Ronald H. Heisser, Angel Bu, Laura Schwendeman, Tamara Rossy, Pavankumar Umashankar, Vincent Butty, Ritu Raman
Exercise promotes human mobility by tuning the function of skeletal muscle, and recent studies highlight exercise's broader impacts on human health via muscle's paracrine and endocrine roles beyond force generation. In vitro models of tissue engineered skeletal muscle enable precise investigation of adaptation to exercise, with emerging approaches for optogenetic muscle stimulation providing a less invasive alternative to traditional techniques for electrical stimulation. In this study, we present a high‐throughput muscle culture and optical exercise protocol for scalable in vitro exercise studies. First, we characterize optical rheobase for 2D muscle monolayers, finding that optical intensities as low as 5 μW mm −2 can trigger functional contraction. We then leverage RNA sequencing to map changes in muscle gene expression in response to various optical exercise regimens, highlighting how changing stimulation parameters impact myogenic and broader physiological and pathological transcriptional responses. Our platform and results establish a practical foundation for high‐throughput in vitro exercise studies of skeletal muscle.
{"title":"Physiological and functional characterization for high‐throughput optogenetic skeletal muscle exercise assays","authors":"Ronald H. Heisser, Angel Bu, Laura Schwendeman, Tamara Rossy, Pavankumar Umashankar, Vincent Butty, Ritu Raman","doi":"10.1002/btm2.70101","DOIUrl":"https://doi.org/10.1002/btm2.70101","url":null,"abstract":"Exercise promotes human mobility by tuning the function of skeletal muscle, and recent studies highlight exercise's broader impacts on human health via muscle's paracrine and endocrine roles beyond force generation. In vitro models of tissue engineered skeletal muscle enable precise investigation of adaptation to exercise, with emerging approaches for optogenetic muscle stimulation providing a less invasive alternative to traditional techniques for electrical stimulation. In this study, we present a high‐throughput muscle culture and optical exercise protocol for scalable in vitro exercise studies. First, we characterize optical rheobase for 2D muscle monolayers, finding that optical intensities as low as 5 μW mm <jats:sup>−2</jats:sup> can trigger functional contraction. We then leverage RNA sequencing to map changes in muscle gene expression in response to various optical exercise regimens, highlighting how changing stimulation parameters impact myogenic and broader physiological and pathological transcriptional responses. Our platform and results establish a practical foundation for high‐throughput in vitro exercise studies of skeletal muscle.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"47 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Devorah Cahn, Sanjay Pal, Alexa Stern, Nimit L. Patel, Timothy Gower, Senta M. Kapnick, Christopher M. Jewell, Gregg A. Duncan, Matthew T. Wolf
Barriers to nanoparticle drug delivery to the tumor microenvironment such as ECM deposition and clearance by the mononuclear phagocyte system have necessitated strategies for more effective tumor penetration. Adding polyethylene glycol (PEG) chains to the surface of nanoparticles (PEGylation) has been widely used to both enhance accumulation at the tumor site and increase blood circulation time. Recent work has also shown that immune cells (e.g., macrophages, dendritic cells, neutrophils) play an important role in the ability of NPs to effectively target and spread within a tumor. PEG chain characteristics such as size and branching affect how nanoparticles interact with tissues; however, it is unclear how PEGylation type affects NP uptake and cellular distribution in the tumor microenvironment. In this study, we evaluated the influence of both linear and branched PEGylation on nanoparticle biodistribution and uptake in tumor cells as well as tumor‐infiltrating immune cells. As compared to conventional surface coatings with linear PEG, we show that modifying PEG structure to a branched conformation increases nanoparticle accumulation in the spleen of tumor‐bearing mice, primarily due to significantly enhanced uptake by leukocytes. As compared to uncoated particles, we also found that nanoparticles densely coated with linear or branched PEG accumulated to a greater extent in tumors showing ≥8‐fold increases in uptake by tumor‐associated macrophages and dendritic cells. These studies provide insight into PEG architecture as a design parameter in nanomedicine that can facilitate the design of more effective cancer therapies.
