cancers

Review
PIEZO1-Related Physiological and Pathological Processes in
CNS: Focus on the Gliomas
Rui Hong 1,2 , Dianxu Yang 1 , Yao Jing 1 , Shiwen Chen 1 , Hengli Tian 1 and Yang Yang 1, *

1 Department of Neurosurgery, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University
School of Medicine, Shanghai 200233, China
2 School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China
* Correspondence: yang.cne.yang@gmail.com

Simple Summary: We summarized previous studies of PIEZO1 in neurons and glial cells of the central
nervous system, and briefly reviewed its mechanotransduction mechanisms and its role in physiological
and pathological processes. We further elaborated the effects of PIEZO1 in gliomas and its underlying
mechanisms as well as its clinical application. Based on the existing advanced studies, we propose the
promising potential of PIEZO1 in the treatment of neurological diseases, especially gliomas.

Abstract: PIEZO1 is ubiquitously expressed in cells in different kinds of tissues throughout the body,
which can sense physical or mechanical stimuli and translate them into intracellular electrochem-
ical signals to regulate organism functions. In particular, PIEZO1 appears in complex interactive
regulatory networks as a central node, governing normal and pathological functions in the body.
However, the effect and mechanism of the activation or expression of PIEZO1 in diseases of the
central nervous system (CNS) remain unclear. On one hand, in CNS diseases, pathophysiological
processes in neurons and glial are often accompanied by variations in the mechanical properties of
the cellular and extracellular matrix stiffness. The expression of PIEZO1 can therefore be upregulated,
in responding to mechanical stimulation, to drive the biological process in cells, which in turns
indirectly affects the cellular microenvironment, resulting in alterations of the cellular status. On the
other hand, it may have contradictory effects with the change of active patterns and/or subcellular
location. This review highlights the biological processes involved with PIEZO1 in CNS cells, with
special emphasis on its multiple roles in glioma-associated phenotypes. In conclusion, PIEZO1 can
Citation: Hong, R.; Yang, D.; Jing, Y.;
Chen, S.; Tian, H.; Yang, Y.
be used as an indicator to assess the malignancy and prognosis of patients with gliomas, as well
PIEZO1-Related Physiological and as a therapeutic target for clinical application following fully exploring the potential mechanism of
Pathological Processes in CNS: Focus PIEZO1 in CNS diseases.
on the Gliomas. Cancers 2023, 15, 883.
https://doi.org/10.3390/ Keywords: PIEZO1; ion channel; mechanotransduction; glioma; glia cell
cancers15030883

Academic Editor: Shinji Kawabata

Received: 28 December 2022 1. Introduction

Revised: 27 January 2023
In physiological and pathological states, virtually all cells of our organism are stim-
Accepted: 30 January 2023
ulated at all times by a variety of mechanical forces arising intracellularly or persisting
Published: 31 January 2023
extracellularly, including matrix stiffness, tensile and fluid shear stress, and elastic defor-
mations [1]. Sensing and appropriately responding to changes in the physical environment
are essential for cells to perform their physiological functions. PIEZO1, a kind of ionic
Copyright: © 2023 by the authors.
channel protein, was first identified and described in a mouse neuroblastoma cell line. It re-
Licensee MDPI, Basel, Switzerland. sponds to mechanical stimuli and allows cations, such as calcium ions, to flow into cells [2].
This article is an open access article PIEZO1 converts mechanical stimuli (strain) into biochemical signals, inducing alterations
distributed under the terms and in protein conformation and activating intracellular biochemical signaling pathways. This
conditions of the Creative Commons process then specifically regulates the gene to drive cells to perform biological processes
Attribution (CC BY) license (https:// and molecular functions.
creativecommons.org/licenses/by/ Maintaining a stable cytoskeletal structure and homeostasis of the extracellular matrix
4.0/). is the foundation for neurons and glial cells to perform physiological functions in the

Cancers 2023, 15, 883. https://doi.org/10.3390/cancers15030883 https://www.mdpi.com/journal/cancers

Cancers 2023, 15, 883 2 of 14

central nervous system (CNS) [3]. In the development of neurons and glial cells, PIEZO1
can not only drive development and differentiation, but also participate in the neuron-glial
intercellular information exchange. These physiological functions among cells are essential
for memory processes, cognitive functions, learning abilities, and motor capacities [4–7].
Several pathological processes, such as neuroinflammation, apoptosis, and tumor aggres-
siveness, are involved due to variations in the interacting forces between CNS cells and
the extracellular matrix [8,9]. The role of PIEZO1 in other systemic cancers has inspired
researchers to explore its use as a non-invasive ultrasound therapy in neurological diseases,
such as gliomas [10–12]. Despite a proven role for PIEZO1 in the neuromodulation of the
neuroblastoma cell line [13], its efficiency and safety in (pre-)clinical studies have not been
measured to date.

