Sonogenetic nanosystem activated mechanosensitive ion channel to induce cell apoptosis for cancer immunotherapy

SummaryMechanotransduction, the conversion of mechanical stimuli into electrical signals, is a fundamental process underlying several physiological functions such as touch and pain sensing, hearing and proprioception. This process is carried out by specialized mechanosensitive ion channels whose identities have been discovered for most functions except pain sensing. Here we report the identification of TACAN (Tmem120A), an essential subunit of the mechanosensitive ion channel responsible for sensing mechanical pain. TACAN is expressed in a subset of nociceptors, and its heterologous expression increases mechanically-evoked currents in cell lines. Purification and reconstitution of TACAN in synthetic lipids generates a functional ion channel. Finally, knocking down TACAN decreases the mechanosensitivity of nociceptors and reduces behavioral responses to mechanical but not to thermal pain stimuli, without affecting the sensitivity to touch stimuli. We propose that TACAN is a pore-forming subunit of the mechanosensitive ion channel responsible for sensing mechanical pain.

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Mechanosensitive Ion Channel Piezo1 Regulates Myocyte Fusion during Skeletal Myogenesis

10.1101/2020.09.27.315242 ◽

2020 ◽

Author(s):

Huascar Pedro Ortuste Quiroga ◽

Shingo Yokoyama ◽

Massimo Ganassi ◽

Kodai Nakamura ◽

Tomohiro Yamashita ◽

...

Keyword(s):

Ion Channel ◽

Molecular Mechanisms ◽

Myoblast Fusion ◽

Mechanical Stimuli ◽

Muscle Satellite Cell ◽

Myotube Formation ◽

Mechanosensitive Ion Channel ◽

And Function ◽

Sirna Knockdown

AbstractMechanical stimuli such as stretch and resistance training are essential to regulate growth and function of skeletal muscle. However, the molecular mechanisms involved in sensing mechanical stress remain unclear. Here, the purpose of this study was to investigate the role of the mechanosensitive ion channel Piezo1 during myogenic progression. Muscle satellite cell-derived myoblasts and myotubes were modified with stretch, siRNA knockdown and agonist-induced activation of Piezo1. Direct manipulation of Piezo1 modulates terminal myogenic progression. Piezo1 knockdown suppressed myoblast fusion during myotube formation and maturation. This was accompanied by downregulation of the fusogenic protein Myomaker. Piezo1 knockdown also lowered Ca2+ influx in response to stretch. Conversely Piezo1 activation stimulated fusion and increased Ca2+ influx in response to stretch. These evidences indicate that Piezo1 is essential for myotube formation and maturation, which may have implications for msucular dystrophy prevention through its role as a mechanosensitive Ca2+ channel.

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Piezo1-Mediated Mechanotransduction Promotes Cardiac Hypertrophy by Impairing Calcium Homeostasis to Activate Calpain/Calcineurin Signaling

Hypertension ◽

10.1161/hypertensionaha.121.17177 ◽

2021 ◽

Author(s):

Yuhao Zhang ◽

Sheng-an Su ◽

Wudi Li ◽

Yuankun Ma ◽

Jian Shen ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Ion Channel ◽

Calcium Homeostasis ◽

Pressure Overload ◽

Cell Physiology ◽

Hypertrophic Growth ◽

Molecular Features ◽

Mechanosensitive Ion Channel

Hemodynamic overload induces pathological cardiac hypertrophy, which is an independent risk factor for intractable heart failure in long run. Beyond neurohumoral regulation, mechanotransduction has been recently recognized as a major regulator of cardiac hypertrophy under a myriad of conditions. However, the identification and molecular features of mechanotransducer on cardiomyocytes are largely sparse. For the first time, we identified Piezo1 (Piezo type mechanosensitive ion channel component 1), a novel mechanosensitive ion channel with preference to Ca 2+ was remarkably upregulated under pressure overload and enriched near T-tubule and intercalated disc of cardiomyocyte. By applying cardiac conditional Piezo1 knockout mice (Piezo1 fl/fl Myh6Cre+, Piezo1 Cko ) undergoing transverse aortic constriction, we demonstrated that Piezo1 was required for the development of cardiac hypertrophy and subsequent adverse remodeling. Activation of Piezo1 by external mechanical stretch or agonist Yoda1 lead to the enlargement of cardiomyocytes in vitro, which was blocked by Piezo1 silencing or Yoda1 analog Dooku1 or Piezo1 inhibitor GsMTx4. Mechanistically, Piezo1 perturbed calcium homeostasis, mediating extracellular Ca 2+ influx and intracellular Ca 2+ overload, thereby increased the activation of Ca 2+ -dependent signaling, calcineurin, and calpain. Inhibition of calcineurin or calpain could abolished Yoda1 induced upregulation of hypertrophy markers and the hypertrophic growth of cardiomyocytes in vitro. From a comprehensive view of the cardiac transcriptome, most of Piezo1 affected genes were highly enriched in muscle cell physiology, tight junction, and corresponding signaling. This study characterizes an undefined role of Piezo1 in pressure overload induced cardiac hypertrophy. It may partially decipher the differential role of calcium under pathophysiological condition, implying a promising therapeutic target for cardiac dysfunction.

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Boron induces osteogenesis by stimulating NaBC1 in cooperation with BMPR1A

10.1101/2020.03.17.995001 ◽

2020 ◽

Author(s):

Patricia Rico ◽

Aleixandre Rodrigo-Navarro ◽

Laura Sánchez Pérez ◽

Manuel Salmeron-Sanchez

Keyword(s):

Stem Cell ◽

Ion Channel ◽

Cell Fate ◽

Cell Metabolism ◽

Cost Effective ◽

Material System ◽

Mechanosensitive Ion Channel ◽

The Media ◽

Cell Niche ◽

System Approaches

AbstractThe intrinsic properties of Mesenchymal Stem Cells (MSCs) make them ideal candidates for tissue engineering applications as they are regulated by the different signals present in the stem cell niche. Considerable efforts have been made to control stem cell behavior by designing material system approaches to engineer synthetic extracellular matrices and/or include soluble factors in the media. This work proposes a novel and simple approach based on ion-channel stimulation to determine stem cell fate that avoids the use of growth factors (GFs). We used boron ion - essential item in cell metabolism - transported inside cells by the NaBC1-channel. Addition of boron alone enhanced MSC adhesion and contractility, promoted osteogenesis and inhibited adipogenesis. The stimulated NaBC1 promoted osteogenesis via activation of the BMP canonical pathway (comprising Smad1 and YAP nucleus translocation and osteopontin expression) through a mechanism that involves simultaneous NaBC1/BMPR1A and NaBC1/α5β1/αvβ3 co-localization,. We describe a novel function for NaBC1 as a mechanosensitive ion-channel capable of interacting and stimulating GF receptors and fibronectin-binding integrins. Our results open up new biomaterial engineering approaches for biomedical applications by a cost-effective strategy that avoids the use of soluble GFs.

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