{"title":"PEGylation strategies for enhanced nanoparticle delivery to tumor‐associated immune cells","authors":"Devorah Cahn, Sanjay Pal, Alexa Stern, Nimit L. Patel, Timothy Gower, Senta M. Kapnick, Christopher M. Jewell, Gregg A. Duncan, Matthew T. Wolf","doi":"10.1002/btm2.70098","DOIUrl":"https://doi.org/10.1002/btm2.70098","url":null,"abstract":"Barriers to nanoparticle drug delivery to the tumor microenvironment such as ECM deposition and clearance by the mononuclear phagocyte system have necessitated strategies for more effective tumor penetration. Adding polyethylene glycol (PEG) chains to the surface of nanoparticles (PEGylation) has been widely used to both enhance accumulation at the tumor site and increase blood circulation time. Recent work has also shown that immune cells (e.g., macrophages, dendritic cells, neutrophils) play an important role in the ability of NPs to effectively target and spread within a tumor. PEG chain characteristics such as size and branching affect how nanoparticles interact with tissues; however, it is unclear how PEGylation type affects NP uptake and cellular distribution in the tumor microenvironment. In this study, we evaluated the influence of both linear and branched PEGylation on nanoparticle biodistribution and uptake in tumor cells as well as tumor‐infiltrating immune cells. As compared to conventional surface coatings with linear PEG, we show that modifying PEG structure to a branched conformation increases nanoparticle accumulation in the spleen of tumor‐bearing mice, primarily due to significantly enhanced uptake by leukocytes. As compared to uncoated particles, we also found that nanoparticles densely coated with linear or branched PEG accumulated to a greater extent in tumors showing ≥8‐fold increases in uptake by tumor‐associated macrophages and dendritic cells. These studies provide insight into PEG architecture as a design parameter in nanomedicine that can facilitate the design of more effective cancer therapies.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"145 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145717266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yi‐Dan Sun, Tong An, Rong Liang, Yu‐Wen Luo, Hong‐Ze Xia, Lei Fu, Shuo Han, Yi‐Xiao Zhu, Zi‐Yi Song, Xue‐Yan Bai, Yao Fu, Xiang‐Wei Fu, Yun‐Peng Hou, Qun Lu
Oocyte activation deficiency is a primary cause of fertilization failure following intracytoplasmic sperm injection, a problem that can potentially be overcome through artificial oocyte activation (AOA). However, concerns persist regarding the safety and efficacy of AOA in clinical practice. We demonstrated that single‐pulse nanosecond pulsed electric field (nsPEF) stimulation induced Ca 2+ signaling patterns that depend on intensity in both mouse and human oocytes, facilitating parthenogenetic activation and blastocyst formation. The sperm‐initiated physiological Ca 2+ oscillations were effectively replicated by a series of Ca 2+ signals triggered by repeated nsPEF at low or medium intensities, resulting in a significantly higher developmental potential for activated oocytes compared to those treated with A23187 (78.13% vs. 26.70%). The nsPEF stimulation achieved precise manipulation of calcium signaling through two distinct mechanisms: low‐intensity nsPEF pulses mediated repetitive extracellular Ca 2+ influx in an electro‐permeable manner, while medium‐intensity nsPEF stimulation triggered periodic Ca 2+ release from the endoplasmic reticulum via the PIP 2 –IP 3 –IP 3 R pathway, generating intracellular Ca 2+ oscillations that resemble physiological patterns. The non‐invasive nsPEF procedure ensured the safety of oocyte activation by maintaining cellular integrity and minimizing stress responses. The efficacy of nsPEF exposure in precisely manipulating Ca 2+ signaling patterns is also demonstrated in human mature oocytes. This study establishes a quantitative, non‐invasive nsPEF protocol for AOA that mimics the activation signaling delivered by sperm. This innovative approach overcomes the limitations of conventional chemical activators by enhancing biosafety and clinical efficacy, particularly for patients experiencing total fertilization failure due to severe male infertility. Its ability to accurately regulate Ca 2+ signaling presents significant potential for advancing research in various fields, including embryonic development and germ cell differentiation.