2. Structure and Gating Mechanism of PIEZO1

With more than 2500 amino acids and a vast transmembrane domain, PIEZO1 is an
evolutionarily conserved integral membrane protein that serves as a pore-forming subunit
of the ion channel, but its structure and gating mechanism were not initially determined [14].
Due to the development of cryo-electron microscopy, live-cell immunoassays, and X-ray
crystallography, its basic physical body has been identified and described as a homologous
trimer assembled on a membrane with a helical blade-like structure [15,16]. It consists
of a central cap, three peripheral blades, three long intracellular rays, an intracellular C-
terminal domain (CTD), and a transmembrane (TM) fragment [15,16]. Based on the unique
38-TM structure inherent in its protomer, PIEZO1 can be divided into three functional
components: 1. a mechano-sensing module for sensing mechanical stimuli, 2. a C-terminal
ion-conducting pore module that acts as a channel, and 3. a transduction functional compo-
nent for transmitting mechanical stimuli [17]. Each PIEZO1 protomer has an unprecedented
structure of 38 TMs, of which the last 2 TMs at the C-terminus form an outer helix (OH) and
an inner helix (IH), and the three IHs lock together to form a transmembrane pore [17,18].
The remaining TMs form abnormally curved, non-planar transmembrane helical blades
that, all together, form nine tandemly repeating transmembrane helix units (THUs), where
each unit consists of four TM fragments [18]. The partially non-planar TM blades form the
central cap of the ion channel outside the cell, which is called the C-terminal extracellular
structural domain (CED). The beam originates at the lower edge of the peripheral TM and
physically connects the distal blade to the ion conduction pore module via a compound
consisting of the CTD, anchor, and OH-IH. The specific structure of the beam reveals its
dual role: transmembrane support and the transmission of conformational changes in ex-
tracellular blades [15,16]. The CTD, located above the proximal edge of the beam, interacts
with the beam, and contains an anchor consisting of three alpha helices with a unique
hairpin plane structure parallel to the film. The anchoring domain enables the formation of
an inverted V-shape structure that penetrates the inner leaflet of the membrane, interacts
with the IH and OH, and stabilizes the ion conduction pore [17].
It has been shown that PIEZO1 can be directly activated by the mechanical stretching
of lipid bilayers [19,20]. The non-planar TM blades and THU structures form mechanore-
ceptors that directly sense minutiae changes in membrane curvature and tension [20,21].
The motion characteristics of the long rod-like beam and the peripheral THU are analogous
to the lever motion, as the pivot on the beam near the central pore, consisting of residues
L1342 and L1345, allows the PIEZO1 channel to efficiently translate the conformational
changes of the extracellular blade into the opening and closing of the ion conduction pore,
translating mechanical stimuli into chemical signals [18,22]. Based on the characteristic of
PIEZO1 distorting the cytosolic membrane into a dome structure, some researchers have
proposed the mechanism of “membrane doming” [23]. With the opening of the channel,
the morphology of the membrane changes and the energy needed to modify the membrane
is proportional to the change in the projected area under the dome [23]. This membrane
doming mechanism explains the high mechanical sensitivity displayed by PIEZO1 through
the ion selective pore.
Cancers 2023, 15, 883 3 of 14

Since membrane tension is largely dependent on the arrangement of the cytoskeleton

and extracellular matrix (ECM), it is, therefore, reported that the cytoskeletal contractile
protein myosin II stimulates PIEZO1 via the traction generated by myosin light-chain
kinase (MLCK), and induces the change of the gate that triggers cation influx [24,25]. In
addition, PIEZO1 also allows the interactions with a variety of proteins. These include
myotubularin-related protein 2 (MTMR2) and stomatin-like protein3 (STOML3), which
affect the activity of PIEZO1 channels according to cholesterol [26,27]. SERCA2 inhibits
the PIEZO1 protein in a structural manner by binding to the anchored-OH junction of the
linker pore module and the mechanical transduction module [28]. All in all, the PIEZO1
channel adopts both mechanotransduction and an ion channel to carry out its structural
function in mechanosensing, channel opening, and ion conduction, which clarifies the
channel mechanism based on mechanical force control.

