Mechanical stretching induces fibroblasts apoptosis through activating Piezo1 and then destroying actin cytoskeleton

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Mechanical stretching induces fibroblasts apoptosis through activating Piezo1 and then destroying actin cytoskeleton

https://doi.org/10.21203/rs.3.rs-2355864/v1

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Ligaments and muscles maintain the anatomical positions of pelvic floor organs. Stress urinary incontinence (SUI) occurs when pelvic floor tissues are repeatedly stimulated with excessive mechanical tension that is beyond the capacity of ligaments or muscles to endure. In addition, cells respond mechanically to mechanical stimulation by reconstituting the Piezo1 and cytoskeletal system. This study sought to determine how Piezo1 and actin cytoskeletal contribute to MS-induced apoptosis in human anterior vaginal wall fibroblasts (hAVWFs) and the mechanisms involved. A four-point bending device was used to provide mechanical stretching to establish a cellular mechanical damage model . MS significantly induced apoptosis of hAVWFs from non-SUI patients, which exhibited apoptosis rates comparable to those of SUI patients, and silencing of Piezo1 decreased the MS-induced apoptosis. However, the disassembly of actin cytoskeleton suppressed the protective effect of Piezo1 silencing from MS. Based on these findings, Piezo1 links the actin cytoskeleton to apoptosis in hAVWFs, providing insight into the clinical diagnosis and treatment of SUI.

Biological sciences/Cell biology

Earth and environmental sciences/Biogeochemistry

Health sciences/Diseases

Stress urinary incontinence

Mechanical stretching

Actin cytoskeleton

Apoptosis

International Continence Society (ICS) defines stress urinary incontinence (SUI) as the involuntary spilling of urine during a sudden increase in abdominal pressure, such as exercise, sneezing or coughing. Epidemiological data in China show that the total prevalence rate of SUI is 18.9%, and its incidence increases with age, mostly in young and old women during puerperium[1]. Especially in the context of the aging of the global population, the incidence of SUI is expected to increase obviously. Nevertheless, the specific pathogenesis of SUI is unclear, which leads to a lot of confusion and controversy in clinical diagnosis, treatment, and prevention. The study of its pathogenesis is therefore of great clinical importance and of particular social importance at this point. At present, the mainstream view is that the relaxation of pelvic floor supporting structure can lead to SUI. In addition to the degenerative lesions of the pelvic floor supporting structure caused by aging, pregnancy, childbirth, constipation and obesity can lead to the abnormal increase of mechanical force in the pelvic tissue caused by the increase of pelvic and abdominal pressure, resulting in the effect of mechanical force, and causing mechanical damage to the pelvic supporting structure, and finally leading to the occurrence of SUI[2, 3].

The behavior of cells can be influenced by a variety of external mechanical signals, including stretching, shear stress, matrix stiffness, osmotic stress, and the topology of the substrate. They can integrate mechanical signals with genetic and chemical information[4]. In macroscopic terms, an organism's growth, dynamics, and homeostasis are governed by forces that interact between cells and tissues. Thus, biological processes are heavily influenced by mechanical forces, but we know little about how they do so. In cells, mechanical forces are detected by specialized molecules that transmit biochemical signals shaping molecular and genetic processes. Piezo1 has been shown to respond to a wide range of mechanical cues, including membrane stretch, cell indentation, substrate stiffness[5, 6]. The Piezo family consists of two family members, Piezo1 and Piezo2, which perform functions in different tissues and organs. Piezo1 is mainly expressed in unexcited cells[7], and plays an important role in the conversion of mechanical signals on the plasma membrane[8]. Moreover, there is a close relationship between piezo1 and cytoskeleton, and they interact with each other to cope with mechanical forces[9, 10].

In this study, we examined that excessive mechanical stretching (MS) destroys actin cytoskeleton and induces the apoptosis of human anterior vaginal wall fibroblasts (hAVWFs) through the activation of Piezo1.

