Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies

Momin, Ali; Bahrampour, Shahrzad; Min, Hyun-Kee; Chen, Xin; Xian, Wang; Sun, Yu; Huang, Xi

doi:10.1016/j.tips.2021.02.006

Cited by 16 publications

(27 citation statements)

References 132 publications

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“…Mechanistic understanding of mechanical stimuli transduction in glioma is lacking, though recent advances have shed some light on the microenvironment and cellular network interactions that underlie the effects of mechanical properties on disease progression. Hubs of mechanical stimuli transduction in gliomas can be generally categorized as either via mechanosensitive ion channels or non-ion channel-based mechanotransduction which encompasses a complex swath of poorly understood signaling pathways including integrin signaling, ligand-mediated signaling through interaction with ECM components, or receptor-mediated signaling through interaction with ECM components (85). Here, we briefly summarize representative mechanisms in the evolving framework of glioma mechanotransduction (Table 1).…”

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

“…Three main classes of mechanosensitive ion channels have been implicated in gliomas: PIEZO, TRP, and ENaC (Table 1). Of these, mechanotransduction via PIEZO and TRP channels have been the most well characterized (85). PIEZO1 specifically in glioblastoma serves as an intermediary for a variety of downstream affects including cytoskeletal remodeling, ECM remodeling as well as directly regulating stemness and aggression of cancer cells (71,85,88,89).…”

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

“…Of these, mechanotransduction via PIEZO and TRP channels have been the most well characterized (85). PIEZO1 specifically in glioblastoma serves as an intermediary for a variety of downstream affects including cytoskeletal remodeling, ECM remodeling as well as directly regulating stemness and aggression of cancer cells (71,85,88,89). Studies have described colocalization of PIEZO1 to regions of cell membrane stress such as those with focal adhesions and signaling via the integrin-FAK pathway (71,88,89).…”

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

“…Studies have described colocalization of PIEZO1 to regions of cell membrane stress such as those with focal adhesions and signaling via the integrin-FAK pathway (71,88,89). Different subtypes of TRP channels have been implicated in glioma including TRPC1, TRPC6, and TRPM7 (Table 1) (85,86,(90)(91)(92)(93)(94). Similarly, mechanotransduction of physical microenvironmental stimuli through these channels influences downstream regulation of disease progression through effects key cellular structure and function ranging from motility and migration to proliferation and metabolism (86,(90)(91)(92)(93)(94).…”

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

“…Bloodstream-related fluid shear stress and other fluid stresses has been extensively studied in the context of metastatic cancer as well as other disease processes; however, studies characterizing these forces in glioma and examining the impact on the disease process are sparse. Further investigation in this area may provide a more complete view of the stresses at play in the tumor bulk and microenvironment, and early studies suggest that the influence fluid-related stresses may be clinically significant (85,(110)(111)(112)(113)(114)(115)(116). Interstitial fluid flow refers to fluid flow generally through a 3dimensional matrix and interstitial fluid pressure (IFP) refers to the biophysical manifestation of the pressure gradient typically between a capillary and a draining lymphatic vessel.…”

Section: Role Of Fluid Mechanics In Glioma Fluid Shear Stress and Interstitial Fluid Dynamicsmentioning

confidence: 99%

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Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

et al. 2022

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Gliomas represent the most common malignant primary brain tumors, and a high-grade subset of these tumors including glioblastoma are particularly refractory to current standard-of-care therapies including maximal surgical resection and chemoradiation. The prognosis of patients with these tumors continues to be poor with existing treatments and understanding treatment failure is required. The dynamic interplay between the tumor and its microenvironment has been increasingly recognized as a key mechanism by which cellular adaptation, tumor heterogeneity, and treatment resistance develops. Beyond ongoing lines of investigation into the peritumoral cellular milieu and microenvironmental architecture, recent studies have identified the growing role of mechanical properties of the microenvironment. Elucidating the impact of these biophysical factors on disease heterogeneity is crucial for designing durable therapies and may offer novel approaches for intervention and disease monitoring. Specifically, pharmacologic targeting of mechanical signal transduction substrates such as specific ion channels that have been implicated in glioma progression or the development of agents that alter the mechanical properties of the microenvironment to halt disease progression have the potential to be promising treatment strategies based on early studies. Similarly, the development of technology to measure mechanical properties of the microenvironment in vitro and in vivo and simulate these properties in bioengineered models may facilitate the use of mechanical properties as diagnostic or prognostic biomarkers that can guide treatment. Here, we review current perspectives on the influence of mechanical properties in glioma with a focus on biophysical features of tumor-adjacent tissue, the role of fluid mechanics, and mechanisms of mechanical signal transduction. We highlight the implications of recent discoveries for novel diagnostics, therapeutic targets, and accurate preclinical modeling of glioma.

