Recapitulate Organotypic Mesenchyme and Endothelium via Vascularized Lung and Intestine Organoids
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE250399 | GEO | 2025/06/29
REPOSITORIES: GEO
Similar Datasets
Project description:Recapitulate Organotypic Mesenchyme and Endothelium via Vascularized Lung and Intestine Organoids
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Project description:Mouse Vascularized Adipose Spheroids: An Organotypic Model for Thermogenic Adipocytes
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Project description:Adipose tissues, particularly beige and brown adipose tissue, play crucial roles in energy metabolism. Brown adipose tissues’ thermogenic capacity and the appearance of beige cells within white adipose tissue have spurred interest in their metabolic impact and therapeutic potential. Brown and beige fat cells, activated by factors like cold exposure, share mechanisms that drive non-shivering thermogenesis. Understanding their behavior requires sophisticated, yet universal in vitro models that replicate the complex microenvironment and vasculature of adipose tissues. Here we present mouse vascularized adipose spheroids of the stromal vascular microenvironment from inguinal white adipose tissue. We show that scaffold embedding improves vascular sprouting, enhances spheroid growth, and upregulates adipogenic markers. Transcriptional profiling via RNA sequencing revealed distinct metabolic pathways upregulated in our vascularized adipose spheroids, with increased expression of genes involved in glucose metabolism, lipid metabolism, and thermogenesis. Functional assessment demonstrated increased oxygen consumption in vascularized adipose spheroids compared to 2D cultures, which was further enhanced by β-adrenergic receptor stimulation via isoproterenol correlating with elevated β-adrenergic receptor expression. Moreover, stimulation with the naturally occurring adipokine, FGF21, induced Ucp1 mRNA expression in the vascularized adipose spheroids. In conclusion, our vascularized inguinal white adipose tissue spheroids provide a physiologically relevant platform to study how the stromal vascular microenvironment shapes adipocyte responses and influence activated thermogenesis in beige adipocytes.
2024-05-02 | GSE261267 | GEO
Project description:Tumor angiogenesis is regarded as a promising target for limiting cancer progression because tumor-associated vasculature supplies blood and provides a path for metastasis. Thus, in vitro recapitulation of vascularized tumors is critical to understand the pathology of cancer and identify the mechanisms by which tumor cells proliferate, metastasize, and respond to drugs. In this study, we microengineered a vascularized tumor spheroid (VTS) model to reproduce the pathological features of solid tumors. We first generated tumor cell-EC hybrid spheroids with self-assembled intratumoral vessels, which enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids comprised only with cancer cells. Notably, the hybrid spheroid also exhibited expression profiles associated with aggressive behavior. The blood vessels sprouting around the hybrid spheroids on the VTS chip were interconnected with intratumoral vessels and displayed the distinctive characteristics of leaky tumor vessels. With the VTS chip showing a progressive tumor phenotype, we validated the suppressive effects of axitinib on tumor growth and angiogenesis, which depended on exposure dose and time, highlighting the significance of tumor vascularization to predict the efficacy of anticancer drugs. Ultimately, we effectively induced both lymphangiogenesis and angiogenesis around the tumor spheroid by promoting interstitial flow. Thus, our VTS model is a valuable platform with which to investigate the interactions between tumor microenvironments and explore therapeutic strategies in cancer.
2022-09-07 | GSE212669 | GEO
Project description:Novel therapeutic strategies are needed to improve the efficacy of chimeric antigen receptor (CAR)-T cells in the treatment of solid tumors. Multiple tumor microenvironmental factors are thought to contribute to CAR-T cell therapy resistance in solid tumors, and appropriate model systems to identify and examine these factors using clinically relevant biospecimens are limited. Here, we examined the activity of B7-H3 (CD276) directed CAR-T (B7-H3.CAR-T) using 3D microfluidic cultures of patient-derived organotypic tumor spheroids (PDOTS) and confirmed activity of B7-H3.CAR-T in PDOTS. While B7-H3 expression in PDOTS was associated with B7-H3.CAR-T sensitivity, mechanistic studies revealed dynamic upregulation of co-inhibitory receptors on CAR-T cells following target cell encounter that led to CAR-T cell dysfunction and limited efficacy against B7-H3 expressing tumors. PD-1 blockade restored CAR-T activity in monotypic and organotypic tumor spheroids with improved tumor control and upregulation of effector cytokines. Given the emerging role of TANK-binding kinase 1 (TBK1) as an immune evasion gene, we examined the effect of TBK1 inhibition on CAR-T efficacy. Similar to PD-1 blockade, TBK1 inhibition restored CAR-T activity in monotypic and organotypic tumor spheroids, prevented CAR-T cell dysfunction, and enhanced T cell proliferation. Inhibition or deletion of TBK1 also enhanced sensitivity of cancer cells to immune-mediated killing. Taken together, our results demonstrate the feasibility and utility of ex vivo profiling of CAR-T cells using PDOTS and suggest that targeting TBK1 is a novel strategy to enhance CAR-T efficacy by overcoming tumor-intrinsic and -extrinsic resistance mechanisms.
