Pub Date : 2024-09-02DOI: 10.1016/j.mbm.2024.100094
The ovarian tumor microenvironment plays a critical yet is poorly understood role in the regulation of cancer cell behaviors including proliferation, migration, and response to chemotherapy treatments. Ovarian cancer is the deadliest gynecological cancer, due to diagnosis at late stages of the disease and increased resistance to chemotherapies for recurrent disease. Understanding how the tumor microenvironment (TME) interacts with biomechanical forces to drive changes to ovarian cancer cell behaviors could elucidate novel treatment strategies for this patient population. Additionally, limitations in current preclinical models of the ovarian TME do not permit investigation of crosstalk between signaling pathways and mechanical forces. Our study focused on uncovering how strains and hyaluronic acid (HA) interact to signal through the CD44 receptor to alter ovarian cancer cell growth, migration, and response to a commonly used chemotherapy, paclitaxel. Using an advanced 3D in vitro model, we were able to identify how interactions of strain and HA as in the TME synergistically drive enhanced proliferation and migration in an ovarian tumor model line, while decreasing response to paclitaxel treatment. This study demonstrates the importance of elucidating how the mechanical forces present in the ovarian TME drive disease progression and response to treatment.
{"title":"Strain and hyaluronic acid interact to regulate ovarian cancer cell proliferation, migration, and drug resistance","authors":"","doi":"10.1016/j.mbm.2024.100094","DOIUrl":"10.1016/j.mbm.2024.100094","url":null,"abstract":"<div><p>The ovarian tumor microenvironment plays a critical yet is poorly understood role in the regulation of cancer cell behaviors including proliferation, migration, and response to chemotherapy treatments. Ovarian cancer is the deadliest gynecological cancer, due to diagnosis at late stages of the disease and increased resistance to chemotherapies for recurrent disease. Understanding how the tumor microenvironment (TME) interacts with biomechanical forces to drive changes to ovarian cancer cell behaviors could elucidate novel treatment strategies for this patient population. Additionally, limitations in current preclinical models of the ovarian TME do not permit investigation of crosstalk between signaling pathways and mechanical forces. Our study focused on uncovering how strains and hyaluronic acid (HA) interact to signal through the CD44 receptor to alter ovarian cancer cell growth, migration, and response to a commonly used chemotherapy, paclitaxel. Using an advanced 3D <em>in vitro</em> model, we were able to identify how interactions of strain and HA as in the TME synergistically drive enhanced proliferation and migration in an ovarian tumor model line, while decreasing response to paclitaxel treatment. This study demonstrates the importance of elucidating how the mechanical forces present in the ovarian TME drive disease progression and response to treatment.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000573/pdfft?md5=bf83a1132a805e7989290d565149d346&pid=1-s2.0-S2949907024000573-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142122418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-27DOI: 10.1016/j.mbm.2024.100096
Bone tissue engineering requires a combination of materials, cells, growth factors and mechanical cues to recapitulate bone formation. In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction. Hybrid hydrogels consisting of alginate and decellularized, demineralised bone extracellular matrix (ALG/ECM) were seeded with Stro-1+ human bone marrow stromal cells (HBMSCs). Dual combinations of growth factors within staged-release polylactic-co-glycolic acid (PLGA) microparticles were added to hydrogels to mimic, in part, the signalling events in bone regeneration: VEGF, TGF-β3, PTHrP (fast release), or BMP-2, vitamin D3 (slow release). Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles (MNP) targeted to TREK1 ion channels. Hybrid hydrogels were implanted subcutaneously within mice for 28 days, and evaluated for bone formation using micro-CT and histology. Control hydrogels lacking HBMSCs, growth factors, or MNP became mineralised, and neither growth factors, HBMSCs, nor mechanotransduction increased bone formation. However, structural differences in the newly-formed bone were influenced by growth factors. Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD3 increased bone formation. However, fast-release of TGF-β3 and VEGF resulted in thin trabeculae. Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD3. Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure. This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.
