Hyaluronic Acid Hydrogels with Phototunable Supramolecular Cross-Linking for Spatially Controlled Lymphatic Tube Formation

Fan, Fei; Su, Bo; Kolodychak, Alexander; Ekwueme, Ephraim; Alderfer, Laura; Saha, Sanjoy; Webber, Matthew J.; Hanjaya-Putra, Donny

doi:10.1021/acsami.3c12514

Cited by 2 publications

(1 citation statement)

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“…To investigate the central hypothesis of how a stiffening extracellular environment alters pHi, we used two tunable-stiffness hydrogel models to control ECM stiffness with high specificity and using two unique modes of mechanical modulation. To mimic the effects of ECM stiffness changes resulting from altered ECM protein crosslinking, we used a hyaluronic-acid (HA) gel system where variable crosslinking density tunes ECM stiffness independent of protein concentration and composition 21 , 22 . HA is a non-sulfated linear polysaccharide of (1-β-4)d-glucuronic acid and (1-β-3)N-acetyl-d-glucosamine, and is a ubiquitous component of the ECM 19 .…”

Section: Resultsmentioning

confidence: 99%

Intracellular pH dynamics respond to microenvironment stiffening and mediate vasculogenic mimicry through β-catenin

Lund,

Marchi,

Alderfer

et al. 2024

Preprint

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Dysregulated intracellular pH (pHi) dynamics and an altered tumor microenvironment have emerged as drivers of cancer cell phenotypes. However, the molecular integration between the physical properties of the microenvironment and dynamic intracellular signaling responses remains unclear. Here, we use two metastatic cell models, one breast and one lung, to assess pHi response to varying extracellular matrix (ECM) stiffness. To experimentally model ECM stiffening, we use two tunable-stiffness hydrogel systems: Matrigel and hyaluronic acid (HA) gels, which mimic the increased protein secretion and crosslinking associated with ECM stiffening. We find that single-cell pHi decreases with increased ECM stiffness in both hydrogel systems and both metastatic cell types. We also observed that stiff ECM promotes vasculogenic mimicry (VM), a phenotype associated with metastasis and resistance. Importantly, we show that decreased pHi is both a necessary and sufficient mediator of VM, as raising pHi on stiff ECM reduces VM phenotypes and lowering pHi on soft ECM drives VM. We characterize β-catenin as a pH-dependent molecular mediator of pH-dependent VM, where stiffness-driven changes in β-catenin abundance can be overridden by increased pHi. We uncover a dynamic relationship between matrix stiffness and pHi, thus suggesting pHi dynamics can override mechanosensitive cell responses to the extracellular microenvironment.

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Section: Resultsmentioning

confidence: 99%