Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 473
Страница 221 из 548-
Modeling Moyamoya disease using patient-derived induced pluripotent stem cells and organoids.
The underlying mechanisms of Moyamoya disease (MMD), a rare, progressive cerebrovascular disorder marked by distal internal carotid artery stenosis or occlusion and the formation of fragile collaterals, remain poorly understood, in part because conventional models fail to capture the genetic, vascular, and neurovascular complexity of human MMD. Driven by recent advances in disease modeling, MMD research has moved beyond early endothelial progenitor cell studies toward patient-derived induced pluripotent stem cell (iPSC)-based platforms. Here, we summarize the generation and validation of MMD-specific iPSCs and their differentiation into endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and related vascular lineages, and we discuss how two-dimensional (2D) iPSC-based models have provided insights into impaired angiogenesis, endothelial dysfunction, abnormal VSMC behavior, and disrupted vascular cell interactions. We then highlight the emerging use of three-dimensional vascular and neurovascular organoids, which reproduce cellular heterogeneity, vessel-like organization, and neurovascular unit interactions more closely than conventional 2D cultures. These models may provide a more integrated platform for investigating the complex vascular pathophysiology of MMD. Finally, we discuss future directions for MMD modeling, including the integration of multi-omics profiling and CRISPR-mediated genome editing with patient-derived iPSC and organoid platforms. These approaches may help clarify genotype-phenotype relationships, RNF213-dependent and RNF213-independent mechanisms, and disease-relevant molecular pathways. With further standardization and validation, iPSC- and organoid-based models could support mechanistic studies, therapeutic screening, and personalized disease modeling. Our review underscores the emerging role of patient-derived stem cell and organoid technologies in advancing MMD research and in informing future translational efforts.
-
Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation.
The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiological and pathophysiological processes that are unable to be studied using other model systems. Increased understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell system and display increased secretion of fibroblast growth factor 19 (FGF19) (intestine) and downregulation of P450 enzyme cholesterol 7 α-hydroxylase (CYP7A) (liver) in response to apical exposure of the intestine to bile acids. This work establishes that organoid cultures can be used to study and therapeutically modulate interorgan interactions and advance the development of personalized approaches to medical care.NEW & NOTEWORTHY Interorgan signaling is a critical feature of human biology and physiology, yet has remained difficult to study due to the lack of in vitro models. Here, we demonstrate that physical coupling of ex vivo human intestine and liver epithelial organoid cultures recapitulates in vivo interorgan bile acid signaling. These results suggest that coupling of multiple organoid systems provides new models to investigate interorgan communication and advances our knowledge of human physiological and pathophysiological processes.
-
Limosilactobacillus reuteri promotes melatonin release from human intestinal organoids via 5'ectonucleotidase activity.
Strains of Limosilactobacillus reuteri have been used to prevent or treat various conditions; however, the mechanisms by which they exert beneficial effects are not completely understood. Infant colic is one example in which L. reuteri DSM 17938 reduces clinical symptoms. While the etiology of colic is unknown, abnormal melatonin levels in infants have been suggested as a possible contributor. L. reuteri DSM 17938 has been shown to produce adenosine from AMP via production of the extracellular enzyme 5'ectonucleotidase (5'NT). Adenosine is a potent signaling molecule that impacts several important aspects of host physiology, including the release of melatonin from the pineal gland in the brain. A second major source of melatonin production is enteroendocrine cells in the intestine. We hypothesized that the adenosine generated via the 5'NT activity of L. reuteri DSM 17938, would stimulate melatonin release from human intestinal organoids. Here, we characterized the growth conditions that impact L. reuteri DSM 17938 5'NT activity, including carbon source utilization and required metal cofactors. We found zinc to be an essential cofactor for 5'NT activity by L. reuteri and observed carbon utilization altered 5'NT activity levels. Stachyose and raffinose increased levels of 5'NT activity while sucrose decreased 5'NT activity. We demonstrated that L. reuteri DSM 17938 stimulates melatonin release from pediatric human intestinal organoids in a 5'NT-dependent manner. Surprisingly, adenosine was necessary, but not sufficient, for the induction of epithelial melatonin release, thereby suggesting that an additional secreted factor was also required. Furthermore, L. reuteri BG-R46®, an evolved strain of DSM 17938 that is known to express higher 5'NT activity, was shown to induce higher levels of melatonin secretion. Taken together, this work identifies zinc and carbon sources as key factors altering L. reuteri 5'NT activity levels and demonstrates that the L. reuteri strains stimulate intestinal melatonin release via 5'NT.
