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Vascularization of pluripotent stem cell-derived islet organoids improves β-cell function

ABSTRACT: Vascularization of pluripotent stem cell-derived islet organoids improves β-cell function

PROVIDER: PRJNA890151 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21890244_1.fastq.gz	Fastqsanger.gz
	SRR21890244_2.fastq.gz	Fastqsanger.gz
	SRR21890245_1.fastq.gz	Fastqsanger.gz
	SRR21890245_2.fastq.gz	Fastqsanger.gz
	SRR21890246_1.fastq.gz	Fastqsanger.gz

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Vascularization of pluripotent stem cell-derived islet organoids improves β-cell function

Project description:Blood vessels play a critical role in pancreatic islet health and function, yet current culture methods to generate islet organoids from human pluripotent stem cells (SC-islets) lack a vascular component. Here, we engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts both in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+ influx into SC-β-cells; a hallmark of β-cell function that is blunted in non-vascularized SC-islets. We show that an islet-like basement membrane is formed by vasculature and contributes to the functional improvement of SC-β-cells. Furthermore, cell-cell communication networks based on scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-β-cells. Correspondingly, BMP4 augmented the SC-β-cell Ca2+ response and insulin secretion. The here-described vascularized SC-islet models will enable further studies of crosstalk between β-cells and ECs and serve as an in vivo-mimicking platform for disease modeling and therapeutic testing.

2023-05-01 | GSE215376 | GEO

Pre-adaptation of Stem Cell-Derived Islet Organoids to Hypoxia via Zinc Transportation Inhibition Drives Rapid Neo-vascularization

Project description:Human stem cell-derived islet organoids (SC-islets) hold great potential for diabetes treatment, but their clinical application is hindered by immaturity and ischemia-induced dysfunction post transplantation. Hypoxia-driven angiogenesis via the HIF1A-VEGFA axis is a common adaptation, but the metabolic fragility of SC-islet β cell leads to early functional damage and suppressed VEGFA release, thereby delaying vascularization and causing graft loss. The key challenge in SC-islet transplantation is how to prevent hypoxia-induced stress and promote rapid neo-vascularization. To reconcile this discrepancy, we targeted zinc transportation using a chemical inhibitor to enhance SC-islet maturation, hypoxia resistance and vascularization. We found that excessive zinc in SC-islet β-cells induces oxidative modification that inhibits AMPK activity. Chemical inhibition of zinc transportation activates AMPK, simultaneously enhances functional maturation, improves hypoxia resistance and increases VEGFA expression to facilitate endothelial cell integration. In diabetic animal models, this approach significantly improved hypoxia resistance, accelerated neo-vascularization, and enhanced glycemic control. Our findings demonstrate that chemical inhibition of zinc transportation boosts SC-islet functional competence, offering a potential strategy to advance the paradigm of functional pre-adaptation to stress in regenerative medicine.

2026-02-10 | GSE293322 | GEO

Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Project description:Blood vessels play a critical role in pancreatic islet function, yet current methods for deriving islet organoids from human pluripotent stem cells (SC-islets) lack vasculature. We engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+ influx into SC-β-cells, a hallmark of β-cell function that is blunted in non-vascularized SC-islets. Furthermore, vascularization accelerated diabetes reversal post-engraftment of a subtherapeutic SC-islet dose. We show that vasculature leads to formation of an islet-like basement membrane that contributes to functional improvement of SC-β-cells. Furthermore, scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-β cells, and correspondingly, BMP4 enhanced the SC-β cell Ca2+ response and insulin secretion. Vascularized SC-islets will enable further studies of crosstalk between β-cells and ECs and will serve as an in vitro platform for disease modeling and therapeutic testing.