{"title":"In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair","authors":"","doi":"10.1016/j.mbm.2024.100096","DOIUrl":"10.1016/j.mbm.2024.100096","url":null,"abstract":"<div><p>Bone tissue engineering requires a combination of materials, cells, growth factors and mechanical cues to recapitulate bone formation. In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction. Hybrid hydrogels consisting of alginate and decellularized, demineralised bone extracellular matrix (ALG/ECM) were seeded with Stro-1+ human bone marrow stromal cells (HBMSCs). Dual combinations of growth factors within staged-release polylactic-co-glycolic acid (PLGA) microparticles were added to hydrogels to mimic, in part, the signalling events in bone regeneration: VEGF, TGF-β<sub>3,</sub> PTHrP (fast release), or BMP-2, vitamin D<sub>3</sub> (slow release). Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles (MNP) targeted to TREK1 ion channels. Hybrid hydrogels were implanted subcutaneously within mice for 28 days, and evaluated for bone formation using micro-CT and histology. Control hydrogels lacking HBMSCs, growth factors, or MNP became mineralised, and neither growth factors, HBMSCs, nor mechanotransduction increased bone formation. However, structural differences in the newly-formed bone were influenced by growth factors. Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD<sub>3</sub> increased bone formation. However, fast-release of TGF-β<sub>3</sub> and VEGF resulted in thin trabeculae. Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD<sub>3</sub>. Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure. This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000597/pdfft?md5=c4df681df7c8d540057e5c6a0cc4449b&pid=1-s2.0-S2949907024000597-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142150304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1016/j.mbm.2024.100095
Prostate cancer (PCa) continues to rank among the most common malignancies in Europe and North America with significant mortality rates despite advancements in detection and treatment. Physical activity is often recommended to PCa patients due to its benefits in preventing disease recurrence and managing treatment-related side effects. However, physical activity may be challenging for elderly or bedridden patients. As such, vibration therapy has been proposed as a safe, effective, and easy to perform alternative treatment that may confer similar effects as physical exercise. Specifically, low-magnitude high frequency (LMHF) vibration has been shown to decrease breast cancer extravasation into the bone and reduce other types of cancer proliferation by impacting cell viability. Here, we investigated the effects of daily application of LMHF vibration (0.3 g, 60 Hz, 1 hour/day for 3 days) on prostate cancer growth and bone metastasis in vitro. Our findings suggest that LMHF vibration significantly reduces colony formation through a decrease in cell growth and proliferation. Moreover, using a 3D cell culture model, LMHF vibration significantly reduces PC3 spheroid size. Additionally, LMHF vibration reduces PCa cell extravasation into the bone microenvironment through the stimulation of osteocytes and subsequent osteocyte-endothelial cell cross talk. These findings highlight the potential of LMHF vibration for managing PCa growth and metastasis.
{"title":"Low-magnitude high-frequency vibration reduces prostate cancer growth and extravasation in vitro","authors":"","doi":"10.1016/j.mbm.2024.100095","DOIUrl":"10.1016/j.mbm.2024.100095","url":null,"abstract":"<div><p>Prostate cancer (PCa) continues to rank among the most common malignancies in Europe and North America with significant mortality rates despite advancements in detection and treatment. Physical activity is often recommended to PCa patients due to its benefits in preventing disease recurrence and managing treatment-related side effects. However, physical activity may be challenging for elderly or bedridden patients. As such, vibration therapy has been proposed as a safe, effective, and easy to perform alternative treatment that may confer similar effects as physical exercise. Specifically, low-magnitude high frequency (LMHF) vibration has been shown to decrease breast cancer extravasation into the bone and reduce other types of cancer proliferation by impacting cell viability. Here, we investigated the effects of daily application of LMHF vibration (0.3 g, 60 Hz, 1 hour/day for 3 days) on prostate cancer growth and bone metastasis <em>in vitro</em>. Our findings suggest that LMHF vibration significantly reduces colony formation through a decrease in cell growth and proliferation. Moreover, using a 3D cell culture model, LMHF vibration significantly reduces PC3 spheroid size. Additionally, LMHF vibration reduces PCa cell extravasation into the bone microenvironment through the stimulation of osteocytes and subsequent osteocyte-endothelial cell cross talk. These findings highlight the potential of LMHF vibration for managing PCa growth and metastasis.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000585/pdfft?md5=948df38812a9b1c7c90cfc8e5ef3d321&pid=1-s2.0-S2949907024000585-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142129716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1016/j.mbm.2024.100093