3. Agonists and Antagonists

Many studies have investigated the ion conduction and mechanical gating mechanisms
of the PIEZO1 channel. It has been reported that GsMTx4, an amphiphilic peptide toxin,
may mechanically perturb PIEZO1 by modulating local membrane tension rather than
directly acting on PIEZO1 itself [29]. Similarly, the amphiphilic macromolecule amyloid β
(Aβ) can modulate channel activity by altering the membrane structure or cytoskeleton
instead of working on it [30,31]. Ruthenium red (RR) works on the two residues with a
negative charge in the intracellular CTD, blocking the ion conduction of PIEZO1 through a
pore-plugging mechanism, while a series of TRPV channels other than the PIEZO1 channel
are also inhibited by RR [14,22].
The cell membrane is composed of a lipid bilayer; saturated and polyunsaturated fatty
acids can, therefore, regulate the activity of the PIEZO1 channel by adjusting membrane
stiffness and lipids [32]. Compared with the antagonists of the PIEZO1 channels, Yoda1, the
specific agonist of PIEZO1, is highly selective, acting exclusively on the variable binding
domain of PIEZO1 [33]. As novel specifical activators of PIEZO1, Jedi1 and Jedi2 have
been identified from more than 3000 compounds by using the fluorescent imaging plate
technique as a calcium indicator [18]. Compared to Yoda1, Jedi1 and Jedi2 have higher water
solubility, a faster onset current, and a shorter decay duration. More importantly, the joint
application of Jedi1 and Yoda1 produces a synergistic effect of enhancing the inward current
of PIEZO1 [18]. Recent studies have demonstrated that PIEZO1 is associated with various
pathophysiological processes [34–39]. Drugs targeting it may, therefore, be promising for
the treatment of many diseases [17,40–42]. However, the specific physiological mechanisms
of its ligand-binding crystals still need to be further investigated since drugs that work
on PIEZO1 lack robust specificity and potency [17]. Overall, with rapid progress in the
elucidation of the structure and mechanism of PIEZO1, a growing number of agents are
being developed for the treatment of PIEZO1 dysfunction-related diseases.

4. PIEZO1-Related Physiological and Pathological Processes

As an evolutionarily highly conserved protein, the PIEZO1 channel is expressed in
a wide variety of cells that participate in different mechanotransduction processes under
physiological and pathological conditions. The shear stress generated by the blood flow
and membrane stretch caused by blood pressure fluctuations activates PIEZO1 channels
embedded in the endothelium [43–45]. Several studies have shown that PIEZO1 regulates
vascular remodeling, blood pressure, erythrocyte volume homeostasis, and lymphatic
vessel development through Ca2+ influx or its interaction with integrin [44–47]. PIEZO1
has been shown to be overexpressed in osteoblasts as well as to affect the differentiation
of osteoclasts and the resorption of bone by mediating the expression of type II and type
IX collagen in osteoblasts that are governed by the YAP signaling pathway. In the case of
PIEZO1 deletion, the osteoblast osteoclast crosstalk is out of balance, thus leading to the
rapid loss of bone mass and causing spontaneous fractures [48,49].
Cancers 2023, 15, 883 4 of 14

Furthermore, the activation of PIEZO1 in myeloid cells initiates the effects of activator
protein-1 (AP-1) and endothelin-1 (EDN1), thereby stabilizing the hypoxia-inducible factor
1α (HIF-1α) and inducing the expression of pro-inflammatory factors [50]. Another study
suggests that toll-like receptor 4 (TLR4) works in synergy with PIEZO1 to strengthen
the phagocytosis of macrophages to clear bacteria and resist the invasion of foreign sub-
stances [51]. Interestingly, PIEZO1 interacts with the classical inflammatory pathway
JAK/STAT, the inflammasome NLPR3, the Ca2+ -sensitive MAPK family, integrins, focal
adhesion kinase (FAK), and calcium-dependent proteases to participate in the development
and progression of inflammation [9,52–60]. PIEZO1 has been reported to be associated
with iron metabolism in the organism, enhancing the ability of macrophages to engulf
erythrocytes and inhibiting the expression of hepcidin, thereby leading to iron overload in
the blood [61]. In radiation-injured endothelial cells of pulmonary microvascularization,
PIEZO1 degrades cadherin in the vascular endothelium via calpain, causing an increase in
ROS and the oxidation of lipids [62]. That is, PIEZO1 may also be involved in the regulation
of endothelial cell ferroptosis.
In addition, PIEZO1 is overexpressed in a variety of tumors. The resting state of
PIEZO1 has been reported to inhibit proliferation, migration, and invasion of tumor cells,
and promote apoptosis of the cancer cells [9,11,12,34,63–67]. Mechanistically, the process
is mediated mainly by an increase in the cytosolic calcium ion concentration, which initi-
ates a series of relevant transductions of signals in the downstream, involving ERK1/2,
AKT/mTOR, and YAP/TAZ [9,11,12,34,63–67]. To summarize, cells sense the mechanical
stimuli via the PIEZO1 protein and then trigger calcium influx, which in turn triggers a
cascade of downstream effects that ultimately induce conformational shifts of proteins
and regulate gene expression, thus driving the cellular functions in physiological and
pathological processes.