{"title":"Precise mimicry of physiological Ca 2+ oscillations for mammalian oocyte activation by nanosecond pulsed electric field","authors":"Yi‐Dan Sun, Tong An, Rong Liang, Yu‐Wen Luo, Hong‐Ze Xia, Lei Fu, Shuo Han, Yi‐Xiao Zhu, Zi‐Yi Song, Xue‐Yan Bai, Yao Fu, Xiang‐Wei Fu, Yun‐Peng Hou, Qun Lu","doi":"10.1002/btm2.70094","DOIUrl":"https://doi.org/10.1002/btm2.70094","url":null,"abstract":"Oocyte activation deficiency is a primary cause of fertilization failure following intracytoplasmic sperm injection, a problem that can potentially be overcome through artificial oocyte activation (AOA). However, concerns persist regarding the safety and efficacy of AOA in clinical practice. We demonstrated that single‐pulse nanosecond pulsed electric field (nsPEF) stimulation induced Ca <jats:sup>2+</jats:sup> signaling patterns that depend on intensity in both mouse and human oocytes, facilitating parthenogenetic activation and blastocyst formation. The sperm‐initiated physiological Ca <jats:sup>2+</jats:sup> oscillations were effectively replicated by a series of Ca <jats:sup>2+</jats:sup> signals triggered by repeated nsPEF at low or medium intensities, resulting in a significantly higher developmental potential for activated oocytes compared to those treated with A23187 (78.13% vs. 26.70%). The nsPEF stimulation achieved precise manipulation of calcium signaling through two distinct mechanisms: low‐intensity nsPEF pulses mediated repetitive extracellular Ca <jats:sup>2+</jats:sup> influx in an electro‐permeable manner, while medium‐intensity nsPEF stimulation triggered periodic Ca <jats:sup>2+</jats:sup> release from the endoplasmic reticulum via the PIP <jats:sub>2</jats:sub> –IP <jats:sub>3</jats:sub> –IP <jats:sub>3</jats:sub> R pathway, generating intracellular Ca <jats:sup>2+</jats:sup> oscillations that resemble physiological patterns. The non‐invasive nsPEF procedure ensured the safety of oocyte activation by maintaining cellular integrity and minimizing stress responses. The efficacy of nsPEF exposure in precisely manipulating Ca <jats:sup>2+</jats:sup> signaling patterns is also demonstrated in human mature oocytes. This study establishes a quantitative, non‐invasive nsPEF protocol for AOA that mimics the activation signaling delivered by sperm. This innovative approach overcomes the limitations of conventional chemical activators by enhancing biosafety and clinical efficacy, particularly for patients experiencing total fertilization failure due to severe male infertility. Its ability to accurately regulate Ca <jats:sup>2+</jats:sup> signaling presents significant potential for advancing research in various fields, including embryonic development and germ cell differentiation.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145680341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xin‐li Chen, Yi‐bin Liu, Cheng‐ye Lin, Shu Lin, He‐fan He, Wei‐feng Liu
This study aimed to evaluate the therapeutic potential of the olfactory ensheathing cells (OECs) exosomes (EXOs) in traumatic brain injury (TBI) and the regulatory role of nuclear factor E2‐related factor (Nrf2). Rats were divided into Sham, TBI, OECs‐EXOs (EXO), and OECs‐EXOs plus Nrf2 inhibitor (ML385) groups. Neurological function was assessed using the modified neurological severity score, the Morris water maze (MWM), and the Barnes maze tests. Brain injury, Fe 2+ accumulation, and mitochondrial damage were evaluated using histopathological imaging and ELISA kits. Expression levels of Nrf2 and ferroptosis‐related proteins were analyzed using western blot and qPCR. TBI rats exhibited significant neurological dysfunction, elevated serum injury markers and inflammatory cytokines, increased brain Fe 2+ and malondialdehyde (MDA), and altered expression of ferroptosis‐related proteins compared with Sham rats. The ML385 group exhibited reduced Nrf2 expression and attenuated OECs‐EXOs‐mediated therapeutic effects, suggesting a critical role of Nrf2 in the efficacy of OECs‐EXOs. Overall, OECs‐EXOs attenuated TBI‐induced neuroinflammation and oxidative stress and promoted neuronal repair and neurological recovery, likely via Nrf2‐regulated ferroptosis‐related pathways.
{"title":"Olfactory ensheathing cells exosomes enhance neurological recovery in brain‐injured rats by modulating Nrf2‐ferroptosis pathway","authors":"Xin‐li Chen, Yi‐bin Liu, Cheng‐ye Lin, Shu Lin, He‐fan He, Wei‐feng Liu","doi":"10.1002/btm2.70097","DOIUrl":"https://doi.org/10.1002/btm2.70097","url":null,"abstract":"This study aimed to evaluate the therapeutic potential of the olfactory ensheathing cells (OECs) exosomes (EXOs) in traumatic brain injury (TBI) and the regulatory role of nuclear factor E2‐related factor (Nrf2). Rats were divided into Sham, TBI, OECs‐EXOs (EXO), and OECs‐EXOs plus Nrf2 inhibitor (ML385) groups. Neurological function was assessed using the modified neurological severity score, the Morris water maze (MWM), and the Barnes maze tests. Brain injury, Fe <jats:sup>2+</jats:sup> accumulation, and mitochondrial damage were evaluated using histopathological imaging and ELISA kits. Expression levels of Nrf2 and ferroptosis‐related proteins were analyzed using western blot and qPCR. TBI rats exhibited significant neurological dysfunction, elevated serum injury markers and inflammatory cytokines, increased brain Fe <jats:sup>2+</jats:sup> and malondialdehyde (MDA), and altered expression of ferroptosis‐related proteins compared with Sham rats. The ML385 group exhibited reduced Nrf2 expression and attenuated OECs‐EXOs‐mediated therapeutic effects, suggesting a critical role of Nrf2 in the efficacy of OECs‐EXOs. Overall, OECs‐EXOs attenuated TBI‐induced neuroinflammation and oxidative stress and promoted neuronal repair and neurological recovery, likely via Nrf2‐regulated ferroptosis‐related pathways.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"219 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joseph Faudou, Anupriya Roul, Mohammed Benwadih, Minh‐Quyen Le, Anthony Medigo, Jean‐François Obadia, Pierre‐Jean Cottinet, Daniel Grinberg
