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Cited by 26Hippo pathway signaling and YAP/TAZCellular Mechanics and InteractionsNuclear Structure and Function

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The cytoskeleton dynamics-dependent LINC complex in periodontal ligament stem cells transmits mechanical stress to the nuclear envelope and promotes YAP nuclear translocation

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Meng, Xuehuan, Zhu, Ye, Tan, Hao, Daraqel, Baraa, Ming, Ye, Li, Xiang, Yang, Guoyin, He, Xinyi, Song, Jinlin, Zheng, Leilei·2024·Stem Cell Research & Therapy
DOI 10.1186/s13287-024-03884-0PMC PMC11380336
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Abstract

BACKGROUND: Periodontal ligament stem cells (PDLSCs) are important seed cells in tissue engineering and clinical applications. They are the priority receptor cells for sensing various mechanical stresses. Yes-associated protein (YAP) is a recognized mechanically sensitive transcription factor. However, the role of YAP in regulating the fate of PDLSCs under tension stress (TS) and its underlying mechanism is still unclear. METHODS: The effects of TS on the morphology and fate of PDLSCs were investigated using fluorescence staining, transmission electron microscopy, flow cytometry and quantitative real-time polymerase chain reaction (qRT-PCR). Then qRT-PCR, western blotting, immunofluorescence staining and gene knockdown experiments were performed to investigate the expression and distribution of YAP and its correlation with PDLSCs proliferation. The effects of cytoskeleton dynamics on YAP nuclear translocation were subsequently explored by adding cytoskeleton inhibitors. The effect of cytoskeleton dynamics on the expression of the LINC complex was proved through qRT-PCR and western blotting. After destroying the LINC complex by adenovirus, the effects of the LINC complex on YAP nuclear translocation and PDLSCs proliferation were investigated. Mitochondria-related detections were then performed to explore the role of mitochondria in YAP nuclear translocation. Finally, the in vitro results were verified by constructing orthodontic tooth movement models in Sprague-Dawley rats. RESULTS: TS enhanced the polymerization and stretching of F-actin, which upregulated the expression of the LINC complex. This further strengthened the pull on the nuclear envelope, enlarged the nuclear pore, and facilitated YAP's nuclear entry, thus enhancing the expression of proliferation-related genes. In this process, mitochondria were transported to the periphery of the nucleus along the reconstructed microtubules. They generated ATP to aid YAP's nuclear translocation and drove F-actin polymerization to a certain degree. When the LINC complex was destroyed, the nuclear translocation of YAP was inhibited, which limited PDLSCs proliferation, impeded periodontal tissue remodeling, and hindered tooth movement. CONCLUSIONS: Our study confirmed that appropriate TS could promote PDLSCs proliferation and periodontal tissue remodeling through the mechanically driven F-actin/LINC complex/YAP axis, which could provide theoretical guidance for seed cell expansion and for promoting healthy and effective tooth movement in clinical practice.

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Figures

Fig. 1 TS led to rearrangement in PDLSCs morphology and affected cell life activities. A Schematic diagram of the TS loading system in vitro. B Fluorescence staining of cytoskeletons after TS application. Scale bars = 200 μm in the first and third rows. The second and fourth rows showed enlarged images of the upper magenta boxes, scale bars = 50 μm. C Quantitative analysis of the cell projected area corresponding to F-actin (n = 38, 38, 30 roi, respectively) and the perinuclear distribution length of microtubules (n = 35 roi per condition) after TS application. The perinuclear distribution length of microtubules was defined as the longest straight-line distance between two boundary points of microtubules passing through the nucleus. D Fluorescence staining of the nucleus and quantitative analysis of the nuclear area and nuclear aspect ratio after TS application (n = 25 roi per condition). Scale bars = 50 μm. E TEM images of the nuclear pores after TS application. Scale bars = 200 nm. The lower row showed enlarged images of the upper magenta boxes, with the magenta arrows and lines indicating the nuclear pores, scale bars = 40 nm. F Quantitative analysis of nuclear pore size after TS application (n = 5 roi per condition). G Fluorescence staining of mitochondria after TS application. Scale bars = 50 μm. H Quantitative analysis of the perinuclear distribution length of mitochondria after TS application (n = 50 roi per condition). The perinuclear distribution length of mitochondria was defined as the longest straight-line distance between two boundary points of mitochondria passing through the nucleus. I The PI and apoptosis ratio after TS application for 6 h or 24 h. J The mRNA level of proliferation-related genes after TS application for 6 h