5. PIEZO1 in CNS Cells

Neurons and glial cells in the CNS exhibit significant mechanosensitivity, being capable
of sensing mechanical stimuli from the ambient environment and converting them into
biochemical signals to regulate their functions [19,36,68]. The critical value of PIEZO1 as
a mechanosensor expressed in the membranes of the CNS is of growing interest, with an
increasing number of studies aiming to discuss its role in neurological diseases [38–40,69].
As shown in Table 1, PIEZO1 is involved in the translation of mechanical signals in the
CNS neurons and glial cells.

Table 1. Mechanotransduction of PIEZO1 in CNS cells.

State of
Cell Type Mechanical Stimuli Effects References
PIEZO1
activated Elevated intracellular Ca2+ [13]
InitiatingCa2+ influx and affecting
Ultrasound the levels of downstream Ca2+
activated [70]
signaling proteins involved in
neuronal function
Axonal growth and pathfinding
Substrate stiffness gradient activated [6]
Neuron errors
Inhibiting axon regeneration via the
Axon injury activated [5]
CamKII-Nos-PKG pathway
Enhanced cell viability inhibition,
Oxygen-glucose
apoptosis, increase intracellular
deprivation/reoxygenation activated [71]
calcium levels and enhanced calpain
injury
activity
Cancers 2023, 15, 883 5 of 14

Table 1. Cont.

State of
Cell Type Mechanical Stimuli Effects References
PIEZO1
Inducing Ca2+ influx, phagocytosis
Amyloid beta fibrils stiffness activated [72]
and compacting of Aβ plaques
Microglial Increasing cytosolic Ca2+ signaling
Osmotic pressure activated and regulate cell function via JNK1 [73]
and mTOR signaling pathway
Evoking Ca2+ response and ATP
Mechanical indentation release as therefore regulates
Astrocytes activated [74]
stimulation neurogenesis and cognitive
functions
Oligodendrocyte Increasing proliferation and
Mechanical stiffness gradient inhibited [7]
progenitor cells differentiation
Directing the fate of the neural stem
Neural stem cells Stretch stress activated [4]
cells toward the desired lineage.
Abbreviations: CamKII: calmodulin-dependent protein kinases; Nos: nitric oxide synthase; PKG: cGMP-
dependent protein kinase G; JNK1: c-Jun N-terminal kinase 1; mTOR: mammalian target of rapamycin; ATP:
adenosine triphosphate.

PIEZO1 is an essential ingredient in maintaining neuronal physiological function

[4–6,75]. In a study measuring focal tissue stiffness in the brain at different developmental
phases by observing brain tissue at different developmental nodes under an atomic force
microscope, it was reported that PIEZO1 is fundamental in mentoring axonal growth and
neurons’ maturation [6]. On the other hand, PIEZO1 channels can be activated to restrict
nerve regeneration through the downstream cGMP kinase or PKG pathway in damaged
neurons, triggering Ca2+ signaling [5,6,71]. Moreover, the mechanical activation of PIEZO1
with ultrasound is accompanied by an increase in Ca2+ influx and an elevated expression of
activated calmodulin-dependent protein kinases (CaMKII) and the cAMP-response element
binding protein (CREB) [70]. These two proteins are intimately implicated in neuronal
plasticity, learning, and memory functions [70]. In addition, it is speculated that in the brain
of those with Alzheimer’s disease (AD), astrocytes sense changes in the environment and
subsequently relay the information to damaged neurons around the Aβ plaques instead of
sensing stimuli via the damaged neurons that lost their PIEZO1 function [75]. Therefore,
PIEZO1 expression is not detectable in the neurons in damaged regions of the AD brain.
In contrast, PIEZO1 mRNA is detected in the neurons in both the non-AD brain and the
non-damaged regions of the AD brain [75,76].
Astrocytes can take in and release a diversity of neuromodulatory signals for message
delivery and account for the largest number of glial cells in the brain [77]. PIEZO1 is ex-
pressed in reactive astrocytes surrounding plaques in AD patients, whereas PIEZO1 mRNA
is not detected in quiescent astrocytes, suggesting that PIEZO1 may be the expression gene
in Aβ plaque-induced astrocytes [78]. Aging and infection can induce the upregulation
of PIEZO1 in the plaque-induced reactive astrocytes, which may in turn trigger astrocyte
proliferation [76]. In primary astrocytes derived from mice, some researchers use LPS
to mimic the infection situation and observe an increase in PIEZO1 expression [79]. The
upregulation of PIEZO1 elevates intracellular Ca2+ concentration while diminishing re-
sponsiveness of astrocytes to adenosine triphosphate (ATP), and inhibits the generation
and release of pro-inflammatory cytokines and chemokines, ultimately suppressing neu-
roinflammation [79]. Moreover, evoked by external mechanical forces to generate cationic
currents and Ca2+ signals, PIEZO1 in astrocytes also mediates spontaneous Ca2+ influx and
triggers the release of ATP to regulate the development and neuronal maturation of neural
stem cells (NSCs) [74]. In addition, the reduced volume of the hippocampal dentate gyrus
in astrocyte-specific PIEZO1-deficient mice suggests that PIEZO1-mediated mechanotrans-
duction affects the long-temporal enhancement (LTP) and the cognitive function of the
Cancers 2023, 15, 883 6 of 14

