The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia

Zhu, Ting; Guo, Jinghui; Wu, Yong; Lei, Ting; Zhu, Jianguo; Chen, Hui; Kala, Shashwati; Wong, Kin Fung; Cheung, Chi Pong; Huang, Xiaohui; Zhao, Xinyi; Yang, Mingwei; Sun, Lei

doi:10.1016/j.isci.2023.105993

Cited by 21 publications

(32 citation statements)

References 64 publications

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“…We found that the previously observed increase in intracellular Ca 2+ induced by distension was suppressed in the presence of gadolinium, indicating that mechanosensitive channels are essential for integrating the mechanical changes induced by distension. We repeated this experiment in the presence of more specific inhibitors: the piezo‐1 channel blocker GsMTx4 (1 μM) and the K Ca1.1 channel blocker paxilline (10 μM) (Sanchez & McManus, 1996; Zhang et al., 2012; Zhu et al., 2022) (Fig. 9).…”

Section: Resultsmentioning

confidence: 99%

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

Wongkrasant

Glover

Balemba

et al. 2023

The Journal of Physiology

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The enteric nervous system (ENS) regulates the motor, secretory and defensive functions of the gastrointestinal tract. Enteric neurons integrate mechanical and chemical inputs from the gut lumen to generate complex motor outputs. How intact enteric neural circuits respond to changes in the gut lumen is not well understood. We recorded intracellular calcium in live‐cell confocal recordings in neurons from intact segments of mouse intestine in order to investigate neuronal response to luminal mechanical and chemical stimuli. Wnt1‐, ChAT‐ and Calb1‐GCaMP6 mice were used to record neurons from the jejunum and colon. We measured neuronal calcium response to KCl (75 mM), veratridine (10 μM), 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP; 100 μM) or luminal nutrients (Ensure®), in the presence or absence of intraluminal distension. In the jejunum and colon, distension generated by the presence of luminal content (chyme and faecal pellets, respectively) renders the underlying enteric circuit unresponsive to depolarizing stimuli. In the distal colon, high levels of distension inhibit neuronal response to KCl, while intermediate levels of distension reorganize Ca2+ response in circumferentially propagating slow waves. Mechanosensitive channel inhibition suppresses distension‐induced Ca2+ elevations, and calcium‐activated potassium channel inhibition restores neuronal response to KCl, but not DMPP in the distended colon. In the jejunum, distension prevents a previously unknown tetrodotoxin‐resistant neuronal response to luminal nutrient stimulation. Our results demonstrate that intestinal distension regulates the excitability of ENS circuits via mechanosensitive channels. Physiological levels of distension locally silence or synchronize neurons, dynamically regulating the excitability of enteric neural circuits based on the content of the intestinal lumen. Key points How the enteric nervous system of the gastrointestinal tract responds to luminal distension remains to be fully elucidated. Here it is shown that intestinal distension modifies intracellular calcium levels in the underlying enteric neuronal network, locally and reversibly silencing neurons in the distended regions. In the distal colon, luminal distension is integrated by specific mechanosensitive channels and coordinates the dynamics of neuronal activation within the enteric network. In the jejunum, distension suppresses the neuronal calcium responses induced by luminal nutrients. Physiological levels of distension dynamically regulate the excitability of enteric neuronal circuits.

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Section: Resultsmentioning

confidence: 99%

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

Wongkrasant

Glover

Balemba

et al. 2023

The Journal of Physiology

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“…Preliminary data from our group indicated that these Ca 2+ changes are extracellular Ca 2+ -dependent [7]. These observations may be explained by the presence of mechano-sensitive, Ca 2+ -permeable PIEZO1 channels in microglia [54,55], whose role in the physiology of these cells has only recently started to be unraveled [54,55].…”

Section: Discussionmentioning

confidence: 99%

ER and SOCE Ca²⁺signals are not required for directed cell migration in human microglia

Granzotto,

McQuade,

Chadarevian

et al. 2024

Preprint

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The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca2+) signaling in the directed migration of induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca2+changes revealed that this phenomenon does not require Ca2+signals generated from the endoplasmic reticulum (ER) and store-operated Ca2+entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca2+-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca2+homeostasis.

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“…During this process, mechanoreceptors integrate mechanical signals into biochemical signals and genomic pathways leading to observable effects on brain cell fate (Procès et al., 2022 ). There is increasing evidence that the regulation of cell behavior by mechanical forces is partly dependent on the Piezo1 channel protein (Blumenthal et al., 2014 ; Chen et al., 2018 ; Koser et al., 2016 ; Pathak et al., 2014 ; Segel et al., 2019 ; Zhu et al., 2023 ). In the next section, we will explore the different roles of Piezo1 channels in different brain cells.…”

Section: The Role Of Piezo1‐mediated Mechanotransduction In Physiolog...mentioning

confidence: 99%

Mechanical properties of the brain: Focus on the essential role of Piezo1‐mediated mechanotransduction in the CNS

et al. 2023

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BackgroundThe brain is a highly mechanosensitive organ, and changes in the mechanical properties of brain tissue influence many physiological and pathological processes. Piezo type mechanosensitive ion channel component 1 (Piezo1), a protein found in metazoans, is highly expressed in the brain and involved in sensing changes of the mechanical microenvironment. Numerous studies have shown that Piezo1‐mediated mechanotransduction is closely related to glial cell activation and neuronal function. However, the precise role of Piezo1 in the brain requires further elucidation.ObjectiveThis review first discusses the roles of Piezo1‐mediated mechanotransduction in regulating the functions of a variety of brain cells, and then briefly assesses the impact of Piezo1‐mediated mechanotransduction on the progression of brain dysfunctional disorders.ConclusionsMechanical signaling contributes significantly to brain function. Piezo1‐mediated mechanotransduction regulates processes such as neuronal differentiation, cell migration, axon guidance, neural regeneration, and oligodendrocyte axon myelination. Additionally, Piezo1‐mediated mechanotransduction plays significant roles in normal aging and brain injury, as well as the development of various brain diseases, including demyelinating diseases, Alzheimer's disease, and brain tumors. Investigating the pathophysiological mechanisms through which Piezo1‐mediated mechanotransduction affects brain function will give us a novel entry point for the diagnosis and treatment of numerous brain diseases.

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The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia

Cited by 21 publications

References 64 publications

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

ER and SOCE Ca²⁺signals are not required for directed cell migration in human microglia

Mechanical properties of the brain: Focus on the essential role of Piezo1‐mediated mechanotransduction in the CNS

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The mechanosensitive ion channel Piezo1 modulates the migration and immune response of microglia

Cited by 21 publications

References 64 publications

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

Intestinal distension orchestrates neuronal activity in the enteric nervous system of adult mice

ER and SOCE Ca2+signals are not required for directed cell migration in human microglia

Mechanical properties of the brain: Focus on the essential role of Piezo1‐mediated mechanotransduction in the CNS

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ER and SOCE Ca²⁺signals are not required for directed cell migration in human microglia