Patients and sample collection

The present study was approved by the Ethics Committee of Renmin Hospital of Wuhan University (Wuhan, China), and verbal and written informed consent was obtained from all patients prior to participation. All methods were performed in accordance with the relevant guidelines and regulations. A total of 23 patients who underwent gynecological surgery in our hospital were selected from March 2020 to December 2021, which including 10 patients with SUI (with anterior vaginal wall prolapse or cystocele, POP-Q Ⅲ ~ Ⅳ: Ba > + 1, as SUI group), and the other 13 patients underwent total hysterectomy for benign tumors (control group). During the operation, the tissue specimens (0.5*0.5*0.5cm³) were obtained from the anterior vaginal wall, and then sent to the laboratory within half an hour for follow-up experiment. There was no evidence of connective tissue disease, endometriosis, or gynecologic malignancy in any of the recruited patients. We excluded patients who had undergone surgery in the anterior vaginal wall site or applied estrogen within the past three months.

Primary cell culture

We cultured and purified hAVWFs according to our previous description [11]. Briefly, the anterior vaginal wall tissues were cut into pieces (approximately 1 mm³), placed in culture bottles and digested with Type I Collagenase (ThermoFisher, catalog No. 17100-017) and trypsinase (Servicebio, catalog No. G4001). The fibroblasts were grown in serum-free DMEM (HyClone, catalog No. SH30243) supplemented with 20% fetal bovine serum (HyClone, catalog No. SV30087), and 100 U/ml penicillin/streptomycin (Beyotime, catalog No. ST488) at 37 °C in an incubator with 5% CO2. Following passage at 85% confluency, hAVMFs were used for subsequent experiments at passages 3 to 6. For the latrunculin A (Lat-A, a potent inhibitor of F-actin assembly; Cayman, catalog No. 10010630) experiment, hAVMFs were treated with Lat-A (0.5 μM) for 24 h.

Immunohistochemistry (IHC)

The paraffin-embedded human anterior vaginal wall samples were cut into 4μm-thick sections, which were then dewaxed with xylene and rehydrated. Incubation with anti-Piezo1 (Affinit, 1:200, catalog No. DF12083) overnight at 4°C followed by secondary antibody (Maxim Biotechnologies, Fuzhou, China) incubation for 1 hour at room temperature was carried out after antigen repair using microwave or citrate antigen retrieval solutions. The DAB kit (Maxim Biotechnologies, Fuzhou, China) was used as the chromogenic agent, and hematoxylin was used for nuclei counterstaining. Dehydration and sealing were performed in sequence, and the positive expression quantification was performed using ImageJ 1.48r software.

Mechanical stretching application

As previously described[12], the mechanical stretching loaded on hAVMFs was generated by a four‑point bending device (SXG4201; Chengdu Miracle Chemicals Co., Ltd., Chengdu, China). Basically, there were three parts to the device: strain plates, dishes, and a drive control. The parameters of mechanical force were set to 2666 με(the loading displacement was 4 mm) as the magnitude of the force on the sample and a frequency of 0.1 Hz for 4 h.

Phalloidin staining

After different treatments, Fluor-phalloidin (CST, catalog no. 8953) was incubated at room temperature for 1 h after hAVWFs had been fixed with 4% fresh paraformaldehyde for 15 minutes and permeabilized with 0.4% Triton X-100 for 5 minutes. Nuclei were stained with DAPI and observed under a fluorescence microscope. Quantitative analyses of indicated stains were performed using ImageJ software.

Flow cytometry

The apoptosis of hAVWFs in different groups were detected by flow cytometry. A total of 100 liters of binding buffer were used to resuspend hAVWFs after digestion with trypsinase and washing with PBS three times. Afterwards, for each group, 5 μL of PE Annexin V and 7μL of 7-AAD were added in accordance with the instructions on the PE Annexin V Apoptosis Detection Kit I (BD Biosciences, catalog No. 559763, USA). Apoptosis was detected by flow cytometry after gently resuspending the hAVWFs and incubating them for 15 minutes at room temperature in the dark.

Small interfering RNA

We transiently transfected primary hAVWFs with siRNA (Piezo1-targeting siRNA) using transfection reagent (GeneChem Co., Ltd., Shanghai, China) according to the manufacturer’s instructions. In order to assess knockdown efficiency, Western blots were used to detect changes in the expression of each protein.

