APL Bioengineering最新文献

{"title":"Pulsatile low shear stress increases susceptibility to endothelial inflammation via upregulation of IFT and activation of YAP.","authors":"Yu Hou, Hazel R C Screen, Martin M Knight","doi":"10.1063/5.0263936","DOIUrl":"10.1063/5.0263936","url":null,"abstract":"<p><p>This study describes the development of a microfluidic chip model of the coronary artery endothelium and its use to examine the mechanism through which pulsatile shear stress regulates inflammation. The chip successfully recapitulates increased susceptibility to cytokine mediated arterial inflammation as observed <i>in vivo</i> in areas of low shear stress (LSS). Previous <i>in vivo</i> data show that low shear stress in the porcine aorta modulates 36 cilia-associated genes of which five are also Yes-associated protein (YAP) target genes. We demonstrate that pulsatile low shear stress (LSS) compared to high shear stress (HSS) preferentially drives YAP nuclear translocation and expression of the YAP target gene, Myosin Heavy Chain 10 (MYH10), which is also one of the cilia genes regulated by shear stress <i>in vivo</i>. LSS also increases expression of the cilia intraflagellar transport protein gene, IFT88, resulting in an increase in the primary cilia length and prevalence. Using a combination of siRNA and pharmaceutical regulators, we show that these changes in YAP, IFT88, and MYH10 drive the increased susceptibility to pro-inflammatory cytokines caused by LSS. Hence, we demonstrate that pulsatile LSS primes endothelial cells, increasing susceptibility to inflammation, and that this occurs through a novel pathway involving modulation of YAP and primary cilia/IFT. Such changes may also influence other cilia and YAP dependent responses. In conclusion, our microfabricated endothelial chip model reveals involvement of mechanosensitive IFT and YAP in arterial inflammation, which may provide novel therapeutic targets for the management of vascular disease such as atherosclerosis.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"026122"},"PeriodicalIF":6.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging mechanomedicines informed by mechanotransduction along the integrin-cytoskeleton-nucleus axis.","authors":"Yuka Yokoyama, Nya Domkam, Hannaneh Kabir, Abdullah Mansour, Shingo Tsukamoto, Ghafar Yerima, Taiji Adachi, Mohammad R K Mofrad","doi":"10.1063/5.0255473","DOIUrl":"10.1063/5.0255473","url":null,"abstract":"<p><p>Mechanical forces are fundamental to the formation of normal biological tissues and the maintenance of physiological health. These forces are transmitted from the extracellular environment to the cell interior through cell-cell and cell-ECM interactions, the cytoskeleton, the LINC complex, the nuclear pore complex, and chromatin, ultimately regulating gene expression via transcription factors. This process, known as mechanotransduction, enables cells to convert mechanical signals into biochemical responses. Due to its critical role in various cellular functions and its influence on disease progression, mechanotransduction emerges as a potential therapeutic target for a range of conditions, including cancer and cardiovascular diseases, by integrating it with biochemistry, molecular biology, and genetics. Mechanomedicine, a burgeoning field, seeks to harness insights from mechanobiology to develop innovative diagnostic and therapeutic strategies. By targeting the molecular and cellular mechanisms underlying mechanotransduction, mechanomedicine aims to create more effective and precise treatments. Despite the potential, current clinical practices largely depend on conventional therapies like chemotherapy, underscoring the challenges of manipulating mechanotransducive pathways within living organisms. This review bridges fundamental mechanotransduction mechanisms with emerging therapeutic approaches, highlighting how mechanomedicine can revolutionize clinical practice. It explores the latest advancements in targeting mechanotransducive elements, discusses the therapeutic efficacy demonstrated in preclinical and clinical studies, and identifies future directions for integrating mechanobiological principles into medical treatments. By connecting basic mechanobiology with clinical applications, mechanomedicine holds the promise of offering targeted and reliable treatment options, ultimately transforming the landscape of disease management and patient care.