The field of cancer research is increasingly recognizing the complex interplay between biomechanics and tumor epigenetics. Biomechanics plays a significant role in the occurrence, development, and metastasis of cancer and may exert influence by impacting the epigenetic modifications of tumors. In this review, we investigate a spectrum of biomechanical tools, including computational models, measurement instruments, and in vitro simulations. These tools not only assist in deciphering the mechanisms behind these epigenetic changes but also provide novel methods for characterizing tumors, which are significant for diagnosis and treatment. Finally, we discuss the potential of new therapies that target the biomechanical properties of the tumor microenvironment. There is hope that by altering factors such as the stiffness of the extracellular matrix or interfering with mechano-sensing pathways, we can halt tumor progression through epigenetic mechanisms. We emphasize the necessity for multidisciplinary efforts to integrate biomechanics with tumor epigenetics more comprehensively. Such collaboration is anticipated to advance therapeutic strategies and enhance our understanding of cancer biology, signaling the dawn of a new era in cancer treatment and research.
{"title":"Application of biomechanics in tumor epigenetic research","authors":"","doi":"10.1016/j.mbm.2024.100093","DOIUrl":"10.1016/j.mbm.2024.100093","url":null,"abstract":"<div><p>The field of cancer research is increasingly recognizing the complex interplay between biomechanics and tumor epigenetics. Biomechanics plays a significant role in the occurrence, development, and metastasis of cancer and may exert influence by impacting the epigenetic modifications of tumors. In this review, we investigate a spectrum of biomechanical tools, including computational models, measurement instruments, and in vitro simulations. These tools not only assist in deciphering the mechanisms behind these epigenetic changes but also provide novel methods for characterizing tumors, which are significant for diagnosis and treatment. Finally, we discuss the potential of new therapies that target the biomechanical properties of the tumor microenvironment. There is hope that by altering factors such as the stiffness of the extracellular matrix or interfering with mechano-sensing pathways, we can halt tumor progression through epigenetic mechanisms. We emphasize the necessity for multidisciplinary efforts to integrate biomechanics with tumor epigenetics more comprehensively. Such collaboration is anticipated to advance therapeutic strategies and enhance our understanding of cancer biology, signaling the dawn of a new era in cancer treatment and research.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000561/pdfft?md5=2b0b12971d7ff6eb0193e7d386c7f22d&pid=1-s2.0-S2949907024000561-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1016/j.mbm.2024.100085
Cardiovascular diseases (CVDs) persistently rank as a leading cause of premature death and illness worldwide. The Hippo signaling pathway, known for its highly conserved nature and integral role in regulating organ size, tissue homeostasis, and stem cell function, has been identified as a critical factor in the pathogenesis of CVDs. Recent findings underscore the significance of the Yes-associated protein (YAP) and the Transcriptional Coactivator with PDZ-binding motif (TAZ), collectively referred to as YAP/TAZ. These proteins play pivotal roles as downstream components of the Hippo pathway, in the regulation of cardiovascular development and homeostasis. YAP/TAZ can regulate various cellular processes such as cell proliferation, migration, differentiation, and apoptosis through their interactions with transcription factors, particularly those within the transcriptional enhancer associate domain (TEAD) family. The aim of this review is to provide a comprehensive overview of the current understanding of YAP/TAZ signaling in cardiovascular physiology and pathogenesis. We analyze the regulatory mechanisms of YAP/TAZ activation, explore their downstream effectors, and examine their association across numerous cardiovascular disorders, including myocardial hypertrophy, myocardial infarction, pulmonary hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, angiogenesis, restenosis, and cardiac fibrosis. Furthermore, we investigate the potential therapeutic implications of targeting the YAP/TAZ pathway for the treatment of CVDs. Through this comprehensive review, our aim is to elucidate the current understanding of YAP/TAZ signaling in cardiovascular biology and underscore its potential implications for the diagnosis and therapeutic intervention of CVDs.