Immunofluorescence

The morphology of hAVWFs was characterized as spindle-shaped and they were identified by Immunocytochemistry staining which showed a positive staining for vimentin and negative staining for cytokeratin. Cells from passages 3-6 of hAVWFs were cultured in chamber slides to 50% confluency. As previously described[13], after fixation with 4% paraformaldehyde and cell membrane permeabilization with Triton X100, hAVWFs were incubated overnight with anti-Piezo1 (Affinit, 1:200, catalog No. DF12083), anti-vimentin (Santa, catalog No. sc-6260; 200 μg/ml) and anti-cytokeratin (Santa, catalog No. sc-376224, 200 μg/ml) at 4 °C. Nuclei were stained with DAPI and observed under a fluorescence microscope. Quantitative analyses of indicated stains were performed using ImageJ software.

Western blotting

After exposure to different treatments, a proteinase inhibitor was added to RIPA lysis buffer, enabling the total proteins of hAVWFs to be isolated. Samples were used to evaluate protein quantification with a BCA assay kit (Beyotime Institute of Biotechnology, catalog No. P0010, Haimen, China). In total, 20 g of total protein were separated by SDS-PAGE then transferred to a polyvinylidene fluoride membrane (PVDF, Merck KGaA) using 10% SDS-PAGE, followed by blocking with 5% nonfat milk-TBST (TBS with 0.1% Tween 20) and incubation with the rabbit primary antibodies purchased from Affinity Biosciences and Abcam: anti-Piezo1 (1:1,000, catalog No. DF12083) and anti-GAPDH (1:2,000, catalog No. ab9485, served as an internal reference control) overnight at 4˚C. Then, the membranes were incubated with relevant HRP-conjugated secondary antibody for 1 h at room temperature. The reactive bands were exposed using 500 μL Western Lightning Plus-ECL (Perkin Elmer; catalog No. NEL105001EA) on a ChemiDoc MP Imaging System (Bio-Rad). Each sample's band density was normalized against the density of GAPDH, and data were obtained from three experiments.

Statistical analysis

Significant differences between groups were evaluated using the GraphPad Prism 6 (GraphPad Prism INC, CA, USA) program using one-way ANOVA (more than two groups) followed by a Tukey’s posttest for multiple comparisons within tested groups. Student’s t test was used to compare two groups. The differences were considered significant with P < 0.05.

Identification of hAVWFs

The primary fibroblasts were isolated from the anterior vaginal wall which shown vimentin is strongly expressed in the cytoplasm, and cytokeratin is not stained under immunofluorescence staining. Cells exhibited spindle- or long-spindle-shaped and some were rod-like under an inverted microscope (Fig. 1). The origin of these connective tissue fibroblasts was confirmed by the findings.

The apoptosis rate of anterior vaginal wall samples increased in SUI patients.

We observed a higher Piezo1 level in the anterior vaginal wall tissue of women with SUI compared with that in the control group (Fig. 2A, B). Of note, the apoptosis rate in SUI group was significantly increased and statistically significant when compared with the control groups (Fig. 2C, D). According to the above data, SUI patients showed increased apoptosis of anterior vaginal wall cells and Piezo1 may be involved in its pathogenesis.

Mechanical Stretching Induced The Disassembly Of Actin Cytoskeleton And Increased The Apoptosis Of Havwfs

In order to investigate the effects of abnormal mechanical forces on fibroblasts, we developed a cellular mechanical stretching loading model. As expected, we discovered that the levels of Piezo1 was significantly increased (Fig. 3A, B, C). Furthermore, MS suppressed the expression of F-actin, an indirect sign that the actin cytoskeleton is depolymerizing. (Fig. 3D, E). Using PE-positive cells as a marker, the apoptosis rate was calculated, with early apoptotic cells negative for 7-AAD and late apoptotic cells positive. MS appeared to induce a strong increase in apoptosis (Fig. 3F, G). It is interesting to note that the hAVWFs from SUI patients and controls with MS exhibit similar differences in Piezo1 expression, apoptosis rate, and actin cytoskeleton disassembly (Fig. 3A, B, C, D, E, F, G). Accordingly, mechanical force may be involved in the occurrence and development of SUI, which induces apoptosis and disassembly of the actin cytoskeleton in hAVWFs.