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"021503"},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of large-scale gastruloid array to identify aberrant developmental phenotypes.","authors":"Ian Jan, Andrew Cearlock, Min Yang, Nancy L Allbritton","doi":"10.1063/5.0269550","DOIUrl":"10.1063/5.0269550","url":null,"abstract":"<p><p>Adherent two-dimensional human gastruloids have provided insights into early human embryogenesis. Even though the model system is highly reproducible, no available automated technology can screen and sort large numbers of these near-millimeter-sized complex structures for large-scale assays. Here, we developed a microraft array-based technology to perform image-based assays of large numbers of fixed or living gastruloids and sort individual gastruloids for downstream assays, such as gene expression analysis. Arrays of 529 indexed magnetic microrafts each (789 µm side length) possessing flat surfaces were photopatterned with a central circular region (500 µm diameter) of extracellular matrix with an accuracy of 93 ± 1% to form a single gastruloid on each raft. An image analysis pipeline extracted features from transmitted light and fluorescence images of the gastruloids. The large microrafts were released and collected by an automated sorting system with efficiencies of 98 ± 4% and 99 ± 2%, respectively. The microraft array platform was used to assay individual euploid and aneuploid (possessing abnormal numbers of chromosomes) gastruloids with clear phenotypic differences. Aneuploid gastruloids displayed significantly less DNA/area than euploid gastruloids. However, even gastruloids with the same condition displayed significant heterogeneity. Both noggin (NOG) and keratin 7 (KRT7), two genes involved in spatial patterning within gastruloids, were upregulated in aneuploid relative to that in the euploid gastruloids. Moreover, relative NOG and KRT7 expressions were negatively correlated with DNA/area. The microraft arrays will empower novel screens of single gastruloids for a better understanding of key mechanisms underlying phenotypic differences between gastruloids.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"026121"},"PeriodicalIF":6.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanotransduction for therapeutic approaches: Cellular aging and rejuvenation.","authors":"Hye-Min Han, Su-Yeon Kim, Dong-Hwee Kim","doi":"10.1063/5.0263236","DOIUrl":"10.1063/5.0263236","url":null,"abstract":"<p><p>Mechanotransduction regulates cytoskeletal remodeling, nuclear mechanics, and metabolic adaptation, which are central to cellular aging and rejuvenation. These responses restore mechanical balance in aged cells, reprogram longevity-related gene expression, and alleviate age-related disorders, including neurodegeneration, musculoskeletal decline, and cardiovascular dysfunction. These insights indicate that mechanotransduction is pivotal in cellular and systemic processes underlying aging. The key signaling pathways, including the Hippo/Yes-associated protein (YAP), mechanistic target of rapamycin (mTOR), and transforming growth factor-beta (TGF-β)/Smad, have been explored in mediating age-related physiological decline, showing potential as therapeutic targets. Aging-dependent stiffening of the extracellular matrix (ECM) is associated with accelerated senescence. Interventions targeting ECM remodeling, such as mechanochemical therapies and nanoparticle delivery systems, provide promising strategies for counteracting cellular deterioration. Research progress has elucidated the critical role of mechanotransduction in organ-specific aging, enabling targeted interventions that align mechanical and biochemical therapeutic strategies. This review highlights the integration of mechanical modulation into therapeutic approaches, emphasizing its potential to restore cellular functionality, improve health, and extend lifespan. Advances in mechanomedicine have opened innovative frontiers in combating aging and age-associated diseases by addressing the interplay between mechanical forces and cellular processes. Cellular rejuvenation-the restoration of aged cells to a functionally younger state through the regulation of mechanotransduction pathways-involves the reversal of senescence-associated phenotypes, including nuclear deformation, mitochondrial alterations, and ECM stiffness. Furthermore, mechanotransduction plays a critical role in cellular rejuvenation by modulating YAP/TAZ activity, promoting autophagy, and maintaining cytoskeletal integrity.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"021502"},"PeriodicalIF":6.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145204/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced biomaterial strategies for overcoming age-associated wound healing impairments.","authors":"Rodrigo Dores, Telma A Rodrigues, Daniel Carvalho, Eva Batista, Myroslava Kozak, Cristina Blanco-Elices, Hugo Fernandes, Luis M Bimbo","doi":"10.1063/5.0251889","DOIUrl":"10.1063/5.0251889","url":null,"abstract":"<p><p>Dermal wounds represent a substantial global healthcare burden, with significant economic impact and reduced quality of life for affected individuals. As skin ages, the wound healing capacity is significantly diminished through multiple pathways, including reduced cellular proliferation, altered inflammatory responses, impaired vascularization, and decreased extracellular matrix production. With worldwide demographics shifting toward an older population, effective wound management has become an increasingly critical healthcare challenge. Biomaterials have emerged as a powerful tool to address the specific challenges of wound healing by providing structural support and delivering therapeutic agents to facilitate