Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing
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ABSTRACT:
PROVIDER: PRJNA1108318 | ENA |
REPOSITORIES: ENA
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Project description:Mechanosensitive Piezo1 is crucial for periosteal stem cell-mediated fracture healing
2024-12-19 | GSE266774 | GEO
Project description:The biomechanical environment plays a dominant role in fracture healing, and Piezo1 is regarded as a major mechanosensor in bone homeostasis. However, the role of Piezo1 in fracture healing is not yet well characterized. In this study, we first delineated that Piezo1 is highly expressed in periosteal stem cells (PSCs) and their derived osteoblastic lineage cells and chondrocytes. Furthermore, downregulation of Piezo1 in callus leads to impaired fracture healing, while activation by its specific agonist promotes fracture healing through stimulation of PSC-modulated chondrogenesis and osteogenesis, along with accelerated cartilage-to-bone transformation. Interestingly, vascular endothelial growth factor A is upregulated after Yoda1 treatment of PSCs, indicating an indirect role of Piezo1 in angiogenesis. Mechanistically, activation of Piezo1 promotes expression of Yes-associated protein (YAP) and its nuclear localization in PSCs, which in turn increases the expression and nuclear localization of β-catenin. In detail, YAP directly interacts with β-catenin in the nucleus and forms a transcriptional YAP/β-catenin complex, which upregulates osteogenic, chondrogenic and angiogenic factors. Lastly, Yoda1 treatment significantly improves fracture healing in a delayed union mouse model generated by tail suspension. These findings indicate that Piezo1 is a potential therapeutic target for fracture delayed union or nonunion.
| S-EPMC9274506 | biostudies-literature
Project description:In China, the incidence of fracture non-unions is relatively high. Impaired endochondral ossification may lead to nonunion due to improper mechanical loading. As a mechanosensitive ion channel protein, Piezo1mediates mechanical transduction and induces calcium inward flow. Our early study showed that the osteogenic and angiogenic capacity of chondrocytes was reduced, if Piezo1 gene was knocked out on chondrocytes. Moreover, the expression of mitochondrion translation related gene LARS2 was signaling increased. Therefore, we hypothesize that the mechanical loading may cause endochondral ossification through the Piezo1- LARS2 signaling pathway. We will use conditioned gene knockout mice and Peizo1 knockdown stable cell line to support the hypothesis. Our goals include investigating the changes of Piezo1 expression during endochondral ossification of femoral fracture healing in mice under mechanical loading; investigating the response of Piezo1 channels on chondrocytes to mechanical stimulation and its role and mechanism in regulating chondrocyte osteogenesis and angiogenesis, maintaining the normal mitochondrial function in vitro; analysing the key molecular and signal network downstream of Piezo1 through the multi-omics techniques; and exploring the response mechanism of Piezo1 under vibrating stimulus. This project aims to study the molecular mechanism of Piezo1-mediated force-biological information transition and its role in endochondral ossification. We hope it provides an effective intervention target for preventing and treating fracture nonunion.
2024-12-19 | GSE242712 | GEO
Project description:Bone regeneration is a highly efficient process allowing scarless healing after injury. The periosteum, the outer layer of bones, is a critical source of skeletal stem/progenitor cells (SSPCs), as well as immune, endothelial and neural cells during bone repair. In our study, we generated a single-nuclei atlas of the murine periosteal response to bone fracture. We generated single nuclei datasets from uninjured periosteum and from injured periosteum and hematoma/fracture callus at days 5 and 7 post-injury from wild-type mice.
2024-04-01 | GSE234451 | GEO
Project description:Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA sequencing revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved lacuno-canalicular network and reduced sclerostin production and receptor activator of nuclear factor kappa beta/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechano-stimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteal-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.
2024-12-18 | GSE276391 | GEO
Project description:Glucocorticoid-induced osteoporosis (GIOP) lacks fully effective treatments. This study investigated the role of Piezo1, a mechanosensitive ion channel component 1, in GIOP. We found reduced Piezo1 expression in cortical bone osteocytes from patients with GIOP and a GIOP mouse model. Yoda1, a Piezo1 agonist, enhanced the mechanical stress response and bone mass and strength, which were diminished by dexamethasone (DEX) administration in GIOP mice. RNA sequencing revealed that Yoda1 elevated Piezo1 expression by activating the key transcription factor Hes1, followed by enhanced CaM kinase II and Akt phosphorylation in osteocytes. This improved lacuno-canalicular network and reduced sclerostin production and receptor activator of nuclear factor kappa beta/osteoprotegerin ratio, which were mitigated by DEX. Comparative analysis of mouse models and human GIOP cortical bone revealed downregulation of mechano-stimulated osteogenic factors, such as osteocrin, and cartilage differentiation markers in osteoprogenitor cells. In human periosteal-derived cells, DEX suppressed differentiation into osteoblasts, but Yoda1 rescued this effect. Our findings suggest that reduced Piezo1 expression and activity in osteocytes and periosteal cells contribute to GIOP, and Yoda1 may offer a novel therapeutic approach by restoring mechanosensitivity.
2024-12-18 | GSE276529 | GEO
Project description:Cystic fibrosis (CF) is a life-shortening genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficit in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, we describe loss of small pulmonary blood vessels in CF patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear stress-dependent mechanism of endothelial barrier failure in CF involving calcium-permeable mechanosensitive channel TRPV4. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another calcium-permeable mechanosensitive channel involved in angiogenesis and wound repair, and further exacerbates loss of small pulmonary blood vessels. We show that CFTR directly interacts with PIEZO1 and enhances its function, and that CFTR deficiency reduces PIEZO1 activity. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.
2024-09-18 | GSE244214 | GEO
Project description:Muscle satellite cells (MuSCs), skeletal muscle-resident stem cells, are crucial for regeneration of myofibers. Mechanical cues are thought to be important for activation and proliferation of muscle satellite cells, but the molecular entity that senses biophysical forces in MuSCs remains to be elucidated. In this study, we identified PIEZO1, a mechanosensitive ion channel that is activated by membrane tension, as a critical determinant for myofiber regeneration. We investigated gene profiles of Piezo1-deficient MuSCs to understand the role of PIEZO1 during myogenesis. Our results suggest that PIEZO1 governs the cytoskeletal reorganization to regulate cellular events in MuSCs (i.e., activation, cell-division, and proliferation) during skeletal muscle regeneration.
2022-11-18 | GSE217417 | GEO
Project description:The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remains to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels, nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes, but also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad “mechanome” with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.
2024-06-05 | GSE269159 | GEO
Project description:Tissue stiffening is a physical hallmark of solid tumor. In our study, we found that the mechanosensitive ion channel PIEZO1 can be tumor cells force sensor and transducer that regulate the altered tissue mechanics. We examined the transcriptional changes modulated by depletion of PIEZO1 in two human GBM cell lines. We found that with PIEZO1 KD, the components involved in ECM organization, focal adhesion formation, cytoskeleton, and mitosis, which contribute to tissue stiffness, are down-regulated.
2018-10-18 | GSE113261 | GEO