hippocampus, consequently impairing learning and memory performance [74]. Consistent

with this, the activity of PIEZO1 expressed on NSCs affects the definitive lineage selection
of NSCs and guides their differentiation into either neurons or astrocytes [4]. Therefore,
it is likely one of the mechanisms for the formation of astrocytes [4]. Collectively, the
interaction between astrocytes and NSCs shows the significance of astrocytes as a center
for intercellular message exchange in the CNS.
Under normal physiological conditions, the expression level of PIEZO1 in microglia
is relatively high [80]. This may be because microglia, as the main residual immune cells
in the brain, need to sense changes in the surrounding environment in time to perform
immune functions for host defense [81]. Some studies have reported that any mechanical
perturbation caused by intra- and extracellular osmotic pressure homeostasis or changes in
environmental stiffness can activate PIEZO1 and provoke Ca2+ influx [72,73,80]. Elevated
concentrations of intracellular Ca2+ interact with intracellular Ca2+ -sensitive transcriptional
regulators to regulate microglia proliferation and migration and to mediate neuroinflamma-
tion [72,80,82]. Immunofluorescence staining analysis of postmortem brain tissue sections
from AD patients indicates that microglia cells cluster around Aβ plaques, and PIEZO1
protein levels are elevated [72]. In a recent study, it was proposed that microglia may
sense the mechanical stimuli of plaques through PIEZO1 and enhance their own phago-
cytosis of foreign bodies, resulting in the cleavage, compaction, and later clearance of
Aβ plaques [72]. Interestingly, the pathological effects of AD may modify the microglia
membrane and cytoskeleton, impairing the PIEZO1-mediated Ca2+ signaling pathway
and initiating downstream malfunction, which ultimately contributes to the inability of
microglia to clear the Aβ amyloid plaques [80]. According to a new study using LPS to
induce an inflammatory phenotype of microglia, the activation of the PIEZO1 channel is
observed to inhibit the activation of microglia to exert anti-inflammatory effects, which
suggests that microglia may regulate neuroinflammation via a novel mechanism involving
PIEZO1 [8].
Recent studies have identified the expression of PIEZO1 as a key effector of sensing
the stiffness of the matrix in oligodendrocyte progenitor cells (OPCs) in rodents [7]. The
differentiation and proliferation of OPCs are stopped in harder substrates, whereas in softer
substrates or those inhibiting the PIEZO1, this phenomenon can be reversed, suggesting that
OPCs are PIEZO1 dependent during growth [7]. Similarly, the expression level of PIEZO1
in human MO3.13 oligodendrocytes changes at different stages of maturation. When
PIEZO1 is suppressed by the antagonist GsMTx4, it induces the enhanced proliferation
and migration of oligodendrocytes [83]. Further investigation reveals that the condition of
oligodendrocytes is related to neurons, as neuronal axonopathy is often accompanied by
the demyelination of oligodendrocytes and vice versa [84]. This can be explained by the
overexpression of PIEZO1 channels in cortical neurons that leads to Ca2+ entering axons,
triggering the release of more Ca2+ from the intracellular calcium reservoirs to activate the
calpain-mediated demyelination [84].
Collectively, all these studies indicate that PIEZO1 mediates the glial-neuron inter-
action and plays a central role in the manifestations and pathological changes of brain
function. Therefore, the specific mechanism needs to be clearly elucidated in future stud-
ies, as drugs that can target PIEZO1 for the neural regeneration and modulation of glial
function have the potential to be used for the treatment of patients with brain diseases.