tissue regeneration. These materials can even be engineered to match the specific mechanical properties of aged tissue while simultaneously releasing key age-tailored bioactive molecules, thereby addressing the complex healing deficits in aged skin. Recent advances in aged skin models have established them as crucial platforms for translational research, enabling more accurate prediction of biomaterial performance in elderly patients. Concurrently, composite biomaterials, which combine multiple functionalities in a single platform, have gained prominence as particularly promising clinical solutions. Though significant progress has been made, challenges persist in optimizing material properties and achieving reproducible clinical outcomes, demanding continued research focused specifically on age-related wound healing impairments.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"021501"},"PeriodicalIF":6.6,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12145203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Survivin modulates stiffness-induced vascular smooth muscle cell motility.","authors":"Thomas Mousso, Kalina Rice, Bat-Ider Tumenbayar, Khanh Pham, Yuna Heo, Su Chin Heo, Kwonmoo Lee, Andrew T Lombardo, Yongho Bae","doi":"10.1063/5.0252766","DOIUrl":"10.1063/5.0252766","url":null,"abstract":"<p><p>Arterial stiffness is a contributor to cardiovascular diseases (CVDs) and is associated with the aberrant migration of vascular smooth muscle cells (VSMCs). However, the mechanisms driving VSMC migration in stiff environments remain unclear. We recently demonstrated that survivin is upregulated in mouse and human VSMCs cultured on stiff hydrogels, where it modulates stiffness-mediated cell proliferation. However, its role in stiffness-dependent VSMC migration remains unknown. To assess its impact on migration, we performed time-lapse microscopy on VSMCs seeded on fibronectin-coated soft and stiff hydrogels, mimicking the physiological stiffness of normal and diseased arteries. We observed that VSMC motility increased under stiff conditions, while pharmacologic or siRNA-mediated inhibition of survivin reduced stiffness-stimulated migration to rates similar to those observed under soft conditions. Further investigation revealed that cells on stiff hydrogels exhibited greater directional movement and robust lamellipodial protrusion compared to those on soft hydrogels. Interestingly, survivin-inhibited cells on stiff hydrogels showed reduced directional persistence and lamellipodial protrusion. We also found that survivin overexpression modestly increased cell motility and partially rescued the lack of directional persistence compared to green fluorescent protein (GFP)-expressing VSMCs on soft hydrogels. Mechanistically, stiffness- and survivin-dependent cell migration involves focal adhesion kinase (FAK) and actin dynamics, as stiffness increases phosphorylated FAK recruitment to focal adhesions and promotes actin organization and stress fiber formation-effects that are disrupted by survivin inhibition. In conclusion, our findings establish that mechanotransduction through a survivin-FAK-actin cascade converts extracellular matrix stiffness into stiffness-sensitive motility, suggesting that targeting this pathway may offer therapeutic strategies for CVD.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"026120"},"PeriodicalIF":6.6,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12140803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144235523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and regulation of EMT cells <i>in vivo</i> by laser stimulation.","authors":"Xiaohui Zhao, Guang Zhu, Meng Xue, Hao He","doi":"10.1063/5.0268350","DOIUrl":"10.1063/5.0268350","url":null,"abstract":"<p><p>Cells undergoing epithelial-to-mesenchymal transition (EMT) exhibit significant plasticity, making them more tumorigenic, invasive, and stem-like. PLCG2 has been identified as being linked to EMT. Specifically, the PLCG2-high subpopulation of tumor cells shows strong correlations with metastasis. However, it remains unclear whether PLCG2 serves as a direct driver of EMT. In this study, we employ an <i>in vivo</i> photostimulation method using tightly focused femtosecond-laser scanning to activate intracellular Ca²⁺ signaling and induce PLCG2 upregulation. By constructing a subcutaneous tumor model with prostate cancer PC3 cells and single-cell RNA sequencing, we identify distinct cell populations, including cancer stem cells, epithelial tumor cells, proliferating cells, and EMT cells. Upon photostimulation, EMT cells are notably expanded among the primary tumor cells, while epithelial tumor cells decrease in number. During the tumor progression, treatment with a specific PLCG2 inhibitor effectively suppresses the growth of the primary tumor but has no significant impact on metastatic cells. These findings offer valuable insights into the role of PLCG2 in regulating EMT and tumor development.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"026119"},"PeriodicalIF":6.