Piezo1 Silencing Alleviated Ms-induced Apoptosis

The purpose of this study was to demonstrate the importance of Piezo1 in MS-induced apoptosis by evaluating the functional effects of Piezo1 silencing. The results showed that MS insult markedly increased the apoptosis rate and actin cytoskeleton disassembly of hAVWFs as compared to the control. However, Piezo1 knockdown significantly reversed the increase induced by MS (Fig. 4A, B, C, D). Silencing of Piezo1 seemed to provide a protection against MS-induced injury, suggesting that Piezo1 may play an important role in MS-induced apoptosis and actin cytoskeleton disassembly.

Disassembly Of Actin Cytoskeleton Suppressed The Protective Effect Of Piezo1 Silencing From Ms

So, under mechanical stretching, does Piezo1 induce apoptosis through increasing actin cytoskeleton disassembly? To address this, the actin cytoskeleton was disrupted using Lat-A, which sequesters monomeric actin and causes actin microfibrils to depolymerize rapidly. Silencing of Piezo1 seemed to provide a protection against MS-induced injury. However, the disassembly of actin cytoskeleton suppressed the protective effect of Piezo1 silencing from MS (Fig. 5A, B). Based on the above data, it is evident that the overexpression of Piezo1 contributed to the depolymerization of actin cytoskeleton to participate in MS-induced apoptosis.

The molecular mechanism of SUI has not been fully elucidated so far. From the anatomical level, the key mechanism leading to the pathogenesis of SUI is the weakening of urethral support function and the defect of urethral inherent sphincter function. The muscles, ligaments and fascia of the pelvic floor work together to provide support for the urethra. Fascia and ligaments achieve urinary self-incontinence by maintaining the position of the bladder neck and urethra and the closure of the urethra. The pelvic floor tissue of women is subject to complex biomechanical changes caused by changes in abdominal pressure during pregnancy and delivery. Maintaining the normal structure and function of the pelvic floor depends on the balance of force produced by the pelvic floor muscles and ligaments. "whole theory" and "hammock hypothesis" also emphasize that the pelvic floor fascia ligament plays an important role in resisting external forces. Studies on the pathogenesis of SUI suggest that the key factors are closely related to the relaxation of support structures, such as the pelvic floor fascia ligaments [14], which are formed largely by fibroblasts. Kokcu et al found that the number of fibroblasts in patients with pelvic floor relaxation was significantly lower than that in patients with non-prolapse[15]. Traumatic mechanical force can significantly inhibit the proliferation of fibroblasts[13]. It can be seen that the decrease of the number of fibroblasts in the pelvic floor is an important reason for the pathogenesis of SUI. In this study, the apoptosis rate of anterior vaginal wall fibroblasts in SUI patients and non-SUI patients with mechanical stretching showed a significant increase. It suggested that the death of fibroblasts in pelvic floor supporting tissue caused by excessive mechanical stimulation may be an important cause of SUI, but its specific mechanism still needs to be explored.

The dynamic mechanical behavior of living cells is based on the Laws of Newtonian mechanics. And fibroblasts possess mechano-sensitive features and the ability to accept and adapted to the mechanical force in accordance with exposure to mechanical stimulations, as they transduce a mechanical force into chemical signals[4]. The mechanical force exerted on cells is sensed by specialized molecules. However, there is still a gap in the understanding of the specific molecular mechanism in this process. Over the past decade, scientists at home and abroad have carried out a large number of in studies to expound how cells sense mechanical forces and how this can be translated into chemical signaling events. The discovery of Piezo is one of the important achievements in this filed. Piezo is an evolutionarily conserved molecule involved in many signal transduction pathways, such as cell development, migration and differentiation, which is activated in many different cell types and in response to a diverse array of cellular forces[16, 17]. Piezo1 is mainly expressed in non-excitable cells, which plays an important role in translating mechanical forces into chemical signaling[7, 8]. In terms of molecular structure, Piezo1 trimeric forms a remarkable three-bladed, propeller-like architecture, exhibited exceptional mechanical behaviour that originate from their unique molecular topologies[18]. In articular chondrocytes, excessive mechanical tension activied Piezo1, and then upregulated caspase-12 further activating the caspase cascade and leading to apoptosis[19]. Meanwhile, it has been reported that the use of GsMTx4 can inhibit Piezo1 activity in the urothelium, affect Piezo1-dependent arterial remodelling and reduce cell death due to high strain mechanical injury[20]. In the present study, we found that the expression of Piezo1 and apoptosis rate were significantly increased in the SUI group when compared to healthy controls. Moreover, the expression of Piezo1 and apoptosis rate were significantly elevated following mechanical stretching. However, silencing of Piezo1 in hAVWFs seemed to provide a protection against mechanical stretching -induced injury. It suggests that Piezo1 plays an important role in mechanical stretching-induced fibroblasts apoptosis.