{"title":"YAP/TAZ as mechanobiological signaling pathway in cardiovascular physiological regulation and pathogenesis","authors":"","doi":"10.1016/j.mbm.2024.100085","DOIUrl":"10.1016/j.mbm.2024.100085","url":null,"abstract":"<div><p>Cardiovascular diseases (CVDs) persistently rank as a leading cause of premature death and illness worldwide. The Hippo signaling pathway, known for its highly conserved nature and integral role in regulating organ size, tissue homeostasis, and stem cell function, has been identified as a critical factor in the pathogenesis of CVDs. Recent findings underscore the significance of the Yes-associated protein (YAP) and the Transcriptional Coactivator with PDZ-binding motif (TAZ), collectively referred to as YAP/TAZ. These proteins play pivotal roles as downstream components of the Hippo pathway, in the regulation of cardiovascular development and homeostasis. YAP/TAZ can regulate various cellular processes such as cell proliferation, migration, differentiation, and apoptosis through their interactions with transcription factors, particularly those within the transcriptional enhancer associate domain (TEAD) family. The aim of this review is to provide a comprehensive overview of the current understanding of YAP/TAZ signaling in cardiovascular physiology and pathogenesis. We analyze the regulatory mechanisms of YAP/TAZ activation, explore their downstream effectors, and examine their association across numerous cardiovascular disorders, including myocardial hypertrophy, myocardial infarction, pulmonary hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, angiogenesis, restenosis, and cardiac fibrosis. Furthermore, we investigate the potential therapeutic implications of targeting the YAP/TAZ pathway for the treatment of CVDs. Through this comprehensive review, our aim is to elucidate the current understanding of YAP/TAZ signaling in cardiovascular biology and underscore its potential implications for the diagnosis and therapeutic intervention of CVDs.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000482/pdfft?md5=452c635adfe6740a9f2f78624f8b36f6&pid=1-s2.0-S2949907024000482-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141985246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-31DOI: 10.1016/j.mbm.2024.100082
The extracellular matrix (ECM) and cells are crucial components of natural tissue microenvironments, and they both demonstrate dynamic mechanical properties, particularly viscoelastic behaviors, when exposed to external stress or strain over time. The capacity to modify the mechanical properties of cells and ECM is crucial for gaining insight into the development, physiology, and pathophysiology of living organisms. As an illustration, researchers have developed hydrogels with diverse compositions to mimic the properties of the native ECM and use them as substrates for cell culture. The behavior of cultured cells can be regulated by modifying the viscoelasticity of hydrogels. Moreover, there is widespread interest across disciplines in accurately measuring the mechanical properties of cells and the surrounding ECM, as well as exploring the interactive relationship between these components. Nevertheless, the lack of standardized experimental methods, conditions, and other variables has hindered systematic comparisons and summaries of research findings on ECM and cell viscoelasticity. In this review, we delve into the origins of ECM and cell viscoelasticity, examine recently developed methods for measuring ECM and cell viscoelasticity, and summarize the potential interactions between cell and ECM viscoelasticity. Recent research has shown that both ECM and cell viscoelasticity experience alterations during in vivo pathogenesis, indicating the potential use of tailored viscoelastic ECM and cells in regenerative medicine.
