uncertain lung adenocarcinoma BM. In this study, we demonstrate that integrin-binding sialoprotein (IBSP), which is highly expressed the cancer cells from metastatic and primary lesions of patients with adenocarcinoma, can facilitate BM directly promote macrophage-to-osteoclast independent RANKL/M-CSF. vivo results further suggest specifically relies on IBSP-induced differentiation. Mechanistically, IBSP regulates Rac family small GTPase 1 (Rac1)-NFAT signaling pathway mediates forward shift differentiation, thereby leading to early osteolysis. Moreover, inhibition Rac1 by EHT-1864 or azathioprine mice models remarkably alleviate cancer. Overall, our study suggests tumor-secreted promotes inducing potential as diagnostic maker for BM, be therapeutic target IBSP-promoted

Language: Английский

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A facile fluid pressure system reveals differential cellular response to interstitial pressure gradients and flow

Biomicrofluidics, Journal Year: 2023, Volume and Issue: 17(5)

Published: Sept. 1, 2023

Interstitial fluid pressure gradients and interstitial flow have been shown to drive morphogenic processes that shape tissues influence progression of diseases including cancer. The advent porous media microfluidic approaches has enabled investigation the cellular response flow, but questions remain as critical biophysical biochemical signals imparted by resulting on resident cells extracellular matrix (ECM). Here, we introduce a low-cost method maintain physiological pressures is built from commonly accessible laboratory equipment, laser pointer, camera, Arduino board, commercially available linear actuator. We demonstrate when system connected device containing 3D hydrogel, physiologic maintained with sub-Pascal resolution basic feedback control directed using an Arduino, constant gradient can be even remodel degrade ECM hydrogel over time. Using this model, characterized breast cancer cell growth changes fibril structure porosity in or flow. observe increased collagen bundling formation structures vicinity compared Collectively, these results further define driver key pathogenic responses cells, systems methods developed here will allow for future mechanistic work investigating mechanotransduction flows.

Language: Английский

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PI3K-C2β limits mTORC1 signaling and angiogenic growth

Science Signaling, Journal Year: 2023, Volume and Issue: 16(813)

Published: Nov. 28, 2023

Phosphoinositide 3-kinases (PI3Ks) phosphorylate intracellular inositol lipids to regulate signaling and vesicular trafficking. Mammals have eight PI3K isoforms, of which class I PI3Kα II PI3K-C2α are essential for vascular development. The PI3K-C2β is also abundant in endothelial cells. Using vivo vitro approaches, we found that was a critical regulator blood vessel growth by restricting mTORC1 signaling. Mice expressing kinase-inactive form displayed enlarged vessels without corresponding changes cell proliferation or migration. Instead, inactivation resulted an increase the size cells, particularly sprouting zone angiogenesis. Mechanistically, showed aberrantly large mutant cells caused activation, sustained these Consistently, pharmacological inhibition with rapamycin normalized morphogenesis mice. Together, results identify as crucial determinant illustrate importance regulation during angiogenic growth.

Language: Английский

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Vascular organs-on-chip made with patient-derived endothelial cells: technologies to transform drug discovery and disease modeling

Expert Opinion on Drug Discovery, Journal Year: 2023, Volume and Issue: 19(3), P. 339 - 351

Published: Dec. 20, 2023

Introduction Vascular diseases impart a tremendous burden on healthcare systems in the United States and across world. Efforts to improve therapeutic interventions are hindered by limitations of current experimental models. The integration patient-derived cells with organ-on-chip (OoC) technology is promising avenue for preclinical drug screening that improves upon traditional cell culture animal

Language: Английский

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