Substratum stiffness tunes membrane voltage in mammary epithelial cells

Silver, Brian B.; Zhang, Sherry X; Rabie, Emann; Nelson, Celeste M.

doi:10.1242/jcs.256313

Cited by 7 publications

(5 citation statements)

References 76 publications

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“…It is generally accepted that changes in cellular mechanical microenvironment play an essential role in cell behavior and progression of disease (D'Urso and Kurniawan, 2020; Silver et al, 2021). In the present study, we investigated the mechanism of renal fibrosis from the perspective of mechanical force.…”

Section: Discussionmentioning

confidence: 93%

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Wan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Renal fibrosis is the most common pathological manifestation of a wide variety of chronic kidney disease. Increased extracellular matrix (ECM) secretion and enhanced microenvironment stiffening aggravate the progression of renal fibrosis. However, the related mechanisms remain unclear. Here, we evaluated the mechanism by which ECM stiffness aggravates renal fibrosis. In the present study, renal mesangial cells (MCs) were cultured on polyacrylamide hydrogels with different stiffness accurately detected by atomic force microscope (AFM), simulating the in vivo growth microenvironment of MCs in normal kidney and renal fibrosis. A series of in vitro knockdown and activation experiments were performed to establish the signaling pathway responsible for mechanics-induced MCs activation. In addition, an animal model of renal fibrosis was established in mice induced by unilateral ureteral obstruction (UUO). Lentiviral particles containing short hairpin RNA (sh RNA) targeting Piezo1 were used to explore the effect of Piezo1 knockdown on matrix stiffness-induced MCs activation and UUO-induced renal fibrosis. An in vitro experiment demonstrated that elevated ECM stiffness triggered the activation of Piezo1, which increased YAP nuclear translocation through the p38MAPK, and consequently led to increased ECM secretion. Furthermore, these consequences have been verified in the animal model of renal fibrosis induced by UUO and Piezo1 knockdown could alleviate UUO-induced fibrosis and improve renal function in vivo. Collectively, our results for the first time demonstrate enhanced matrix stiffness aggravates the progression of renal fibrosis through the Piezo1-p38MAPK-YAP pathway. Targeting mechanosensitive Piezo1 might be a potential therapeutic strategy for delaying the progression of renal fibrosis.

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Section: Discussionmentioning

confidence: 93%

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Wan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Such a relationship between V mem and the mechanical properties of the microenvironment was first reported by Silver et al wherein substrate stiffness was found to tune V mem in mammary epithelial cells. 64 Indeed, V mem has been known to function at the interface of chemical and mechanical signals by creating an electrical gradient across cells, which, in turn, gates voltage-sensitive channels to create a tightly communicated pathway between a cell and its microenvironment. 63,65 …”

Section: Discussionmentioning

confidence: 99%

Three-dimensional matrix stiffness modulates mechanosensitive and phenotypic alterations in oral squamous cell carcinoma spheroids

Sheth,

Sharma,

Lehn

et al. 2024

APL Bioengineering

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Extracellular biophysical cues such as matrix stiffness are key stimuli tuning cell fate and affecting tumor progression in vivo. However, it remains unclear how cancer spheroids in a 3D microenvironment perceive matrix mechanical stiffness stimuli and translate them into intracellular signals driving progression. Mechanosensitive Piezo1 and TRPV4 ion channels, upregulated in many malignancies, are major transducers of such physical stimuli into biochemical responses. Most mechanotransduction studies probing the reception of changing stiffness cues by cells are, however, still limited to 2D culture systems or cell-extracellular matrix models, which lack the major cell–cell interactions prevalent in 3D cancer tumors. Here, we engineered a 3D spheroid culture environment with varying mechanobiological properties to study the effect of static matrix stiffness stimuli on mechanosensitive and malignant phenotypes in oral squamous cell carcinoma spheroids. We find that spheroid growth is enhanced when cultured in stiff extracellular matrix. We show that the protein expression of mechanoreceptor Piezo1 and stemness marker CD44 is upregulated in stiff matrix. We also report the upregulation of a selection of genes with associations to mechanoreception, ion channel transport, extracellular matrix organization, and tumorigenic phenotypes in stiff matrix spheroids. Together, our results indicate that cancer cells in 3D spheroids utilize mechanosensitive ion channels Piezo1 and TRPV4 as means to sense changes in static extracellular matrix stiffness, and that stiffness drives pro-tumorigenic phenotypes in oral squamous cell carcinoma.

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“…Such selectivity may be achieved for electric field interventions by appropriate electrode replacement, however, challenges remain with respect to systemic drug application, when target ion channels may play a key role in regulating Vm in normal tissues, e.g. during mammary gland development/remodelling vs. cancer 18,44 . Further work is required to establish the effect(s) of local and systemic Vm-modulating therapies on both stromal cells in the TME (e.g.…”

Section: Future Perspectives: Therapeutic Vm Targetingmentioning

confidence: 99%

Harnessing the Membrane Potential to Combat Cancer Progression

Yang

Brackenbury

2022

Bioelectricity

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Rapid fluctuations in the plasma membrane potential (Vm) provide the basis underlying the action potential waveform in electrically excitable cells; however, a growing body of literature shows that the Vm is also functionally instructive in non-excitable cells, including cancer cells.Various ion channels play a key role in setting and fine tuning the Vm in cancer and stromal cells within the tumor microenvironment, raising the possibility that the Vm could be targeted therapeutically using ion channel-modulating compounds. Emerging evidence points to the Vm as a viable therapeutic target, given its functional significance in regulating cell cycle progression, migration, invasion, immune infiltration and pH regulation. Several compounds are now undergoing clinical trials and there is increasing interest in therapeutic manipulation of the Vm via application of pulsed electric fields. The purpose of this article is to update the reader on the significant recent and ongoing progress to elucidate the functional significance of Vm regulation in tumors, to highlight key remaining questions and the prospect of future therapeutic targeting. In particular, we focus on key developments in understanding the functional consequences of Vm alteration on tumor development via the activation of small GTPase (K-Ras and Rac1) signalling, as well as the impact of Vm changes within the heterogeneous tumor microenvironment on immune cell function and cancer progression.

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Substratum stiffness tunes membrane voltage in mammary epithelial cells

Cited by 7 publications

References 76 publications

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Targeting Mechanosensitive Piezo1 Alleviated Renal Fibrosis Through p38MAPK-YAP Pathway

Three-dimensional matrix stiffness modulates mechanosensitive and phenotypic alterations in oral squamous cell carcinoma spheroids

Harnessing the Membrane Potential to Combat Cancer Progression

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