{"title":"Viscoelasticity of ECM and cells—origin, measurement and correlation","authors":"","doi":"10.1016/j.mbm.2024.100082","DOIUrl":"10.1016/j.mbm.2024.100082","url":null,"abstract":"<div><p>The extracellular matrix (ECM) and cells are crucial components of natural tissue microenvironments, and they both demonstrate dynamic mechanical properties, particularly viscoelastic behaviors, when exposed to external stress or strain over time. The capacity to modify the mechanical properties of cells and ECM is crucial for gaining insight into the development, physiology, and pathophysiology of living organisms. As an illustration, researchers have developed hydrogels with diverse compositions to mimic the properties of the native ECM and use them as substrates for cell culture. The behavior of cultured cells can be regulated by modifying the viscoelasticity of hydrogels. Moreover, there is widespread interest across disciplines in accurately measuring the mechanical properties of cells and the surrounding ECM, as well as exploring the interactive relationship between these components. Nevertheless, the lack of standardized experimental methods, conditions, and other variables has hindered systematic comparisons and summaries of research findings on ECM and cell viscoelasticity. In this review, we delve into the origins of ECM and cell viscoelasticity, examine recently developed methods for measuring ECM and cell viscoelasticity, and summarize the potential interactions between cell and ECM viscoelasticity. Recent research has shown that both ECM and cell viscoelasticity experience alterations during in vivo pathogenesis, indicating the potential use of tailored viscoelastic ECM and cells in regenerative medicine.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000457/pdfft?md5=d6a24f3aa25c8acf54e6bcfd62d47df9&pid=1-s2.0-S2949907024000457-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142058276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-26DOI: 10.1016/j.mbm.2024.100084
A recent study published in Cell Metabolism entitled “Gut microbial alterations in arginine metabolism determine bone mechanical adaptation” demonstrated that administration of L-arginine enhanced bone mechanical adaptation by activating a nitric oxide-calcium feedback loop in osteocytes. The findings revealed that mechanical regulation of bone adaptation is associated with gut microbiota. The underlying cause of heterogeneity of bone mechanoresponsiveness was the significant difference in the composition of the gut microbiota, in which the family Lachnospiraceae contributed to the inter-individual high variability in bone mechanical adaptation. Additionally, administration of Lachnospiraceae exhibited increased expression levels of L-citrulline and L-arginine and enhanced bone mechanoresponsiveness in recipients. Collectively, this study provides mechanistic insights into inter-individual variability of the gut microbial, which is related to the heterogeneity of bone mechanical adaptation and provides a novel preventive and therapeutic strategy to anti-osteoporotic for maximizing bone mechanoresponsiveness via the microbiota-metabolite axis.
{"title":"A microbiome-dependent gut-bone axis determines skeletal benefits from mechanical loading","authors":"","doi":"10.1016/j.mbm.2024.100084","DOIUrl":"10.1016/j.mbm.2024.100084","url":null,"abstract":"<div><p>A recent study published in <em>Cell Metabolism</em> entitled “Gut microbial alterations in arginine metabolism determine bone mechanical adaptation” demonstrated that administration of L-arginine enhanced bone mechanical adaptation by activating a nitric oxide-calcium feedback loop in osteocytes. The findings revealed that mechanical regulation of bone adaptation is associated with gut microbiota. The underlying cause of heterogeneity of bone mechanoresponsiveness was the significant difference in the composition of the gut microbiota, in which the family <em>Lachnospiraceae</em> contributed to the inter-individual high variability in bone mechanical adaptation. Additionally, administration of <em>Lachnospiraceae</em> exhibited increased expression levels of L-citrulline and L-arginine and enhanced bone mechanoresponsiveness in recipients. Collectively, this study provides mechanistic insights into inter-individual variability of the gut microbial, which is related to the heterogeneity of bone mechanical adaptation and provides a novel preventive and therapeutic strategy to anti-osteoporotic for maximizing bone mechanoresponsiveness via the microbiota-metabolite axis.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000470/pdfft?md5=01576b678e93cfb75c71a174b559d30e&pid=1-s2.0-S2949907024000470-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141851738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-25DOI: 10.1016/j.mbm.2024.100083
Interactions between macromolecules orchestrate many mechanobiology processes. However, progress in the field has often been hindered by the monetary and time costs of obtaining reliable experimental structures. In recent years, deep-learning methods, such as AlphaFold, have democratized access to high-quality predictions of the structural properties of proteins and other macromolecules. The newest implementation, AlphaFold 3, significantly expands the applications of its predecessor, AlphaFold 2, by incorporating reliable models for small molecules and nucleic acids and enhancing the prediction of macromolecular complexes. While several limitations still exist, the continuous improvement of machine learning methods like AlphaFold is producing a significant revolution in the field. The possibility of easily accessing structural predictions of biomolecular complexes may create substantial impacts in mechanobiology. Indeed, structural studies are at the basis of several applications in the field, such as drug discovery for mechanosensing proteins, development of mechanotherapy, understanding the mechanotransduction mechanisms and the mechanistic basis of diseases, or designing biomaterials for tissue engineering.