-
Applications and research trends in organoid based infectious disease models.
Recently, three-dimensional (3D) cell culture technology has been developing rapidly, and disease-specific organoid models that can simulate human diseases are being developed. These models are being studied as a valuable tool that can be applied to pathogen biology research and drug screening analysis platforms to obtain fast, reliable, and reproducible results. Organoids are 3D cell aggregates formed from embryonic stem cells (ESCs), adult stem cells (ASCs), or induced pluripotent stem cells (iPSCs) through self-renewal and self-organization. They are also called mini-organs and have a structure and function similar to those of real organs, providing a more physiologically relevant model compared to traditional 2D cultures. In particular, due to the recent epidemics of infectious diseases such as coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), many studies are using organoids for infectious disease research, enabling more accurate pathogen-host interaction modeling. In this review, we briefly introduce organoids and discuss research trends in developing organoid-based models of infectious diseases, focusing on organoids derived from the brain, liver, intestines, lung, kidney, skin, and blood vessels. These models hold significant potential for advancing our understanding of disease mechanisms and therapeutic development.
-
Development of glioblastoma organoids and their applications in personalized therapy.
Glioblastomas (GBMs) are the brain tumors with the highest malignancy and poorest prognoses. GBM is characterized by high heterogeneity and resistance to drug treatment. Organoids are 3-dimensional cultures that are constructed in vitro and comprise cell types highly similar to those in organs or tissues in vivo, thus simulating specific structures and physiological functions of organs. Organoids have been technically developed into an advanced ex vivo disease model used in basic and preclinical research on tumors. Brain organoids, which simulate the brain microenvironment while preserving tumor heterogeneity, have been used to predict patients' therapeutic responses to antitumor drugs, thus enabling a breakthrough in glioma research. GBM organoids provide an effective supplementary model that reflects human tumors' biological characteristics and functions in vitro more directly and accurately than traditional experimental models. Therefore, GBM organoids are widely applicable in disease mechanism research, drug development and screening, and glioma precision treatments. This review focuses on the development of various GBM organoid models and their applications in identifying new individualized therapies against drug-resistant GBM.
-
Modeling Development and Disease with Organoids.
Recent advances in 3D culture technology allow embryonic and adult mammalian stem cells to exhibit their remarkable self-organizing properties, and the resulting organoids reflect key structural and functional properties of organs such as kidney, lung, gut, brain and retina. Organoid technology can therefore be used to model human organ development and various human pathologies 'in a dish." Additionally, patient-derived organoids hold promise to predict drug response in a personalized fashion. Organoids open up new avenues for regenerative medicine and, in combination with editing technology, for gene therapy. The many potential applications of this technology are only beginning to be explored.
-
Rational Design and Organoid-Based Evaluation of a Cocktail CAR-γδ T Cell Therapy for Heterogeneous Glioblastoma.
Various challenges, including tumor heterogeneity and inadequate T cell infiltration, impede the progress of chimeric antigen receptor T cell (CAR-T) therapy for glioblastoma (GBM). To address these obstacles, a multiple step strategy is designed. Initially, literature review and bioinformatics analysis to screen a set of antigens that are heterogeneously expressed in GBM, which are designated as the target-bank, are leveraged. Then, according to the multiplex immunohistochemistry results of each patient's tumor sample, a personalized panel of antigens based on the principle that most cancer cells in tumor tissues can be covered from the target-bank is selected. To target these antigens, Vδ1 T cells are chosen as CAR vehicles because of its high tissue infiltration and off-the-shelf properties, and an optimized protocol for engineering CAR-Vδ1 T cells with high purity and cytotoxicity, low exhaustion, and cytokine release is developed. Next, the specific panel of cocktail CAR-Vδ1 T cells in the GBM organoids that are directly derived from the same patient's tumor is tested. The term "prof" cocktail therapy is coined to describe the approach using precise and rational combination of tumor antigens, organoid-based evaluation, and fitness of Vδ1 T cells. It may accelerate development of effective CAR-T drugs for heterogeneous solid tumors.