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119126/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guest Editorial: Structure and mechanics of biofluids, biomaterials, and biologics.","authors":"E M Furst, F Scheffold, G H McKinley","doi":"10.1063/5.0274572","DOIUrl":"10.1063/5.0274572","url":null,"abstract":"","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 2","pages":"020401"},"PeriodicalIF":6.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144175212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis.","authors":"Soraya Hernández-Hatibi, Carlos Borau, Neus Martínez-Bosch, Pilar Navarro, José Manuel García-Aznar, Pedro Enrique Guerrero","doi":"10.1063/5.0242490","DOIUrl":"10.1063/5.0242490","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant tumor-associated stroma composed from pancreatic stellate cells, which play a critical role in tumor progression. Developing accurate <i>in vitro</i> models requires understanding the complex interactions between tumor cells and their microenvironment. In this study, we present a quantitative imaging-based characterization of the three dimensional (3D) self-organization of PDAC tumour spheroids using a microfluidic platform that mimics key aspects of the tumor microenvironment. Our model incorporates collagen type I hydrogels to recreate the extracellular matrix, activated human pancreatic stellate cells (HPSCs), and various tumor cell types. Advanced imaging techniques, including Lattice Lightsheet Microscopy, allowed us to analyze the 3D growth and spatial organization of the spheroids, revealing intricate biomechanical interactions. Our results indicate that alterations in matrix properties-such as stiffness, pore size, and hydraulic permeability-due to variations in collagen concentration significantly influence the growth patterns and organization of PDAC spheroids, depending on tumor subtype and epithelial-mesenchymal phenotype. Higher collagen concentrations promoted larger spheroids in epithelial-like cell lines, while mesenchymal-type cells required increased collagen for self-organization into smaller spheroids. Furthermore, coculture with HPSCs affected spheroid formation distinctly based on each PDAC cell line's genetic and phenotypic traits. HPSCs had opposing effects on epithelial-like cell lines: one cell line exhibited enhanced spheroid growth, while another showed inhibited formation, whereas mesenchymal-like spheroids showed minimal impact. These results provide insights into tumor-stroma interactions, emphasizing the importance of the cell-specific and matrix-dependent factors for advancing our understanding of PDAC progression and informing future therapeutic strategies.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 1","pages":"016116"},"PeriodicalIF":6.6,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11952832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced integrated therapy for breast cancer employing Honokiol-loaded mesoporous polydopamine nanoparticles in conjunction with photothermal effects and low-dose metformin.","authors":"Qianqian Du, Qianfan Zhang, Jialing Li, Xiaofei Wang, Xiangyu Gao, Guangyuan Tan, Qian Feng, Jigang Li, Yanchun Meng, Yongsheng Yu","doi":"10.1063/5.0256571","DOIUrl":"10.1063/5.0256571","url":null,"abstract":"<p><p>Breast cancer remains a significant global health challenge, emphasizing the pressing need for innovative therapeutic approaches. Our thorough research investigates the potential of mesoporous polydopamine nanoparticles (MPDA) as a targeted treatment for breast cancer. Meticulously crafted, these nanoparticles were loaded with honokiol (HK), which is a natural product, and then coated with functionalized hyaluronic acid (HA) to boost their ability to target breast cancer cells that overexpress CD44 receptors. The deep penetrating and photothermal (PTT) composite nanosystem combined with low-dose metformin (Met) improves the efficacy of synergetic therapy against breast tumors. The designed nanosystem exhibited exceptional biocompatibility and stability, suggesting its suitability for therapeutic use. Our <i>in vitro</i> studies demonstrated that the nanosystem precisely targeted and penetrated breast cancer cells, resulting in significant cell death. Additionally, <i>in vivo</i> studies showed that the nanosystem markedly inhibited tumor growth compared to the control group. This tumor-inhibiting effect was due to the combined action of the encapsulated HK, free Met, and the photothermal effect induced by near-infrared laser irradiation. This combination potently stimulates the expression of cleaved caspase-3 and cleaved PARP proteins, ultimately triggering cell apoptosis and effectively curbing tumor proliferation. Our research not only underscores the promising potential of nanoparticles for targeted breast cancer therapy but also sets the stage for further exploration and development of novel nanomedicine-based therapeutic strategies.</p>","PeriodicalId":46288,"journal":{"name":"APL Bioengineering","volume":"9 1","pages":"016115"},"PeriodicalIF":6.6,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}