6. PIEZO1 in Gliomas
Gliomas, which originate from glial cells, are some of the most common brain tumors.
The properties and behavior of the glial cells change during tumorigenesis [85,86]. Mechan-
ical forces and biochemical signals control tumor formation and development during this
process [85,86]. Strikingly, PIEZO1 physically localizes to the focal adhesion of glioma cells,
catalyzing the maturation and growth of the focal adhesion through a force-dependent
calcium signaling pathway [9,87]. A functional enrichment analysis of the China Glioma
Genome Atlas (CGGA) dataset and the Gene Set Enrichment Analysis (GSEA) dataset re-
Cancers 2023, 15, 883 7 of 14

vealed that PIEZO1 acts as a central node in a functional regulatory network that integrates
regulators associated with tissue-stiffening molecules [63]. Consistent with this, RNA
sequencing of PIEZO1 knockout glioblastoma cell lines and the TCGA database analysis
for double-determining PIEZO1-related genes show that PIEZO1 is associated with the
extracellular matrix (ECM), actin cytoskeleton remodeling, and the activation of integrin
adhesion signaling [9]. In addition, the expression of PIEZO1 transduces mechanical stimuli
among the glioma cells, promoting tumorigenesis and development [9]. This finding can
explain how the changes in self-stiffness in gliomas are mainly caused by the pressure
gradient generated by the tumor itself instead of collagen deposition or cross-linking [88].
The enhanced stiffness among glioma cells and the ECM microenvironment in turn reg-
ulates the activation of PIEZO1, facilitating the pathological process [9,87,88]. Moreover,
many signaling pathways, including the matrix metalloproteinase (MMP) family, tissue
inhibitors of the metalloproteinases (TIMP) family, the mitogen-activated protein kinase
(MAPK) family, and the phosphoinositide 3-kinase (PI3K) family, are positively associated
with the higher expression of PIEZO1 during the pathological process [63]. In short, an in-
creased expression of PIEZO1 in most aggressive tumors, including glioblastoma, indicates
a mechanical sensing and growth advantage of glioma cells.
Clinical studies on the expression of PIEZO1 in patients with gliomas demonstrate a
similar tendency. The analysis of a clinical database that consists of 325 gliomas cases from
the CGGA dataset and 276 cases from the GSE16011 cohort showed that the expression of
PIEZO1 is highly correlated with the malignancy and molecular subtypes of gliomas [63].
Moreover, the overexpression of PIEZO1 contributes to more severe clinical symptoms,
as was found via a retrospective analysis of imaging data and surgical samples from
64 patients with glioblastoma [89]. Additionally, immunohistochemical analysis of PIEZO1
in 183 patients with gliomas suggested that PIEZO1, as an independent factor, has an
adverse impact on the prognosis of glioma patients [90]. The combination of the PIEZO1
expression level and WHO grade is much more accurate in predicting clinical outcomes [90].
Overall, PIEZO1 can be used as an indicator of glioma malignancy and is able to predict
the clinical outcome in patients with gliomas.
In addition, peritumoral brain edema (PTBE), including vasogenic and cytotoxic
edema, exacerbates neurological signs and clinical symptoms in patients with gliomas,
which can serve as an independent factor for predicting the prognosis and recurrence of
the gliomas in such patients [89,91,92]. It has been postulated that vasogenic edema can be
mediated through Ca2+ influx by opening the PIEZO1 ion channels, and then activating
calpain and degrading the tight-junction protein between adjacent cells in glioblastomas
(Figure 1a). There is, however, a lack of evidence for the further validation of this hy-
pothesis [89]. Theoretically, cytotoxic edema happens due to extracellular cations entering
neurons and glial cells through cation channels and accumulating in cells while cationic
influx drives anions inflow [92]. The PIEZO1 ion channels may play a vital role during this
process. However, no studies have yet supported the relationship between PIEZO1 and
cytotoxic edema.
However, the emerging evidence shows that the activation of PIEZO1 may be a
sonodynamic therapeutic target [10]. Since it helps transient Ca2+ influx combine with the
lipid droplets, it forms a complex that disturbs the energy supply in gliomas in addition to
cell swelling lead by the calcium pathway [10]. Together with previous studies, the opposite
effect, led by the activation of PIEZO1, may be related to different mechanisms. On one
hand, during glioma genesis, PIEZO1 gathers around focal adhesions, which activates
regional calcium fluctuations and leads to adhesion maturation and cell polarization [87].
In addition, PIEZO1 interacts with integrin-dependent kinases (FAKs) and transmits signals
to the transcriptional coactivator with a PDZ-binding motif (TAZ), leading to chromatin
remodeling and changes in transcription levels (Figure 1b). On the other hand, as a
therapeutic target in gliomas, PIEZO1 acts as an ion channel for translating mechanical
stimuli to electrical and chemical signals. The mild calcium influx would change to a large
 Cancers
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2023, 15,883
x FOR PEER REVIEW 8 of 14 8 of 14

intracellular calcium transient stimulated by ultrasound, leading to a drastic change8inofthe