Mitral valve repair (MVr) is the preferred surgical treatment for primary mitral regurgitation; however, its success is limited by the lack of validated, accurate, and objective parameters for assessing the complete restoration of physiological mitral valve (MV) mechanics. Consequently, to address this challenge, intraoperative assessment of mitral valve coaptation pressure (MCP) has emerged as a promising approach. This study presents the first precise transcatheter measurement of MCP in animal hearts. Data were obtained using two custom‐made force sensors: a 3Fr piezoresistive pressure catheter and a 15Fr flexible piezoelectric sensor. Experiments were conducted in both ex vivo (excised pig hearts activated by a pump) and in vivo (transseptal approach in a living pig) models. In a living pig with a healthy MV under normal hemodynamic conditions (peak systolic left ventricular pressure of 100 mmHg), the MCP ranged from 200 to 300 mmHg (25–40 kPa). Ex vivo experiments demonstrated that MCP was affected by transmitral pressure, mitral function changes (i.e., regurgitation), and MV morphology. These findings provide valuable insights into MV biomechanics and establish a solid foundation for developing medical devices to guide MVr procedures.
{"title":"Transcatheter measurement of mitral valve coaptation pressure: A proof‐of‐concept study using animal models","authors":"Joseph Faudou, Anupriya Roul, Mohammed Benwadih, Minh‐Quyen Le, Anthony Medigo, Jean‐François Obadia, Pierre‐Jean Cottinet, Daniel Grinberg","doi":"10.1002/btm2.70095","DOIUrl":"https://doi.org/10.1002/btm2.70095","url":null,"abstract":"Mitral valve repair (MVr) is the preferred surgical treatment for primary mitral regurgitation; however, its success is limited by the lack of validated, accurate, and objective parameters for assessing the complete restoration of physiological mitral valve (MV) mechanics. Consequently, to address this challenge, intraoperative assessment of mitral valve coaptation pressure (MCP) has emerged as a promising approach. This study presents the first precise transcatheter measurement of MCP in animal hearts. Data were obtained using two custom‐made force sensors: a 3Fr piezoresistive pressure catheter and a 15Fr flexible piezoelectric sensor. Experiments were conducted in both ex vivo (excised pig hearts activated by a pump) and in vivo (transseptal approach in a living pig) models. In a living pig with a healthy MV under normal hemodynamic conditions (peak systolic left ventricular pressure of 100 mmHg), the MCP ranged from 200 to 300 mmHg (25–40 kPa). Ex vivo experiments demonstrated that MCP was affected by transmitral pressure, mitral function changes (i.e., regurgitation), and MV morphology. These findings provide valuable insights into MV biomechanics and establish a solid foundation for developing medical devices to guide MVr procedures.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"362 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ali M. Atoom, Media Hamed‐Ahmed, Shaker Al‐Hasnaawei, H. Malathi, Laxmidhar Maharana, Anima Nanda, Vimal Arora, Ashish Singh‐Chauhan, Elham Poursoltani
Extracellular vesicles (EVs) have emerged as promising therapeutic candidates for a range of neonatal diseases, including sepsis, necrotizing enterocolitis, hypoxic–ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD). Derived from diverse sources such as mesenchymal stem cells, breast milk, and even non‐animal systems, EVs exhibit potent anti‐inflammatory, immunomodulatory, and tissue‐regenerative properties. Preclinical studies in neonatal models demonstrate their ability to reduce inflammation, preserve epithelial and endothelial barrier integrity, modulate immune cell phenotypes, and mitigate organ damage. Despite these encouraging findings, several critical barriers hinder their clinical translation. Challenges include incomplete characterization of EV molecular cargo, variability in isolation and quantification methods, lack of standardized dosing protocols, and limited safety data, particularly regarding procoagulant activity and thrombotic risk. The development of standardized, reproducible isolation techniques, rigorous molecular profiling, and GLP‐compliant safety assessments is essential to establish clinical readiness. Current early‐phase clinical trials targeting neonatal BPD, prevention of prematurity‐related brain injury, and HIE indicate growing translational momentum. If these challenges are addressed, EV‐based therapeutics could transform neonatal care, reducing mortality and long‐term disability in vulnerable preterm and term infants.