{"title":"From sequence to mechanobiology? Promises and challenges for AlphaFold 3","authors":"","doi":"10.1016/j.mbm.2024.100083","DOIUrl":"10.1016/j.mbm.2024.100083","url":null,"abstract":"<div><p>Interactions between macromolecules orchestrate many mechanobiology processes. However, progress in the field has often been hindered by the monetary and time costs of obtaining reliable experimental structures. In recent years, deep-learning methods, such as AlphaFold, have democratized access to high-quality predictions of the structural properties of proteins and other macromolecules. The newest implementation, AlphaFold 3, significantly expands the applications of its predecessor, AlphaFold 2, by incorporating reliable models for small molecules and nucleic acids and enhancing the prediction of macromolecular complexes. While several limitations still exist, the continuous improvement of machine learning methods like AlphaFold is producing a significant revolution in the field. The possibility of easily accessing structural predictions of biomolecular complexes may create substantial impacts in mechanobiology. Indeed, structural studies are at the basis of several applications in the field, such as drug discovery for mechanosensing proteins, development of mechanotherapy, understanding the mechanotransduction mechanisms and the mechanistic basis of diseases, or designing biomaterials for tissue engineering.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000469/pdfft?md5=e9e8d648eaef2a1a12526a3a9cbe4a52&pid=1-s2.0-S2949907024000469-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141842240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-20DOI: 10.1016/j.mbm.2024.100081
Many simulated micro-gravity (micro-G) experiments on earth suggest that micro-G conditions are not compatible with early mammalian embryo development. Recently, the first two “space embryo” studies have been published showing that early mouse embryo development can occur in real microgravity (real micro-G) conditions in orbit. In the first of these studies, published in 2020, Lei and collaborators developed automated mini-incubator (AMI) devices for mouse embryos facilitating cultivation, microscopic observation, and fixation1. Within these AMI apparatuses, 3400 non-frozen 2-cell embryos were launched in a recoverable satellite, experiencing sustained microgravity (∼0.001G) for 64 h post-orbit before fixation in space and recovery on earth. In a subsequent study, in 2023, Wakayama and colleagues2 devised Embryo Thawing and Culturing (ETC) devices, enabling manual thawing, cultivation, and fixation of frozen 2-cell mouse embryos by a trained astronaut aboard the International Space Station (ISS). Within the ETCs, a total of 720 2-cell mouse embryos underwent thawing and cultivation for 4 days on the ISS, subject to either microgravity (n = 360) and simulated-1G (n = 360) conditions. The primary findings from both space embryo experiments indicate that mouse embryos can progress through embryogenesis from the 2-cell stage to the blastocyst stage under real micro-G conditions with few defects. Collectively, these studies propose the potential for mammalian reproduction under real micro-G conditions, challenging earlier simulated micro-G research suggesting otherwise.