2024-09-24 | GSE277569 | GEO
Project description:Organotypic human tissue models constitute promising systems to facilitate drug discovery and development. They allow to maintain native cellular phenotypes and functions, which enables long-term pharmacokinetic and toxicity studies, as well as phenotypic screening. To trace relevant phenotypic changes back to specific targets or signaling pathways, comprehensive proteomic profiling is the gold-standard. A multitude of proteomic workflows have been applied on 3D tissue models to quantify their molecular phenotypes; however, their impact on analytical results and biological conclusions has not been evaluated. Here, we compared the performance of twelve mass spectrometry-based global proteomic workflows that differed in the amount of cellular input, lysis protocols and quantification methods for the analysis of primary human liver spheroids. We find that the different protocols differ majorly in the total number and subcellular compartment bias of identified proteins, which is particularly relevant for the reliable quantification of transporters and drug metabolizing enzymes. However, using a model of non-alcoholic fatty liver disease, we show that critical disease pathways are robustly identified using a standardized high throughput-compatible workflow based on thermal lysis, even using only individual spheroids (1,500 cells) as input. The results increase the applicability of proteomic profiling to phenotypic screens in organotypic microtissues and provides a scalable platform for deep phenotyping from limited biological material.
2024-04-29 | PXD047462 | Pride
Project description:Here, we demonstrate a generalized method for organ bud formation from diverse tissues by combining pluripotent stem cell-derived tissue-specific progenitors or relevant tissue samples with endothelial cells and mesenchymal stem cells (MSCs). The MSCs initiated condensation within these heterotypic cell mixtures, which was dependent upon substrate matrix stiffness. Defining optimal mechanical properties promoted formation of 3D, transplantable organ buds from tissues including kidney, pancreas, intestine, heart, lung, and brain. Transplanted pancreatic and renal buds were rapidly vascularized and self-organized into functional, tissue-specific structures. These findings provide a general platform for harnessing mechanical properties to generate vascularized, complex organ buds with broad applications for regenerative medicine. Gene expression profiles of development-related gene expression in kidney bud transplants and murine kidneys.
2015-07-01 | E-GEOD-66454 | biostudies-arrayexpress
Project description:To investigate the cell-cell interactions among the transplanted vascularized organoids, we utilized a Slide-seq-based spatial transcriptomics platform to unbiasedly map the spatial distribution of ligand-receptor pairs.
2025-06-29 | GSE296429 | GEO
Project description:Replacement of lost beta cells in patients with diabetes has the potential to alleviate them of their disease, yet current protocols to make beta cells are inadequate for therapy. In vitro screens can reveal the signals necessary for endocrine maturation to improve beta cell production, however the complexities of in vivo development that lead to beta cell formation are lost in two-dimensional systems. Here, we create three-dimensional organotypic pancreatic cultures, named pancreatoids, composed of embryonic day 10.5 murine epithelial progenitors and native mesenchyme. These progenitors assemble in scaffold-free, floating conditions and, with the inclusion of native mesenchyme, develop into pancreatoids expressing markers of different pancreatic lineages including endocrine-like cells. Treatment of pancreatoids with (-)-Indolactam-V or phorbol 12-myristate 13-acetate, two protein kinase C activators, leads to altered morphology which otherwise would be overlooked in two-dimensional systems. Protein kinase C activation also led to fewer Insulin+ cells, decreased Ins1 and Ins2 mRNA levels, and increased Pdx1 and Hes1 mRNA levels with a high number of DBA+ cells. Thus, organotypic pancreatoids provide a useful tool for developmental studies, and can further be used for disease modeling, small molecules and genetic screens, or applied to human pluripotent stem cell differentiation for beta-like cell formation.
| S-EPMC5589819 | biostudies-literature
Project description:The poor osseointegration of dental implants in diabetic patients has become a long-standing clinical problem. Magnesium has been proved to promote bone healing under normal conditions. Here, we elucidate the mechanism by which Mg2+ promotes vascularized osseointegration in diabetic status. We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised, with significantly decreased angiogenesis. We then developed Mg-coating implants with hydrothermal synthesis. These implants sucessfully improved the vascularization and osseointegration in diabetic status. Mechanically, Mg2+ promoted the degradation of Kelch-like ECH associated protein 1 (Keap1) and the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) by up-regulating the expression of sestrin 2 (SESN2) in endothelial cells, thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia. Altogether, our data proved that Mg2+ promoted vascularized osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.
2024-02-07 | GSE236139 | GEO