{"title":"Therapeutic potential and translational challenges of extracellular vesicles in neonatal medicine","authors":"Ali M. Atoom, Media Hamed‐Ahmed, Shaker Al‐Hasnaawei, H. Malathi, Laxmidhar Maharana, Anima Nanda, Vimal Arora, Ashish Singh‐Chauhan, Elham Poursoltani","doi":"10.1002/btm2.70093","DOIUrl":"https://doi.org/10.1002/btm2.70093","url":null,"abstract":"Extracellular vesicles (EVs) have emerged as promising therapeutic candidates for a range of neonatal diseases, including sepsis, necrotizing enterocolitis, hypoxic–ischemic encephalopathy (HIE), and bronchopulmonary dysplasia (BPD). Derived from diverse sources such as mesenchymal stem cells, breast milk, and even non‐animal systems, EVs exhibit potent anti‐inflammatory, immunomodulatory, and tissue‐regenerative properties. Preclinical studies in neonatal models demonstrate their ability to reduce inflammation, preserve epithelial and endothelial barrier integrity, modulate immune cell phenotypes, and mitigate organ damage. Despite these encouraging findings, several critical barriers hinder their clinical translation. Challenges include incomplete characterization of EV molecular cargo, variability in isolation and quantification methods, lack of standardized dosing protocols, and limited safety data, particularly regarding procoagulant activity and thrombotic risk. The development of standardized, reproducible isolation techniques, rigorous molecular profiling, and GLP‐compliant safety assessments is essential to establish clinical readiness. Current early‐phase clinical trials targeting neonatal BPD, prevention of prematurity‐related brain injury, and HIE indicate growing translational momentum. If these challenges are addressed, EV‐based therapeutics could transform neonatal care, reducing mortality and long‐term disability in vulnerable preterm and term infants.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"17 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145593597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Qisheng Su, Liang Yue, Leixing Ge, Meida Xiang, Qi Liu, Jiru Wang, Zhimin Yun, He Liu, Congji Shan, Hebing Chen, Chengjun Wu, Zhuo Gao, Yingxia Tan
Acute kidney injury (AKI) is a serious condition with significant global impact. To explore mechanisms and biomarkers of heat‐stress‐induced AKI, we used human kidney organoids derived from induced pluripotent stem cells via suspension culture. Organoids were exposed to 37, 39, and 41°C. At 41°C, we found the viability decreased over time, with cytoskeleton damage, impaired tubule absorption, apoptosis, and collagen deposition. Under extreme heat (41°C), elevated AKI markers KIM‐1 and NGAL, along with cell cycle arrest markers TIMP‐2*IGFBP7 were detected. Notably, TIMP‐2*IGFBP7 appeared at 12 h post‐exposure, preceding NGAL and KIM‐1. Nascent and steady‐state RNA analyses revealed suppressed oxidative phosphorylation and ATP metabolism, along with elevated histone expression, implicating their roles in heat‐induced AKI. The data support that kidney organoids serve as a valuable model for investigating heat‐induced AKI, providing insights into early injury biomarkers that are valuable for the development of treatments.
{"title":"Kidney organoids as a novel platform to evaluate heat‐stress‐induced acute kidney injury pathogenesis","authors":"Qisheng Su, Liang Yue, Leixing Ge, Meida Xiang, Qi Liu, Jiru Wang, Zhimin Yun, He Liu, Congji Shan, Hebing Chen, Chengjun Wu, Zhuo Gao, Yingxia Tan","doi":"10.1002/btm2.70092","DOIUrl":"https://doi.org/10.1002/btm2.70092","url":null,"abstract":"Acute kidney injury (AKI) is a serious condition with significant global impact. To explore mechanisms and biomarkers of heat‐stress‐induced AKI, we used human kidney organoids derived from induced pluripotent stem cells via suspension culture. Organoids were exposed to 37, 39, and 41°C. At 41°C, we found the viability decreased over time, with cytoskeleton damage, impaired tubule absorption, apoptosis, and collagen deposition. Under extreme heat (41°C), elevated AKI markers KIM‐1 and NGAL, along with cell cycle arrest markers TIMP‐2*IGFBP7 were detected. Notably, TIMP‐2*IGFBP7 appeared at 12 h post‐exposure, preceding NGAL and KIM‐1. Nascent and steady‐state RNA analyses revealed suppressed oxidative phosphorylation and ATP metabolism, along with elevated histone expression, implicating their roles in heat‐induced AKI. The data support that kidney organoids serve as a valuable model for investigating heat‐induced AKI, providing insights into early injury biomarkers that are valuable for the development of treatments.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145554099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaotian Zhang, Aaron D. Simmons, Kimberly S. Huggler, Austin K. Feeney, Vladislav Leonov, Hee Jae Jang, Timothy J. Kamp, Jason R. Cantor, Melissa C. Skala, Sean P. Palecek