How then, does Piezo1 lead to fibroblasts apoptosis upon mechanical stretching? Actin cytoskeletons are composed of proteins that serve a variety of biological functions, including cell contraction, motility, and apoptosis. An actin filament is formed by reversibly polymerizing 42 kDa globular proteins (G-actin) into filaments (F-actin, which can combine with phalloidin). Various stages of apoptosis are marked by dramatic changes in actin filament organization, which demonstrates the importance of the actin cytoskeleton during apoptosis[21]. For example, in the final stages of apoptosis, the actin cytoskeleton is degraded, followed by phagocytosis of apoptotic bodies[22]. As evidence mounts that actin mediates and initiates apoptosis signaling, actin plays an important role in morphological hallmarks of apoptosis. In our precious study[12], the disruption of the cellular cytoskeleton increased the apoptosis induced by mechanical stretching. At the same time, there are other significant changes in this study that deserve our attention. We found that the disassembly of actin cytoskeleton suppressed the protective effect of Piezo1 silencing from mechanical stretching-induced apoptosis. As mentioned earlier, Piezo1, a mechanosensitive ion channel protein, is activated by mechanical stimuli. Several intracellular processes are triggered by Piezo1 activity, including some that affect the cytoskeleton. For Piezo1, the initial effect of this outside-in mechanical transduction was a large inflow of Ca²⁺, which may even be used to reflect the activation of Piezo1 [23]. In the past, studies have demonstrated that Ca²⁺ signaling modulates the actin cytoskeleton by acting with actin binding proteins[24]. On the other hand, Piezo1 activates the proteins associated with cytoskeletal dynamics, such as Calpain 2, which is central to the cytoskeletal changes[25, 26]. Combined with our experimental results, it is clear that Piezo1 is close to the actin cytoskeleton, and that piezo1 regulates the state of its disassembly.

Collectively, the results of our report illustrate the important role of Piezo1 in the mechanical stretching-induced apoptosis via regulating actin cytoskeleton disassembly in hAVWFs. Moreover, we establish the links among Piezo1, actin cytoskeleton and apoptosis with respect to mechanical stretching-induced SUI. Based on these findings, the strategies to regulate the balance of the Piezo1 expression and actin cytoskeleton disassembly could be a therapeutic target to SUI in the clinical practice.

SUI: stress urinary incontinence; hAVWFs: human anterior vaginal wall fibroblasts; MS: mechanical stretching; ICS: International Continence Society.

Acknowledgments

The authors would like to thank all the teachers in the Department of Gynecology and Obstetrics and Central Laboratory, Renmin Hospital of Wuhan University, for their technical assistance.

Funding

Financial support for the present study comes from the Fundamental Research Funds for the Central Universities (grant number: 2042022kf1110), the National Key R&D Program of China (grant number: 2018YFC2002204 and 2021YFC2701302), and the National Natural Science Foundation of China (grant number: 81971364 ).

Data availability

The corresponding author may provide access to the analyzed datasets generated during the study upon reasonable request.

Conflicts of interest

None.

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No competing interests reported.

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Mechanical stretching induces fibroblasts apoptosis through activating Piezo1 and then destroying actin cytoskeleton

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Abstract

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Introduction

Materials And Methods

Results

Identification of hAVWFs

The apoptosis rate of anterior vaginal wall samples increased in SUI patients.

Mechanical Stretching Induced The Disassembly Of Actin Cytoskeleton And Increased The Apoptosis Of Havwfs

Piezo1 Silencing Alleviated Ms-induced Apoptosis

Disassembly Of Actin Cytoskeleton Suppressed The Protective Effect Of Piezo1 Silencing From Ms

Discussion

Abbreviations

Declarations

References

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