{"title":"Effects of gravity, microgravity or microgravity simulation on early mouse embryogenesis: A review of the first two space embryo studies","authors":"","doi":"10.1016/j.mbm.2024.100081","DOIUrl":"10.1016/j.mbm.2024.100081","url":null,"abstract":"<div><p>Many simulated micro-gravity (micro-G) experiments on earth suggest that micro-G conditions are not compatible with early mammalian embryo development. Recently, the first two “space embryo” studies have been published showing that early mouse embryo development can occur in real microgravity (real micro-G) conditions in orbit. In the first of these studies, published in 2020, Lei and collaborators developed automated mini-incubator (AMI) devices for mouse embryos facilitating cultivation, microscopic observation, and fixation<sup>1</sup>. Within these AMI apparatuses, 3400 non-frozen 2-cell embryos were launched in a recoverable satellite, experiencing sustained microgravity (∼0.001G) for 64 h post-orbit before fixation in space and recovery on earth. In a subsequent study, in 2023, Wakayama and colleagues<sup>2</sup> devised Embryo Thawing and Culturing (ETC) devices, enabling manual thawing, cultivation, and fixation of frozen 2-cell mouse embryos by a trained astronaut aboard the International Space Station (ISS). Within the ETCs, a total of 720 2-cell mouse embryos underwent thawing and cultivation for 4 days on the ISS, subject to either microgravity (n = 360) and simulated-1G (n = 360) conditions. The primary findings from both space embryo experiments indicate that mouse embryos can progress through embryogenesis from the 2-cell stage to the blastocyst stage under real micro-G conditions with few defects. Collectively, these studies propose the potential for mammalian reproduction under real micro-G conditions, challenging earlier simulated micro-G research suggesting otherwise.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000445/pdfft?md5=7fac1cfeb0aa7e577b2502ddcad5ca49&pid=1-s2.0-S2949907024000445-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.1016/j.mbm.2024.100080
Biomanufacturing relies on living cells to produce biotechnology-based therapeutics, tissue engineering constructs, vaccines, and a vast range of agricultural and industrial products. With the escalating demand for these bio-based products, any process that could improve yields and shorten outcome timelines by accelerating cell proliferation would have a significant impact across the discipline. While these goals are primarily achieved using biological or chemical strategies, harnessing cell mechanosensitivity represents a promising – albeit less studied – physical pathway to promote bioprocessing endpoints, yet identifying which mechanical parameters influence cell activities has remained elusive. We tested the hypothesis that mechanical signals, delivered non-invasively using low-intensity vibration (LIV; <1 g, 10–500 Hz), will enhance cell expansion, and determined that any unique signal configuration was not equally influential across a range of cell types. Varying frequency, intensity, duration, refractory period, and daily doses of LIV increased proliferation in Chinese Hamster Ovary (CHO)-adherent cells (+79% in 96 hr) using a particular set of LIV parameters (0.2 g, 500 Hz, 3 × 30 min/d, 2 hr refractory period), yet this same mechanical input suppressed proliferation in CHO-suspension cells (−13%). Another set of LIV parameters (30 Hz, 0.7 g, 2 × 60 min/d, 2 hr refractory period) however, were able to increase the proliferation of CHO-suspension cells by 210% and T-cells by 20.3%. Importantly, we also reported that T-cell response to LIV was in-part dependent upon AKT phosphorylation, as inhibiting AKT phosphorylation reduced the proliferative effect of LIV by over 60%, suggesting that suspension cells utilize mechanism(s) similar to adherent cells to sense specific LIV signals. Particle image velocimetry combined with finite element modeling showed high transmissibility of these signals across fluids (>90%), and LIV effectively scaled up to T75 flasks. Ultimately, when LIV is tailored to the target cell population, it's highly efficient transmission across media represents a means to non-invasively augment biomanufacturing endpoints for both adherent and suspended cells, and holds immediate applications, ranging from small-scale, patient-specific personalized medicine to large-scale commercial bio-centric production challenges.