Maturing human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) in vitro is critical for advancing drug discovery and cardiotoxicity screening applications of these cells. However, the metabolic compositions of basal media used for hPSC‐CM culture typically offer limited relevance to human cardiac physiology. Here, we examined how culture in human plasma‐like medium (HPLM) versus conventional basal media affects the behavior of hPSC‐CMs. Starting with Day 16 hPSC‐CMs, we cultured cells for 2 weeks in either HPLM or RPMI‐based media and then assessed maturation outcomes at Day 30. Compared to RPMI/B27 media containing either RPMI‐defined (11.1 mM) or physiologic glucose levels (5 mM), HPLM/B27 enhanced hPSC‐CM maturity as evinced by concerted transcriptomic, structural, and metabolic phenotypes. These effects included a higher extent of myosin heavy chain isoform switching (α‐MHC to β‐MHC), accelerated ventricular‐specific myosin light chain isoform switching (MLC2a to MLC2v), elongated sarcomeres, increased multinucleation, enhanced calcium transient kinetics, and coordinated activation of oxidative and glycolytic metabolism. Collectively, these findings demonstrate that medium composition has substantial effects on hPSC‐CM biology and also establish HPLM as a basal medium for driving hPSC‐CM maturation in vitro.
{"title":"Human plasma‐like medium enhances structural and metabolic maturation of human pluripotent stem cell‐derived cardiomyocytes","authors":"Xiaotian Zhang, Aaron D. Simmons, Kimberly S. Huggler, Austin K. Feeney, Vladislav Leonov, Hee Jae Jang, Timothy J. Kamp, Jason R. Cantor, Melissa C. Skala, Sean P. Palecek","doi":"10.1002/btm2.70089","DOIUrl":"https://doi.org/10.1002/btm2.70089","url":null,"abstract":"Maturing human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) in vitro is critical for advancing drug discovery and cardiotoxicity screening applications of these cells. However, the metabolic compositions of basal media used for hPSC‐CM culture typically offer limited relevance to human cardiac physiology. Here, we examined how culture in human plasma‐like medium (HPLM) versus conventional basal media affects the behavior of hPSC‐CMs. Starting with Day 16 hPSC‐CMs, we cultured cells for 2 weeks in either HPLM or RPMI‐based media and then assessed maturation outcomes at Day 30. Compared to RPMI/B27 media containing either RPMI‐defined (11.1 mM) or physiologic glucose levels (5 mM), HPLM/B27 enhanced hPSC‐CM maturity as evinced by concerted transcriptomic, structural, and metabolic phenotypes. These effects included a higher extent of myosin heavy chain isoform switching (α‐MHC to β‐MHC), accelerated ventricular‐specific myosin light chain isoform switching (MLC2a to MLC2v), elongated sarcomeres, increased multinucleation, enhanced calcium transient kinetics, and coordinated activation of oxidative and glycolytic metabolism. Collectively, these findings demonstrate that medium composition has substantial effects on hPSC‐CM biology and also establish HPLM as a basal medium for driving hPSC‐CM maturation in vitro.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"33 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Indira Sigdel, Awurama Ofori‐Kwafo, Earshed Al Mamun, Amit K. Tiwari, Yuan Tang
Metastasis is the principal cause of mortality in breast cancer, but therapies specifically targeting metastatic mechanisms are scarce. In triple‐negative breast cancer (TNBC), hypoxia within the tumor microenvironment (TME) promotes endothelial dysfunction, increasing vascular permeability and facilitating cancer cell intravasation. This study presents a microfluidic‐based idealized microvascular on‐chip (iMVoC) model utilizing human umbilical vein endothelial cells and TNBC cells (SUM159PTX) to model a hypoxic TME. This model mimicked dynamic flow perfusion, promoting endothelial alignment along the flow direction, while supporting 3D tumor structures exhibiting varying oxygen levels in the tissue compartment. The iMVoC model enabled cell–cell interactions and the exchange of media and nutrients between compartments. Hypoxia was confirmed by increased nuclear translocation of hypoxia inducible factors (HIF)‐1α and HIF‐2α in TNBC cells, indicating hypoxia‐based signaling. Hypoxia‐induced endothelial cell (EC) inflammation was validated through elevated permeability, upregulation of adhesion molecules, and increased reactive oxygen species (ROS) production, suggesting activation of the HIF‐ROS pathway. Enhanced tumor cell intravasation was observed across inflamed endothelium, and cytokine profiling further confirmed EC activation through inflammatory signaling. Application of the protein kinase C delta (PKCδ) inhibitor (PKCδ‐TAT) significantly mitigated these effects, shifting HIF localization from the nucleus to the cytoplasm, reducing ROS production, downregulating inflammatory cytokines, and lowering TNBC intravasation. These findings demonstrate PKCδ as a key mediator linking hypoxia to EC dysfunction and tumor dissemination. Protecting EC barrier integrity emerges as a promising strategy to mitigate hypoxia‐driven TNBC metastasis, with the iMVoC platform offering a valuable tool for testing anti‐cancer therapeutics or drug combinations involving PKCδ‐TAT.
