Humanoid robot upregulates cellular stress pathways in tendon tissue engineering
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1142423 | ENA |
REPOSITORIES: ENA
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Project description:Mechanical stimulation is essential in tissue engineering and regenerative medicine for proper tissue maturation. However, conventional dynamic stimulation is typically achieved with uniaxial platforms, which limit functionality due to the oversimplified mechanics compared to the complex mechanical inputs of the human body. In this study, we explore human cell responses to stimulation using a humanoid robot shoulder and a uniaxial platform at equivalent strains. A flexible, biocompatible sensor monitoring in situ strains shows that external maximum forces of 25 N and 50 N during robot abduction-adduction motions lead to strains of approximately 3.5% and 9.5%, respectively. Additionally, we demonstrate in situ cell imaging by utilizing the transparency of the bioreactor membrane. The robot motions significantly enhance cell orientation and induce notable changes in gene and protein expression, particularly within the PI3K-Akt signaling pathway, compared to both static and uniaxial stimulation controls. These findings underscore the need to better match human biomechanics in bioreactor platforms to improve tissue engineering outcomes.
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Project description:Tendon degeneration and injury often result in significant pain and functional impairment. Typically, tendon healing occurs through a scar-mediated response and may progress to chronic tendinopathy without timely intervention. However, the molecular mechanisms underlying early tendon repair remain poorly understood. Further investigation is also impeded by the limited availability of early tendon injury samples in clinical settings. In this study, we established a puncture-induced tendon injury model to investigate the molecular patterns and cellular subpopulations involved in early tendon injury across multiple time points. RNA sequencing identified seven gene sets with distinct expression profiles during the early stages of tendon injury. Single-cell RNA sequencing further revealed eight myeloid cell types and seven mesenchymal cell types participating in the tendon repair process. Together, these findings illuminate the molecular and cellular dynamics coordinating early tendon repair, providing insights that could inform future clinical treatments for tendinopathy and tendon injury.
2025-04-23 | GSE288444 | GEO
Project description:Tendon degeneration and injury often result in significant pain and functional impairment. Typically, tendon healing occurs through a scar-mediated response and may progress to chronic tendinopathy without timely intervention. However, the molecular mechanisms underlying early tendon repair remain poorly understood. Further investigation is also impeded by the limited availability of early tendon injury samples in clinical settings. In this study, we established a puncture-induced tendon injury model to investigate the molecular patterns and cellular subpopulations involved in early tendon injury across multiple time points. RNA sequencing identified seven gene sets with distinct expression profiles during the early stages of tendon injury. Single-cell RNA sequencing further revealed eight myeloid cell types and seven mesenchymal cell types participating in the tendon repair process. Together, these findings illuminate the molecular and cellular dynamics coordinating early tendon repair, providing insights that could inform future clinical treatments for tendinopathy and tendon injury.
2025-04-23 | GSE288443 | GEO
Project description:Rotator cuff injuries result in over 500,000 surgeries performed annually, an alarmingly high number of which fail. These procedures typically involve repair of the injured tendon and removal of the subacromial bursa. However, recent identification of a resident population of mesenchymal stem cells and inflammatory responsiveness of the bursa to tendinopathy indicate an unexplored biological role of the bursa in the context of rotator cuff disease. Therefore, we aimed to understand the clinical relevance of bursa-tendon crosstalk, characterize the biologic role of the bursa within the shoulder, and test the therapeutic potential for targeting the bursa. Proteomic profiling of patient bursa and tendon samples demonstrated that the bursa is activated by tendon injury. Using a rat to model rotator cuff injury and repair, tenotomy-activated bursa protected the intact tendon adjacent to the injured tendon and maintained the morphology of the underlying bone. The bursa also promoted an early inflammatory response in the injured tendon, initiating key players in wound healing. In vivo results were supported by targeted organ culture studies of the bursa. To examine the potential to therapeutically target the bursa, dexamethasone was delivered to the bursa, prompting a shift in cellular signaling towards modulating inflammation in the healing tendon. In conclusion, contrary to current clinical practice, the bursa should be retained to the greatest extent possible and provides a new therapeutically target for improving tendon healing outcomes.