-
Evolution of Preclinical Models for Glioblastoma Modelling and Drug Screening.
PURPOSE OF REVIEW: Isocitrate dehydrogenase wild-type glioblastoma is an extremely aggressive and fatal primary brain tumour, characterised by extensive heterogeneity and diffuse infiltration of brain parenchyma. Despite multimodal treatment and diverse research efforts to develop novel therapies, there has been limited success in improving patient outcomes. Constructing physiologically relevant preclinical models is essential to optimising drug screening processes and identifying more effective treatments. RECENT FINDINGS: Traditional in-vitro models have provided critical insights into glioblastoma pathophysiology; however, they are limited in their ability to recapitulate the complex tumour microenvironment and its interactions with surrounding cells. In-vivo models offer a more physiologically relevant context, but often do not fully represent human pathology, are expensive, and time-consuming. These limitations have contributed to the low translational success of therapies from trials to clinic. Organoid and glioblastoma-on-a-chip technology represent significant advances in glioblastoma modelling and enable the replication of key features of the human tumour microenvironment, including its structural, mechanical, and biochemical properties. Organoids provide a 3D system that captures cellular heterogeneity and tumour architecture, while microfluidic chips offer dynamic systems capable of mimicking vascularisation and nutrient exchange. Together, these technologies hold tremendous potential for high throughput drug screening and personalised, precision medicine. This review explores the evolution of preclinical models in glioblastoma modelling and drug screening, emphasising the transition from traditional systems to more advanced organoid and microfluidic platforms. Furthermore, it aims to evaluate the advantages and limitations of both traditional and next-generation models, investigating their combined potential to address current challenges by integrating complementary aspects of specific models and techniques.
-
Organotypic Neurovascular Models: Past Results and Future Directions.
The high failure rates of clinical trials in neurodegeneration, perhaps most apparent in recent high-profile failures of potential Alzheimer's disease therapies, have partially motivated the development of improved human cell-based models to bridge the gap between well-plate assays and preclinical efficacy studies in mice. Recently, cerebral organoids derived from stem cells have gained significant traction as 3D models of central nervous system (CNS) regions. Although this technology is promising, several limitations still exist; most notably, improper structural organization of neural cells and a lack of functional glia and vasculature. Here, we provide an overview of the cerebral organoid field and speculate how engineering strategies, including biomaterial fabrication and templating, might be used to overcome existing challenges.
-
A thermally actuated 3D foldable bioelectronic interface for multimodal electrophysiological and cytokine profiling of human spinal cord organoids.
Three-dimensional (3D) organoids provide physiologically relevant models for studying human neural development and disease; however, stable bioelectronic interfacing with curved and dynamic organoid surfaces remains challenging. Here, we present a thermally actuated, shape-memory polymer (SMP)-based foldable bioelectronic interface for simultaneous electrophysiological recording and electrochemical cytokine sensing in human spinal cord organoids (hSCOs). Near physiological temperature (36-37 °C), the SMP substrate undergoes pronounced mechanical softening, enabling conformal 3D wrapping around organoids without external mechanical compression. The platform integrates gold microelectrodes for extracellular neural recording and antibody-functionalized sensing electrodes for label-free cytokine detection. Finite element simulations and experimental mechanical analyses confirmed temperature-dependent bending, enhanced conformal contact, low interfacial stress, and mechanically stable biointerfacing. Electrochemical characterization demonstrated linear cytokine sensing responses over 1-100 ng/ml, with calculated limits of detection (LOD) of 0.44 ng/ml for TNF-α and 0.41 ng/ml for IL-8. Using this multimodal platform, stable electrophysiological recordings and cytokine monitoring were simultaneously obtained from hSCOs under inflammatory stimulation. TNF-α treatment induced dose-dependent increases in neural firing activity together with corresponding electrochemical cytokine responses. Collectively, this thermally adaptive bioelectronic interface provides a minimally invasive platform for integrated electrical and biochemical profiling of intact organoids and offers a promising tool for neuroinflammatory organoid studies.