{"title":"Protein Kinase C‐Delta (PKCδ) inhibition stabilizes endothelium and suppresses triple‐negative breast cancer ( TNBC) intravasation in a microfluidic hypoxic tumor model","authors":"Indira Sigdel, Awurama Ofori‐Kwafo, Earshed Al Mamun, Amit K. Tiwari, Yuan Tang","doi":"10.1002/btm2.70090","DOIUrl":"https://doi.org/10.1002/btm2.70090","url":null,"abstract":"Metastasis is the principal cause of mortality in breast cancer, but therapies specifically targeting metastatic mechanisms are scarce. In triple‐negative breast cancer (TNBC), hypoxia within the tumor microenvironment (TME) promotes endothelial dysfunction, increasing vascular permeability and facilitating cancer cell intravasation. This study presents a microfluidic‐based idealized microvascular on‐chip (iMVoC) model utilizing human umbilical vein endothelial cells and TNBC cells (SUM159PTX) to model a hypoxic TME. This model mimicked dynamic flow perfusion, promoting endothelial alignment along the flow direction, while supporting 3D tumor structures exhibiting varying oxygen levels in the tissue compartment. The iMVoC model enabled cell–cell interactions and the exchange of media and nutrients between compartments. Hypoxia was confirmed by increased nuclear translocation of hypoxia inducible factors (HIF)‐1α and HIF‐2α in TNBC cells, indicating hypoxia‐based signaling. Hypoxia‐induced endothelial cell (EC) inflammation was validated through elevated permeability, upregulation of adhesion molecules, and increased reactive oxygen species (ROS) production, suggesting activation of the HIF‐ROS pathway. Enhanced tumor cell intravasation was observed across inflamed endothelium, and cytokine profiling further confirmed EC activation through inflammatory signaling. Application of the protein kinase C delta (PKCδ) inhibitor (PKCδ‐TAT) significantly mitigated these effects, shifting HIF localization from the nucleus to the cytoplasm, reducing ROS production, downregulating inflammatory cytokines, and lowering TNBC intravasation. These findings demonstrate PKCδ as a key mediator linking hypoxia to EC dysfunction and tumor dissemination. Protecting EC barrier integrity emerges as a promising strategy to mitigate hypoxia‐driven TNBC metastasis, with the iMVoC platform offering a valuable tool for testing anti‐cancer therapeutics or drug combinations involving PKCδ‐TAT.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"125 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145535644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Soukaina El Hajj, Caroline Gorin, Martial Bankoué Ntaté, Romane Lesieur, Elina Casas, Catherine Chaussain, Didier Letourneur, Joelle Amédée, Hervé Duval, Bruno Paiva Dos Santos, Bertrand David
Stem cells from human exfoliated deciduous teeth (SHEDs) offer a promising alternative to bone marrow‐derived mesenchymal stem cells (BMSCs) for bone tissue engineering due to their accessibility, high proliferative potential, and multipotency. In this study, we compared the osteogenic and angiogenic potential of two mesenchymal stem cells subpopulations, SHEDs and BMSCs, when co‐cultured with human umbilical vein endothelial cells (HUVECs) into spheroids over a period of 28 days in porous pullulan/dextran scaffolds loaded with hydroxyapatite (HAp) particles as the sole osteoinductive cue. Spheroids were cultured under static and dynamic conditions, with the latter employing a perfusion flow bioreactor to enhance solute transport and oxygenation. Dynamic culture conditions significantly improved cell viability compared to static culture (85% vs. 54% at Day 28), maintained spheroid integrity, and promoted the expression of angiogenic markers, such as the cluster of differentiation 31 (CD31) and von Willebrand factor (vWF), which under static culture were largely confined to the spheroid periphery. Furthermore, alpha‐smooth muscle actin/neural‐glial‐antigen 2 (αSMA/NG2) and CD31/NG2 colocalization reflected close spatial associations between SHEDs and HUVECs, suggesting a supportive perivascular interaction under dynamic culture. In the presence of HUVECs, we found that HAp particles alone were insufficient to induce robust osteogenic differentiation in SHEDs. Weak alkaline phosphatase activity, minimal osteopontin and osteocalcin expression, and incomplete mineralization were observed under both static and dynamic conditions. In contrast, BMSC/HUVEC spheroids exhibited robust osteogenic differentiation and consistent mineral deposition. These results show intrinsic differences in the behavior of SHEDs and BMSCs when co‐cultured with endothelial cells; while BMSCs tend to favor osteogenesis, SHEDs appear to adopt a more perivascular or pericytic behavior.