Fig. 1 TS led to rearrangement in PDLSCs morphology and affected cell life activities. A Schematic diagram of the TS loading system in vitro. B Fluorescence staining of cytoskeletons after TS application. Scale bars = 200 μm in the first and third rows. The second and fourth rows showed enlarged images of the upper magenta boxes, scale bars = 50 μm. C Quantitative analysis of the cell projected area corresponding to F-actin (n = 38, 38, 30 roi, respectively) and the perinuclear distribution length of microtubules (n = 35 roi per condition) after TS application. The perinuclear distribution length of microtubules was defined as the longest straight-line distance between two boundary points of microtubules passing through the nucleus. D Fluorescence staining of the nucleus and quantitative analysis of the nuclear area and nuclear aspect ratio after TS application (n = 25 roi per condition). Scale bars = 50 μm. E TEM images of the nuclear pores after TS application. Scale bars = 200 nm. The lower row showed enlarged images of the upper magenta boxes, with the magenta arrows and lines indicating the nuclear pores, scale bars = 40 nm. F Quantitative analysis of nuclear pore size after TS application (n = 5 roi per condition). G Fluorescence staining of mitochondria after TS application. Scale bars = 50 μm. H Quantitative analysis of the perinuclear distribution length of mitochondria after TS application (n = 50 roi per condition). The perinuclear distribution length of mitochondria was defined as the longest straight-line distance between two boundary points of mitochondria passing through the nucleus. I The PI and apoptosis ratio after TS application for 6 h or 24 h. J The mRNA level of proliferation-related genes after TS application for 6 hCC BY-NC-ND · PubMed Central
Fig. 2 TS triggered YAP nuclear translocation in PDLSCs and PDL tissue and promoted cell proliferation. A The mRNA level of YAP after TS application. B The protein expression of YAP and quantitative analysis after TS application. C Immunofluorescence staining of YAP and quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after TS application (n = 44, 33 roi, respectively). Scale bars = 100 μm. D The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after TS application. E The mRNA level of proliferation-related genes after siRNA transfection. F The representative 3D reconstruction and X-ray images of rat maxillary bones after force loading 0 day (Con), 3 days, 7 days and 14 days. The arrow indicated the direction of tooth movement. Scale bars = 2 mm. G Quantitative analysis of tooth movement distance in rats (n = 5). H Representative HE staining of the distal buccal root of the maxillary first molar in rats. The arrow indicated the direction of tooth movement, and dotted lines marked the boundary of PDL. Ab, Alveolar bone; P, PDL; R, Root; Pu, Pulp. Scale bars = 100 μm. I YAP immunofluorescence staining of the tension side PDL tissue in rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm. J PCNA immunofluorescence staining of the tension side PDL tissue in rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm
Fig. 2 TS triggered YAP nuclear translocation in PDLSCs and PDL tissue and promoted cell proliferation. A The mRNA level of YAP after TS application. B The protein expression of YAP and quantitative analysis after TS application. C Immunofluorescence staining of YAP and quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after TS application (n = 44, 33 roi, respectively). Scale bars = 100 μm. D The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after TS application. E The mRNA level of proliferation-related genes after siRNA transfection. F The representative 3D reconstruction and X-ray images of rat maxillary bones after force loading 0 day (Con), 3 days, 7 days and 14 days. The arrow indicated the direction of tooth movement. Scale bars = 2 mm. G Quantitative analysis of tooth movement distance in rats (n = 5). H Representative HE staining of the distal buccal root of the maxillary first molar in rats. The arrow indicated the direction of tooth movement, and dotted lines marked the boundary of PDL. Ab, Alveolar bone; P, PDL; R, Root; Pu, Pulp. Scale bars = 100 μm. I YAP immunofluorescence staining of the tension side PDL tissue in rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm. J PCNA immunofluorescence staining of the tension side PDL tissue in rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μmCC BY-NC-ND · PubMed Central