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Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

Section: Mechanisms Of Mechanical Stimuli Transduction In Gliomamentioning

confidence: 99%

Section: Role Of Fluid Mechanics In Glioma Fluid Shear Stress and Interstitial Fluid Dynamicsmentioning

confidence: 99%

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Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

et al. 2022

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Dynamically Crosslinked Poly(ethylene‐glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D

Sinha

Ayushman

Tong

et al. 2022

Adv Healthcare Materials

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Glioblastoma multiforme (GBM) is the most prevalent and aggressive brain tumor in adults. Hydrogels have been employed as 3D in vitro culture models to elucidate how matrix cues such as stiffness and degradation drive GBM progression and drug responses. Recently, viscoelasticity has been identified as an important niche cue in regulating stem cell differentiation and morphogenesis in 3D. Brain is a viscoelastic tissue, yet how viscoelasticity modulates GBM fate and drug response remains largely unknown. Using dynamic hydrazone crosslinking chemistry, a poly(ethylene‐glycol)‐based hydrogel system with brain‐mimicking stiffness and tunable stress relaxation is reported to interrogate the role of viscoelasticity on GBM fates in 3D. The hydrogel design allows tuning stress relaxation without changing stiffness, biochemical ligand density, or diffusion. The results reveal that increasing stress relaxation promotes invasive GBM behavior, such as cell spreading, migration, and GBM stem‐like cell marker expression. Furthermore, increasing stress relaxation enhances GBM proliferation and drug sensitivity. Stress‐relaxation induced changes on GBM fates and drug response are found to be mediated through the cytoskeleton and transient receptor potential vanilloid‐type 4. These results highlight the importance of incorporating viscoelasticity into 3D in vitro GBM models and provide novel insights into how viscoelasticity modulates GBM cell fates.

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Piezo1 channel‐mediated Ca²⁺ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells

Malko

Jia

Wood

et al. 2022

Glia

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Microglial cells are crucial in maintaining central nervous system (CNS) homeostasis and mediating CNS disease pathogenesis. Increasing evidence supports that alterations in the mechanical properties of CNS microenvironments influence glial cell phenotypes, but the mechanisms regulating microglial cell function remain elusive.Here, we examined the mechanosensitive Piezo1 channel in microglial cells, particularly, how Piezo1 channel activation regulates pro-inflammatory activation and production of pro-inflammatory cytokines, using BV2 and primary microglial cells.Piezo1 expression in microglial cells was detected both at mRNA and protein levels.Application of Piezo1 channel activator Yoda1 induced Ca 2+ flux to increase intracellular Ca 2+ concentration that was reduced by treatment with ruthenium red, a Piezo1 inhibitor, or Piezo1-specific siRNA, supporting that Piezo1 functions as a cell surface Ca 2+ -permeable channel. Priming with lipopolysaccharide (LPS) induced microglial cell activation and production of TNF-α and IL-6, which were inhibited by treatment with Yoda1. Furthermore, LPS priming induced the activation of ERK, p38 MAPKs, and NF-κB. LPS-induced activation of NF-κB, but not ERK and p38, was inhibited by treatment with Yoda1. Yoda1-induced inhibition was blunted by siRNA-mediated depletion of Piezo1 expression and, furthermore, treatment with BAPTA-AM to prevent intracellular Ca 2+ increase. Collectively, our results support that Piezo1 channel activation downregulates the pro-inflammatory function of microglial cells, especially production of TNF-α and IL-6, by initiating intracellular Ca 2+ signaling to inhibit the NF-κB inflammatory signaling pathway. These findings reveal Piezo1 channel activation as a previously unrecognized mechanism regulating microglial cell function, raising an interesting perspective on targeting this molecular mechanism to alleviate neuroinflammation and associated CNS pathologies.

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Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies

Cited by 16 publications

References 132 publications

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

Dynamically Crosslinked Poly(ethylene‐glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D

Piezo1 channel‐mediated Ca²⁺ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells

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Channeling Force in the Brain: Mechanosensitive Ion Channels Choreograph Mechanics and Malignancies

Cited by 16 publications

References 132 publications

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

Mechanical Properties in the Glioma Microenvironment: Emerging Insights and Theranostic Opportunities

Dynamically Crosslinked Poly(ethylene‐glycol) Hydrogels Reveal a Critical Role of Viscoelasticity in Modulating Glioblastoma Fates and Drug Responses in 3D

Piezo1 channel‐mediated Ca2+ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells

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Piezo1 channel‐mediated Ca²⁺ signaling inhibits lipopolysaccharide‐induced activation of the NF‐κB inflammatory signaling pathway and generation of TNF‐α and IL‐6 in microglial cells