Cancers 2023, 15, x FOR PEER REVIEW 14
intracellular calcium transient stimulated by ultrasound, leading to a drastic change in the
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Figure
Figure1.1.Schematic
Schematic diagram
diagram of theofmechanism
the mechanism of activated PIEZO1 in
of activated glioma in
PIEZO1 progression and peri-
glioma progression and
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peritumoral edema. (a) Stiffening of the extracellular matrix activates PIEZO1, resulting in an influx in an influx of
calcium. Intracellular elevated concentrations of Ca2+ catalyzes the assembling and maturation of
of calcium. Intracellular elevated concentrations of Ca2+ catalyzes the assembling and maturation
focal adhesion, and (in-)directly activates integrin-focal adhesion pathways that stimulates cell prolif-
Figure
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Figure 2. Schematic diagram of the mechanism of PIEZO1 as an anti-glioma therapeutic target.

PIEZO1 is activated by ultrasound and constantly opens, leading to Ca 2+ influx and increased

Figure
Figure2.2.Schematic
Schematicdiagram
diagramofofthe
themechanism
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PIEZO1asasanan
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therapeutic target. PIEZO1
PIEZO1 is activated by ultrasound and constantly opens, leading to Ca 2+ influx and increased
Cancers 2023, 15, 883 9 of 14

is activated by ultrasound and constantly opens, leading to Ca2+ influx and increased concentration of
intracellular Ca2+ . The osmotic pressure between intracellular and extracellular leads to cell swelling
and induces cell death. High concentration of cytoplasmic Ca2+ enters mitochondria and elevates
intra-mitochondria Ca2+ , resulting in impaired electron transport chain (ETC) function. Subsequently,
impaired ETC leads to the elevation of reactive oxygen species (ROS). All above are contributed to
mitochondrial dysfunction, leading to cell death. In addition, the instantaneous opening of PIEZO1
leads to the rapid transmembrane of cations and a rapid increase in intra- and extracellular voltage
difference.

7. Conclusions and Perspective

Neurons and glia cells are exposed to and respond to different types of stimuli, dis-
playing high sensitivity in the CNS [19,68]. The study of mechanotransduction pathways
is an emerging field in the treatment of neurological diseases. The recently identified
mechanosensitive ion channel PIEZO1 shows distinct properties in the development of
neurological disorders, particularly in its interactions with intracellular soluble signals,
which may help identify potential therapeutic targets [36]. In this review, we summarized
the role of PIEZO1 in neurons and glial cells and described the pioneering research in
gliomas.
PIEZO1-mediated cellular responses have been reported to exhibit contradictory phe-
notypes, such as anti- versus pro-inflammatory and pro-regenerative versus regenerative
inhibition, but the most important thing is the confirmation of the ability of PIEZO1 to
move the phenotype of glial cells in the required direction [8,51]. Similarly, PIEZO1 has
been found to promote tumor aggression and development [9]. It is also reported to act as
a mediator of tumor apoptosis in gliomas [10]. This can be theoretically explained as it may
depend on the subcellular localization of PIEZO1 and the way PIEZO1 is activated [9,87].
Traction on the local plasma membrane and cytoplasm induces cell division, whereas extru-
sion on the local cytoplasm forms cytoplasmic aggregates and induces apoptosis [9,65]. In
the absence of the contact inhibition of tumor cells in glioma development, the mechanosen-
sory function of PIEZO1 is reconnected with the unidirectional ability to promote malignant
tumor progression [9].
Although the clear relationship and mechanisms between PIEZO1 and neurologi-
cal diseases such as AD, Parkinson’s disease, stroke, and spinal cord injury are still un-
clear, a rising number of studies are gradually uncovering the underlying mechanisms
involved [3,36,40,41,93]. With further research on PIEZO1, we can leverage the potential
anti-inflammatory effects of astrocytes and microglia to restore mechanotransduction path-
ways and neuron-glia crosstalk homeostasis around amyloid plaques by using PIEZO1
as a new drug target for neurodegenerative diseases and CNS injury [8,76,79]. One of the
challenges of neural stem cell transplantation therapy is determining how to best direct
cell differentiation after transplantation, and PIEZO1 plays a pivotal role in the spectral
specification of neural stem cells [4]. Drugs that target and regulate the activity of PIEZO1
may therefore provide opportunities for neural stem cell transplantation therapy.
In addition to neurodegenerative diseases, gliomas are some of the most common
brain tumors [85,86]. Several studies have explored the use of PIEZO1 as an indicator of
tumor malignance and prognosis [63,89,90]. A recent study has reported a linear correla-
tion between the expression level of PIEZO1 and the severity of peritumoral edema [89].
Edema is postulated to be caused by the opening of the blood–brain barrier (BBB), leading
to an influx of calcium and the activation of calpain that degrades the tight junctions of
the BBB [89,94]. The inhibition of PIEZO1 may, therefore, reduce clinical symptoms in
patients with gliomas and can be a therapeutic target for diseases involving the collapse
of the BBB [89]. As a non-selective cation channel, PIEZO1 is located in both plasma and
endoplasmic reticulum membranes. Once opened, it will lead to the accumulation of cyto-
toxic Ca2+ in the cytoplasm and mitochondria, which, in combination with chemotherapy
and radiotherapy, promotes the apoptosis of cancer cells [95,96]. Previous studies have
suggested that it is feasible to treat glioblastoma with autologous T-cell therapies expressing
Cancers 2023, 15, 883 10 of 14