Fig. 3 F-actin dynamics participated in TS-induced YAP nuclear translocation in PDLSCs. A Fluorescence staining of cytoskeletons after adding cytoskeleton inhibitors. Scale bars = 100 μm. B The mRNA level of YAP after adding cytoskeleton inhibitors. C The immunofluorescence staining of YAP after adding cytoskeleton inhibitors. Scale bars = 100 μm. D Quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after adding cytoskeleton inhibitors (n = 45, 45, 36, 45 roi, respectively). E, F The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adding cytoskeleton inhibitors. G The mRNA level of proliferation-related genes after adding F-actin inhibitor. H The nuclear and cytoplasmic protein expression of F-actin and quantitative analysis after adding F-actin inhibitor. I Nuclear fluorescence staining and quantitative analysis of nuclear area and nuclear aspect ratio after adding F-actin inhibitor (n = 55 roi per condition). Scale bars = 50 μm
Fig. 3 F-actin dynamics participated in TS-induced YAP nuclear translocation in PDLSCs. A Fluorescence staining of cytoskeletons after adding cytoskeleton inhibitors. Scale bars = 100 μm. B The mRNA level of YAP after adding cytoskeleton inhibitors. C The immunofluorescence staining of YAP after adding cytoskeleton inhibitors. Scale bars = 100 μm. D Quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after adding cytoskeleton inhibitors (n = 45, 45, 36, 45 roi, respectively). E, F The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adding cytoskeleton inhibitors. G The mRNA level of proliferation-related genes after adding F-actin inhibitor. H The nuclear and cytoplasmic protein expression of F-actin and quantitative analysis after adding F-actin inhibitor. I Nuclear fluorescence staining and quantitative analysis of nuclear area and nuclear aspect ratio after adding F-actin inhibitor (n = 55 roi per condition). Scale bars = 50 μmCC BY-NC-ND · PubMed Central
Fig. 4 The F-actin dynamics-dependent LINC complex was indispensable for TS-induced YAP nuclear translocation in PDLSCs. A The mRNA level of Nesprin1-4 after TS application. B The mRNA level of Nesprin1 after adding cytoskeleton inhibitors. C The protein expression of Nesprin1 and quantitative analysis after adding cytoskeleton inhibitors. D Immunofluorescence staining showed Nesprin1’s nuclear envelope localization after adenovirus transfection. The mCherry was self-fluorescence of adenovirus. Scale bars = 25 μm. E Immunofluorescence staining of YAP after adenovirus transfection. The lowest row showed the cells with restricted YAP nuclear translocation were just the cells whose LINC complex was destroyed (the magenta arrows indicated). Scale bars = 50 μm. F Quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after adenovirus transfection (n = 30 roi per condition). G, H The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adenovirus transfection. I The mRNA level of proliferation-related genes after adenovirus transfection
Fig. 4 The F-actin dynamics-dependent LINC complex was indispensable for TS-induced YAP nuclear translocation in PDLSCs. A The mRNA level of Nesprin1-4 after TS application. B The mRNA level of Nesprin1 after adding cytoskeleton inhibitors. C The protein expression of Nesprin1 and quantitative analysis after adding cytoskeleton inhibitors. D Immunofluorescence staining showed Nesprin1’s nuclear envelope localization after adenovirus transfection. The mCherry was self-fluorescence of adenovirus. Scale bars = 25 μm. E Immunofluorescence staining of YAP after adenovirus transfection. The lowest row showed the cells with restricted YAP nuclear translocation were just the cells whose LINC complex was destroyed (the magenta arrows indicated). Scale bars = 50 μm. F Quantitative analysis of nuclear/cytoplasmic YAP fluorescence ratio after adenovirus transfection (n = 30 roi per condition). G, H The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adenovirus transfection. I The mRNA level of proliferation-related genes after adenovirus transfectionCC BY-NC-ND · PubMed Central