生物制造依赖活细胞来生产基于生物技术的治疗药物、组织工程结构、疫苗以及大量农业和工业产品。随着对这些生物基产品的需求不断增长,任何能够通过加速细胞增殖来提高产量和缩短结果时间的工艺都将对整个学科产生重大影响。虽然这些目标主要是通过生物或化学策略实现的,但利用细胞的机械敏感性是促进生物加工终点的一种很有前景的物理途径,尽管研究较少。我们测试了利用低强度振动(LIV; <1 g, 10-500 Hz)以非侵入方式传递机械信号将促进细胞扩增的假设,并确定任何独特的信号配置对一系列细胞类型的影响都不相同。使用一组特定的 LIV 参数(0.2 克、500 赫兹、3 × 30 分钟/天、2 小时耐受期),不同频率、强度、持续时间、耐受期和每日剂量的 LIV 会增加中国仓鼠卵巢(CHO)粘附细胞的增殖(96 小时内增殖 79%),但同样的机械输入会抑制 CHO 悬浮细胞的增殖(-13%)。然而,另一组 LIV 参数(30 赫兹、0.7 克、2 × 60 分钟/天、2 小时耐受期)却能使 CHO 悬浮细胞的增殖增加 210%,T 细胞的增殖增加 20.3%。重要的是,我们还报告了 T 细胞对 LIV 的反应部分依赖于 AKT 磷酸化,因为抑制 AKT 磷酸化会使 LIV 的增殖效应降低 60% 以上,这表明悬浮细胞利用了与贴壁细胞类似的机制来感知特定的 LIV 信号。粒子图像测速仪与有限元建模相结合,显示了这些信号在流体中的高传递率(90%),而且 LIV 可以有效地扩展到 T75 烧瓶。最终,当 LIV 适合于目标细胞群时,它在介质间的高效传输代表了一种无创增强粘附细胞和悬浮细胞的生物制造终点的方法,并具有直接的应用前景,从小规模、特定患者的个性化医疗到以生物为中心的大规模商业生产挑战,不一而足。
{"title":"Low intensity mechanical signals promote proliferation in a cell-specific manner: Tailoring a non-drug strategy to enhance biomanufacturing yields","authors":"","doi":"10.1016/j.mbm.2024.100080","DOIUrl":"10.1016/j.mbm.2024.100080","url":null,"abstract":"<div><p>Biomanufacturing relies on living cells to produce biotechnology-based therapeutics, tissue engineering constructs, vaccines, and a vast range of agricultural and industrial products. With the escalating demand for these bio-based products, any process that could improve yields and shorten outcome timelines by accelerating cell proliferation would have a significant impact across the discipline. While these goals are primarily achieved using <em>biological</em> or <em>chemical</em> strategies, harnessing cell mechanosensitivity represents a promising – albeit less studied – <em>physical</em> pathway to promote bioprocessing endpoints, yet identifying which mechanical parameters influence cell activities has remained elusive. We tested the hypothesis that mechanical signals, delivered non-invasively using low-intensity vibration (LIV; <1 g, 10–500 Hz), will enhance cell expansion, and determined that any unique signal configuration was not equally influential across a range of cell types. Varying frequency, intensity, duration, refractory period, and daily doses of LIV increased proliferation in Chinese Hamster Ovary (CHO)-adherent cells (+79% in 96 hr) using a particular set of LIV parameters (0.2 g, 500 Hz, 3 × 30 min/d, 2 hr refractory period), yet this same mechanical input <em>suppressed</em> proliferation in CHO-suspension cells (−13%). Another set of LIV parameters (30 Hz, 0.7 g, 2 × 60 min/d, 2 hr refractory period) however, were able to increase the proliferation of CHO-suspension cells by 210% and T-cells by 20.3%. Importantly, we also reported that T-cell response to LIV was in-part dependent upon AKT phosphorylation, as inhibiting AKT phosphorylation reduced the proliferative effect of LIV by over 60%, suggesting that suspension cells utilize mechanism(s) similar to adherent cells to sense specific LIV signals. Particle image velocimetry combined with finite element modeling showed high transmissibility of these signals across fluids (>90%), and LIV effectively scaled up to T75 flasks. Ultimately, when LIV is tailored to the target cell population, it's highly efficient transmission across media represents a means to non-invasively augment biomanufacturing endpoints for both adherent and suspended cells, and holds immediate applications, ranging from small-scale, patient-specific personalized medicine to large-scale commercial bio-centric production challenges.</p></div>","PeriodicalId":100900,"journal":{"name":"Mechanobiology in Medicine","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2949907024000433/pdfft?md5=018ef78186c038e68b40852d4fefb32a&pid=1-s2.0-S2949907024000433-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141736469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}