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Project description:Background: Heterotopic ossification (HO), characterized by pathological bone formation in extra-skeletal tissues such as tendon, often results in debilitating tissue dysfunction. HO of tendons primarily arises from abnormal osteogenic differentiation of tendon stem cells following injury. Despite being a common clinical occurrence, the cellular and molecular mechanisms of tendon HO are poorly understood, and effective treatments remain elusive. Farnesol, a natural isoprenoid alcohol abundant in citrus fruits, lavender, and royal jelly, is known for its potent anti-inflammatory, antioxidant, and antitumor properties. However, its applications in tissue engineering are rarely explored, particularly in musculoskeletal repair. Here, we provide the first report on the therapeutic potential of Farnesol in attenuating tendon HO and elucidate the associated molecular mechanisms.Methods: This study evaluated the effects of Farnesol on osteogenic differentiation of tendon-derived stem cells using both in vitro and in vivo models. The molecular mechanisms underlying the therapeutic effects of Farnesol on tendon HO were revealed by RNA sequencing combined with network pharmacology analysis, identifying the GSTP1/MAPK axis as a potential target pathway. In vitro rescue experiments using a specific GSTP1 inhibitor were conducted to confirm whether Farnesol primarily exerted its therapeutic effects through GSTP1.Results: The results demonstrated significant effects of Farnesol on attenuating tendon HO both in vitro and in vivo. Combined analysis of transcriptomics and network pharmacology indicated that Farnesol functions by targeting the GSTP1/MAPK signaling axis. These findings were further validated by in vitro experiments using the GSTP1 inhibitor, which reversed the suppressive effects of Farnesol on osteogenesis.Conclusion: Farnesol inhibits the progression of post-traumatic tendon HO by targeting the GSTP1/MAPK pathway. These findings provide new insights into the potential of using Farnesol as a therapeutic agent for HO.
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Project description:Tendon from young and old donors was used for RNA-Seq analysis. The aim of the study was to identify differentially expressed tendon transcripts in ageing in order to to characterize molecular mechanisms associated with age-related changes in tendon.
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Project description:Tendon injuries can occur due to sports related incidents, as a result of trauma to overuse or during disease or ageing. Tissue engineering can offer great potential in the treatment of a tendon injury. The preferred cell source is autologous in order to reduce immune response in the treated individual. However, in elderly patients age-related changes in metabolism of the implanted cells may affect results of such therapy. In this study the effect of donor age on synthetic activity of cells used for creation of tendon tissue-engineered constructs was investigated by using label-free proteomic comparison.
2018-10-26 | PXD005322 | Pride
Project description:Synthetic Notch (synNotch) receptors are modular synthetic components that are genetically engineered into mammalian cells to detect signals presented by neighboring cells and respond by activating prescribed transcriptional programs. To date, synNotch has been used to program therapeutic cells and pattern morphogenesis in multicellular systems. However, cell-presented ligands have limited versatility for applications that require spatial precision, such as tissue engineering. To address this, we developed a suite of materials to activate synNotch receptors and serve as generalizable platforms for generating user-defined material-to-cell signaling pathways. First, we demonstrate that synNotch ligands, such as GFP, can be conjugated to cell- generated ECM proteins via genetic engineering of fibronectin produced by fibroblasts. We then used enzymatic or click chemistry to covalently link synNotch ligands to gelatin polymers to activate synNotch receptors in cells grown on or within a hydrogel. To achieve microscale control over synNotch activation in cell monolayers, we microcontact printed synNotch ligands onto a surface. We also patterned tissues comprising cells with up to three distinct phenotypes by engineering cells with two distinct synthetic pathways and culturing them on surfaces microfluidically patterned with two synNotch ligands. We showcase this technology by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined spatial patterns towards the engineering of muscle tissue with prescribed vascular networks. Collectively, this suite of approaches extends the synNotch toolkit and provides novel avenues for spatially controlling cellular phenotypes in mammalian multicellular systems, with many broad applications in developmental biology, synthetic morphogenesis, human tissue modeling, and regenerative medicine.
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Project description:Synthetic Notch (synNotch) receptors are modular synthetic components that are genetically engineered into mammalian cells to detect signals presented by neighboring cells and respond by activating prescribed transcriptional programs. To date, synNotch has been used to program therapeutic cells and pattern morphogenesis in multicellular systems. However, cell-presented ligands have limited versatility for applications that require spatial precision, such as tissue engineering. To address this, we developed a suite of materials to activate synNotch receptors and serve as generalizable platforms for generating user-defined material-to-cell signaling pathways. First, we demonstrate that synNotch ligands, such as GFP, can be conjugated to cell- generated ECM proteins via genetic engineering of fibronectin produced by fibroblasts. We then used enzymatic or click chemistry to covalently link synNotch ligands to gelatin polymers to activate synNotch receptors in cells grown on or within a hydrogel. To achieve microscale control over synNotch activation in cell monolayers, we microcontact printed synNotch ligands onto a surface. We also patterned tissues comprising cells with up to three distinct phenotypes by engineering cells with two distinct synthetic pathways and culturing them on surfaces microfluidically patterned with two synNotch ligands. We showcase this technology by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined spatial patterns towards the engineering of muscle tissue with prescribed vascular networks. Collectively, this suite of approaches extends the synNotch toolkit and provides novel avenues for spatially controlling cellular phenotypes in mammalian multicellular systems, with many broad applications in developmental biology, synthetic morphogenesis, human tissue modeling, and regenerative medicine.
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