chimeric antigen receptors (CARs). However, the off-target effect, caused by the tumor
microenvironment, tumor heterogeneity, and the antigenic loss of the glioblastoma, makes
it difficult to accurately kill the glioblastoma [97]. We can attempt to achieve controllable,
non-invasive, and precise immunotherapy for gliomas by expressing PIEZO1 on T-cells,
and, subsequently, by using ultrasound or drugs targeting PIEZO1 to locally stimulate
gliomas, thereby activating PIEZO1 and inducing the activation of the nuclear factor of the
T-cell (NFAT) that drives the expression performance of target genes [98].
In summary, PIEZO1, as a rising star molecule, can guide the functional phenotypes
of neurons and glial cells, and participate in a variety of neurological diseases. In particular,
PIEZO1 can be used as an indicator to assess the malignancy and prognosis of patients with
gliomas, as well as a therapeutic target to control tumor progression. Specific mechanistic
studies centered on PIEZO1 will contribute to our understanding of the mechanobiology of
CNS diseases and help us develop new therapeutic approaches for patients with gliomas.

Author Contributions: Conceptualization, Y.Y.; literature retrieving, R.H. and Y.Y.; draft writing,
R.H., D.Y. and Y.Y.; review and editing, D.Y., Y.J. and S.C.; supervision, S.C., H.T. and Y.Y. All authors
have read and agreed to the published version of the manuscript.
Funding: This work was supported by grants from the National Natural Science Foundation of China
(No. 82001310).
Conflicts of Interest: The authors declare no potential conflict of interest.

Abbreviations
Aβ: amyloid β; AD: Alzheimer’s disease; AKT: protein kinase B; AP-1: activator protein-1; ATP:
adenosine triphosphate; BBB: blood-brain barrier; CamKII: calmodulin-dependent protein kinases;
CARs: chimeric antigen receptors; CED: C-terminal extracellular structural domain; CGGA: China
Glioma Genome Atlas; CNS: central nervous system; CREB: cAMP-response element binding protein;
CTD: C-terminal domain; ECM: extracellular matrix; EDN1: endothelin-1; ERK1/2: extracellular
signal-regulated kinase 1/2; ETC: electron transport chain; FAK: focal adhesion kinase; GSEA: Gene
Set Enrichment Analysis; HIF-1α: hypoxia-inducible factor 1α; IH: inner helix; JAK: janus kinase;
JNK1: c-jun N-terminal kinase 1; LPS: Lipopolysaccharide; LTP: long-temporal enhancement; MAPK:
mitogen-activated protein kinase; MLCK: myosin light chain kinase; MMP: matrix metalloproteinase;
MTMR2: myotubularin-related protein 2; mTOR: mammalian target of rapamycin; NFAT: nuclear
factor of T-cell; NLPR3: Nucleotide-binding oligomerization domain, leucine- rich repeat and pyrin
domain-containing 3; Nos: nitric oxide synthase; NSCs: neural stem cells; OH: outer helix; OPCs:
oligodendrocyte progenitor cells; piezo1: Piezo-type mechanosensitive ion channel component 1;
PI3K: phosphoinositide 3-kinase; PKG: cGMP-dependent protein kinase G; PTBE: peritumoral brain
edema; ROS: reactive oxygen species; RR: Ruthenium Red; SERCA2: Sarco/endoplasmic reticu-
lum Ca2+ -ATPase; STAT: signal transducers and activators of transcription; STOML3: stomatin-like
protein 3; TAZ: transcriptional coactivator with PDZ-binding motif; TCGA: The Cancer Genome
Atlas; THU: transmembrane helix unit; TIMP: tissue inhibitors of metalloproteinases; TRPV: transient
receptor potential cation channel, subfamily V; TLR4: Toll-like receptor 4; TM: transmembrane; WHO:
World Health Organization; YAP: yes-associated protein.

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