人脱落乳牙干细胞因其可获得性、高增殖潜力和多能性，为骨组织工程提供了一种有前途的骨髓间充质干细胞（BMSCs）替代品。在这项研究中，我们比较了两种间充质干细胞亚群（SHEDs）和骨髓间充质干细胞（BMSCs）与人脐静脉内皮细胞（HUVECs）共培养成球状后28天内的成骨和血管生成潜能。球体在静态和动态条件下培养，后者采用灌注流生物反应器来增强溶质运输和氧化。与静态培养相比，动态培养条件显著提高了细胞活力（第28天为85% vs 54%），保持了球体完整性，并促进了血管生成标志物的表达，如分化簇31 （CD31）和血管性血液病因子（vWF），这些标志物在静态培养下主要局限于球体外围。此外，α -平滑肌肌动蛋白/神经胶质抗原2 （αSMA/NG2）和CD31/NG2共定位反映了舍和HUVECs之间密切的空间关联，表明在动态培养下，舍和HUVECs之间存在支持性的血管周围相互作用。在huvec存在的情况下，我们发现单独的HAp颗粒不足以诱导shed的强大成骨分化。在静态和动态条件下均观察到碱性磷酸酶活性弱，骨桥蛋白和骨钙素表达极低，矿化不完全。相比之下，BMSC/HUVEC球体表现出强大的成骨分化和一致的矿物沉积。这些结果表明，当与内皮细胞共培养时，舍和骨髓间充质干细胞的行为存在内在差异；虽然骨髓间充质干细胞倾向于成骨，但细胞似乎更倾向于血管周围或周细胞的行为。
{"title":"SHEDs and BMSCs exhibit distinct lineage preferences in HUVECs dynamic spheroid co‐cultures: vascular versus osteogenic commitment","authors":"Soukaina El Hajj, Caroline Gorin, Martial Bankoué Ntaté, Romane Lesieur, Elina Casas, Catherine Chaussain, Didier Letourneur, Joelle Amédée, Hervé Duval, Bruno Paiva Dos Santos, Bertrand David","doi":"10.1002/btm2.70091","DOIUrl":"https://doi.org/10.1002/btm2.70091","url":null,"abstract":"Stem cells from human exfoliated deciduous teeth (SHEDs) offer a promising alternative to bone marrow‐derived mesenchymal stem cells (BMSCs) for bone tissue engineering due to their accessibility, high proliferative potential, and multipotency. In this study, we compared the osteogenic and angiogenic potential of two mesenchymal stem cells subpopulations, SHEDs and BMSCs, when co‐cultured with human umbilical vein endothelial cells (HUVECs) into spheroids over a period of 28 days in porous pullulan/dextran scaffolds loaded with hydroxyapatite (HAp) particles as the sole osteoinductive cue. Spheroids were cultured under static and dynamic conditions, with the latter employing a perfusion flow bioreactor to enhance solute transport and oxygenation. Dynamic culture conditions significantly improved cell viability compared to static culture (85% vs. 54% at Day 28), maintained spheroid integrity, and promoted the expression of angiogenic markers, such as the cluster of differentiation 31 (CD31) and von Willebrand factor (vWF), which under static culture were largely confined to the spheroid periphery. Furthermore, alpha‐smooth muscle actin/neural‐glial‐antigen 2 (αSMA/NG2) and CD31/NG2 colocalization reflected close spatial associations between SHEDs and HUVECs, suggesting a supportive perivascular interaction under dynamic culture. In the presence of HUVECs, we found that HAp particles alone were insufficient to induce robust osteogenic differentiation in SHEDs. Weak alkaline phosphatase activity, minimal osteopontin and osteocalcin expression, and incomplete mineralization were observed under both static and dynamic conditions. In contrast, BMSC/HUVEC spheroids exhibited robust osteogenic differentiation and consistent mineral deposition. These results show intrinsic differences in the behavior of SHEDs and BMSCs when co‐cultured with endothelial cells; while BMSCs tend to favor osteogenesis, SHEDs appear to adopt a more perivascular or pericytic behavior.","PeriodicalId":9263,"journal":{"name":"Bioengineering & Translational Medicine","volume":"28 1","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145532080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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