Fig. 5 The disrupted LINC complex prevented TS-induced YAP nuclear translocation in PDL tissue and hindered tooth movement. A Schematic diagram of adenovirus local injection and rat OTM model construction. B The representative 3D reconstruction and X-ray images of rat maxillary bones after force loading 3 days, 7 days and 14 days. The arrow indicated the direction of tooth movement. Scale bars = 2 mm. C Quantitative analysis of tooth movement distance in each group of rats (n = 5). D Representative HE staining of the distal buccal root of the maxillary first molar in each group of rats. The arrow indicated the direction of tooth movement, and dotted lines marked the boundary of PDL. Ab, Alveolar bone; P, PDL; R, Root; Pu, Pulp. Scale bars = 100 μm. E YAP immunofluorescence staining of the tension side PDL tissue in each group of rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm. F PCNA immunofluorescence staining of the tension side PDL tissue in each group of rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm
Fig. 5 The disrupted LINC complex prevented TS-induced YAP nuclear translocation in PDL tissue and hindered tooth movement. A Schematic diagram of adenovirus local injection and rat OTM model construction. B The representative 3D reconstruction and X-ray images of rat maxillary bones after force loading 3 days, 7 days and 14 days. The arrow indicated the direction of tooth movement. Scale bars = 2 mm. C Quantitative analysis of tooth movement distance in each group of rats (n = 5). D Representative HE staining of the distal buccal root of the maxillary first molar in each group of rats. The arrow indicated the direction of tooth movement, and dotted lines marked the boundary of PDL. Ab, Alveolar bone; P, PDL; R, Root; Pu, Pulp. Scale bars = 100 μm. E YAP immunofluorescence staining of the tension side PDL tissue in each group of rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μm. F PCNA immunofluorescence staining of the tension side PDL tissue in each group of rats. Scale bars = 20 μm. The last column showed enlarged images of the left magenta boxes. Ab, Alveolar bone; P, PDL; R, Root. Scale bars = 4 μmCC BY-NC-ND · PubMed Central
Fig. 6 TS enhanced mitochondrial dynamics to provide ATP for YAP nuclear translocation in PDLSCs. A Fluorescence co-localization staining of mitochondria and microtubules after adding microtubule inhibitor. Scale bars = 25 μm. B TEM showed the positional relationship of mitochondria and nucleus after TS application. The blue line depicted the nucleus outline and the red line depicted the mitochondria outline. Scale bars = 2 μm. The right column showed enlarged images of the left magenta boxes and the red shadow highlighted the mitochondria, scale bars = 200 nm. C JC-1 fluorescence staining after TS application. Scale bars = 100 μm. D Quantitative analysis of JC-1 fluorescence staining after TS application. E The mRNA level of mitochondrial biogenesis-related genes (NRF1, PGC1-α), mitochondrial fission-related gene (DRP1) and mitochondrial fusion-related genes (MFN1, MFN2) after TS application. F ATP content in PDLSCs after TS application. G ATP content in PDLSCs after adding ATP synthase inhibitor. H, I The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adding ATP synthase inhibitor. J Fluorescence staining of cytoskeletons after adding ATP synthase inhibitor. Scale bars = 100 μm. K Fluorescence intensity analysis of cytoskeletons after adding ATP synthase inhibitor. L The protein expression of Nesprin1 and quantitative analysis after adding ATP synthase inhibitor
Fig. 6 TS enhanced mitochondrial dynamics to provide ATP for YAP nuclear translocation in PDLSCs. A Fluorescence co-localization staining of mitochondria and microtubules after adding microtubule inhibitor. Scale bars = 25 μm. B TEM showed the positional relationship of mitochondria and nucleus after TS application. The blue line depicted the nucleus outline and the red line depicted the mitochondria outline. Scale bars = 2 μm. The right column showed enlarged images of the left magenta boxes and the red shadow highlighted the mitochondria, scale bars = 200 nm. C JC-1 fluorescence staining after TS application. Scale bars = 100 μm. D Quantitative analysis of JC-1 fluorescence staining after TS application. E The mRNA level of mitochondrial biogenesis-related genes (NRF1, PGC1-α), mitochondrial fission-related gene (DRP1) and mitochondrial fusion-related genes (MFN1, MFN2) after TS application. F ATP content in PDLSCs after TS application. G ATP content in PDLSCs after adding ATP synthase inhibitor. H, I The nuclear and cytoplasmic protein expression of YAP and quantitative analysis after adding ATP synthase inhibitor. J Fluorescence staining of cytoskeletons after adding ATP synthase inhibitor. Scale bars = 100 μm. K Fluorescence intensity analysis of cytoskeletons after adding ATP synthase inhibitor. L The protein expression of Nesprin1 and quantitative analysis after adding ATP synthase inhibitorCC BY-NC-ND · PubMed Central
