Stiff Substrate Induces Nucleus Pulposus Cell Ferroptosis via YAP and N‐Cadherin Mediated Mechanotransduction

Ke, Wencan; Liao, Zhiwei; Liang, Huaizhen; Tong, Bide; Song, Yu; Li, Gaocai; Ma, Liang; Wang, Kun; Feng, Xiaobo; Li, Shuai; Hua, Wenbin; Wang, Bingjin; Yang, Cao

doi:10.1002/adhm.202300458

Cited by 5 publications

(2 citation statements)

References 74 publications

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“…Statistical analyses were performed using GraphPad Prism 8 software (La Jolla, CA, USA). Student's t test was used to evaluate differences between two groups and one-way ANOVA was used to determine differences between multiple groups [37][38][39]. Statistical significance was set at P < 0.05 while P > 0.05 was considered nonsignificant (#).…”

Section: Discussionmentioning

confidence: 99%

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration

Ke,

Wang,

Liao

et al. 2023

J Transl Med

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Background Extracellular matrix stiffness is emerging as a crucial mechanical cue that drives the progression of various diseases, such as cancer, fibrosis, and inflammation. The matrix stiffness of the nucleus pulposus (NP) tissues increase gradually during intervertebral disc degeneration (IDD), while the mechanism through which NP cells sense and react to matrix stiffness remains unclear. In addition, mitochondrial dynamics play a key role in various cellular functions. An in-depth investigation of the pathogenesis of IDD can provide new insights for the development of effective therapies. In this study, we aim to investigate the effects of matrix stiffness on mitochondrial dynamics in IDD. Methods To build the gradient stiffness model, NP cells were cultured on polystyrene plates with different stiffness. Western blot analysis, and immunofluorescence staining were used to detect the expression of mitochondrial dynamics-related proteins. Flow cytometry was used to detect the mitochondrial membrane potential and intracellular Ca2+ levels. Apoptosis related proteins, ROS level, and TUNEL staining were performed to assess the effect of substrate stiffness on NP cells. Results Stiff substrate increased phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 by activating extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, which promoted mitochondrial fission and apoptosis in NP cells. Furthermore, Piezo1 activation was involved in the regulation of the post-translational modifications of Drp1 and mitochondrial fission caused by matrix stiffness. Inhibition of Piezo1 and ERK1/2 can effectively reduce stiffness-induced ROS elevation and apoptosis in NP cells. Conclusions Our results revealed that stiff substrate causes Piezo1 activation and Ca2+ influx, results in ERK1/2 activation and phosphorylation of Drp1 at S616, and finally leads to mitochondrial fission and apoptosis in NP cells. These findings reveal a new mechanism of mechanotransduction in NP cells, providing novel insights into the development of therapies for treating IDD.

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Section: Discussionmentioning

confidence: 99%

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration

Ke,

Wang,

Liao

et al. 2023

J Transl Med

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“…[ 161 ] Cell apoptosis is also induced by the compressive stress in epithelial monolayer through the inactivation of YAP and the activation of caspase‐3. [ 18 ] In addition to apoptosis, ferroptosis is emerging to relate with mechanotransduction through a variety of pathways, [ 162 , 163 , 164 ] despite of the elusive underlying molecular pathways.…”

Section: Mechanotransduction At the Cellular Levelmentioning

confidence: 99%

A Hierarchical Mechanotransduction System: From Macro to Micro

Cao,

Tian,

Tian

et al. 2023

Advanced Science

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Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole‐body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

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YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis

Lin,

Luo,

Wei

et al. 2023

Advanced Science

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Chronic prostatic inflammation promotes cell survival and fibrosis, leading to benign prostatic hyperplasia (BPH) with aggravated urinary symptoms. It is investigated whether yes‐associated protein 1 (YAP1), an organ size controller and mechanical transductor, is implicated in inflammation‐induced BPH. The correlation between YAP1 expression and fibrosis in human and rat BPH specimens is analyzed. Furthermore, the effects of YAP1 activation on prostatic cell survival and fibrosis, as well as the underlying mechanism, are also studied. As a result, total and nuclear YAP1 expression, along with downstream genes are significantly upregulated in inflammation‐associated human and rat specimens. There is a significant positive correlation between YAP1 expression and the severity of fibrosis or clinical performance. YAP1 silencing suppresses cell survival by decreasing cell proliferation and increasing apoptosis, and alleviates fibrosis by reversing epithelial‐mesenchymal transition (EMT) and extracellular matrix (ECM) deposition in prostatic BPH‐1 and WPMY‐1 cells. Mechanistically, inflammatory stimulus and rigid matrix stiffness synergistically activate the RhoA/ROCK1 pathway to provoke cytoskeleton remodeling, thereby promoting YAP1 activation to exacerbate BPH development. Overall, inflammation‐triggered mechanical stiffness reinforcement activates the RhoA/ROCK1/F‐actin/YAP1 axis, thereby promoting prostatic cell survival and fibrosis to accelerate BPH progression.

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Stiff Substrate Induces Nucleus Pulposus Cell Ferroptosis via YAP and N‐Cadherin Mediated Mechanotransduction

Cited by 5 publications

References 74 publications

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration

Matrix stiffness induces Drp1-mediated mitochondrial fission through Piezo1 mechanotransduction in human intervertebral disc degeneration

A Hierarchical Mechanotransduction System: From Macro to Micro

YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis

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