Fig. 7 Mechanism diagram. During the OTM process, PDLSCs on the tension side received continuous TS stimulus, which enhanced the polymerization and stretching of F-actin and then upregulated the expression of the LINC complex, thus strengthening the pull on the nuclear envelope, enlarging the nuclear pore and facilitating YAP’s entry into the nucleus. At the same time, the mitochondria were activated and moved towards the nucleus along the reconstructed microtubules under the stress state, producing ATP to assist YAP nuclear translocation and to drive F-actin polymerization to a certain extent. YAP further promoted the expression of downstream proliferation-related genes after entering the nucleus, thus promoting cell proliferation and finally leading to effective tooth movement
Fig. 7 Mechanism diagram. During the OTM process, PDLSCs on the tension side received continuous TS stimulus, which enhanced the polymerization and stretching of F-actin and then upregulated the expression of the LINC complex, thus strengthening the pull on the nuclear envelope, enlarging the nuclear pore and facilitating YAP’s entry into the nucleus. At the same time, the mitochondria were activated and moved towards the nucleus along the reconstructed microtubules under the stress state, producing ATP to assist YAP nuclear translocation and to drive F-actin polymerization to a certain extent. YAP further promoted the expression of downstream proliferation-related genes after entering the nucleus, thus promoting cell proliferation and finally leading to effective tooth movementCC BY-NC-ND · PubMed Central

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Metadata

Authors
Meng, X., Zhu, Y., Tan, H., Daraqel, B., Ming, Y., Li, X., Yang, G., He, X., Song, J., & Zheng, L.
Affiliations
  • Chongqing Medical University (CN)
  • Al-Quds University (PS)
Corresponding author
  • Song, Jinlin
  • Zheng, Leilei
ORCID
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2024-09-06
Volume
15
Issue
1
Pages
284-284
ISSN
1757-6512 (ISSN-L)
DOI
10.1186/s13287-024-03884-0
PMC
PMC11380336
OpenAlex
W4402308709
Cited by
26
References
1
Citations by year
2026: 17 · 2025: 8 · 2024: 1
FWCI
5.85
Type
journal article
Language
en
Open access
Licence
Locations
  • Stem Cell Research & Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (81470772)
  • Chongqing Talent Program: Innovative leading talents (CQYC20210303384)
  • Chongqing Medical Scientific Research Project (cstc2020jcyj-msxmX0307, CSTB2023NSCQ-MSX0233)
  • Program for Youth Innovation in Future Medicine, Chongqing Medical University (W0033)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
periodontal ligament stem cells, LINC complex, YAP nuclear translocation, tensile stress, cytoskeletal dynamics, F-actin polymerization, nuclear envelope, mitochondria, microtubules, cell proliferation, periodontal tissue remodeling, orthodontic tooth movement, mechanotransduction
MeSH terms
YAP-Signaling Proteins, Animals, Cells, Cultured, Cytoskeleton, Humans, Male, Nuclear Envelope, Periodontal Ligament, Stem Cells, Stress, Mechanical, Transcription Factors, Adaptor Proteins, Signal Transducing, Cell Proliferation, Rats

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CoChat. (2026). Citation check: The cytoskeleton dynamics-dependent LINC complex in periodontal ligament stem cells transmits mechanical stress to the nuclear envelope and promotes YAP nuclear translocation. https://app.cochat.ai/papers/10.1186/s13287-024-03884-0
The paper
Meng, X., Zhu, Y., Tan, H., Daraqel, B., Ming, Y., Li, X., Yang, G., He, X., Song, J., & Zheng, L. (2024). The cytoskeleton dynamics-dependent LINC complex in periodontal ligament stem cells transmits mechanical stress to the nuclear envelope and promotes YAP nuclear translocation. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03884-0