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Pre-adaptation of Stem Cell-Derived Islet Organoids to Hypoxia via Zinc Transportation Inhibition Drives Rapid Neo-vascularization

Project description:Pre-adaptation of Stem Cell-Derived Islet Organoids to Hypoxia via Zinc Transportation Inhibition Drives Rapid Neo-vascularization

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Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

Project description:Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids

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Encapsulation boosts islet-cell signature in differentiating human induced pluripotent stem cells via integrin signalling

Project description:Cell replacement therapies hold great therapeutic potential. Nevertheless, our knowledge of the mechanisms governing the developmental processes is limited, impeding the quality of differentiation protocols. Generating insulin-expressing cells in vitro is no exception, with the guided series of differentiation events producing heterogeneous cell populations that display mixed pancreatic islet phenotypes and immaturity. The achievement of terminal differentiation ultimately requires the in vivo transplantation of, usually, encapsulated cells. Here we show the impact of cell confinement on the pancreatic islet signature during the guided differentiation of alginate encapsulated human induced pluripotent stem cells (hiPSCs). Our results show that encapsulation improves differentiation by significantly reshaping the proteome landscape of the cells towards an islet-like signature. Pathway analysis is suggestive of integrins transducing the encapsulation effect into intracellular signalling cascades promoting differentiation. These analyses provide a molecular framework for understanding the confinement effects on hiPSCs differentiation while confirming its importance for this process.

2020-01-24 | GSE141891 | GEO

Transcriptional Programming of Adult Human Pancreas-Derived Progenitor Cells into Functional Islet-Like Organoids

Project description:This study investigates the transcriptional programming of adult human pancreas-derived progenitor cells into functional islet-like organoids using single-cell RNA sequencing. Progenitor cell-derived monolayers, clusters, islet-like organoids, and human islet comparator samples were profiled to define progenitor-associated transcriptional states, endocrine lineage progression, polyhormonal early endocrine-like populations, and beta- and alpha-lineage-associated differentiation programs.

2026-05-29 | GSE332956 | GEO

Human-induced pluripotent Stem Cell-Derived Hepatic Stellate Cells in Liver Organoids: Maturation Promotion and Essential Role in Vascularization

Project description:Human-induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) are valuable for studying human liver organogenesis but face challenges in faithfully recapitulating certain processes, like vasculogenesis, due to the lack of specific cell components. Hepatic stellate cells (HSCs), which are liver-specific pericytes and might be crucial for liver vasculogenesis, remain underutilized in developmental studies because of their disease-related "activated" status and inefficient generation process. Here, we present an efficient method for generating hiPSC-derived HSCs (hiPSC-HSCs) resembling non-activated HSCs in the healthy human liver. These hiPSC-HSCs exhibit exceptional expandability (>105-fold) while maintaining essential cellular features. Additionally, in entirely hiPSC-derived LOs consisting of HSCs, hepatic endoderm, and endothelial cells, hiPSC-HSCs play a vital role in LO maturation and vascularization, both in vitro and in vivo. This work represents a significant advancement in understanding HSC roles in human liver development, and LOs containing non-activated hiPSC-HSCs hold potential in modeling congenital human liver diseases.

2026-03-20 | GSE249826 | GEO

Temsirolimus and Bevacizumab in Treating Patients With Advanced Endometrial, Ovarian, Liver, Carcinoid, or Islet Cell Cancer

Project description:This phase II trial studies how well temsirolimus and bevacizumab work in treating patients with advanced endometrial, ovarian, liver, carcinoid, or islet cell cancer. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of cancer by blocking blood flow to the tumor. Giving temsirolimus together with bevacizumab may kill more tumor cells.

| 2080521 | ecrin-mdr-crc

Human-induced pluripotent Stem Cell-Derived Hepatic Stellate Cells in Liver Organoids: Maturation Promotion and Essential Role in Vascularization [scRNA-Seq]

Project description:Human-induced pluripotent stem cell (hiPSC)-derived liver organoids (LOs) are valuable for studying human liver organogenesis but face challenges in faithfully recapitulating certain processes, like vasculogenesis, due to the lack of specific cell components. Hepatic stellate cells (HSCs), which are liver-specific pericytes and might be crucial for liver vasculogenesis, remain underutilized in developmental studies because of their disease-related "activated" status and inefficient generation process. Here, we present an efficient method for generating hiPSC-derived HSCs (hiPSC-HSCs) resembling fetal HSCs’ transcriptomic profiles. These hiPSC-HSCs exhibit exceptional expandability (>105-fold) while maintaining essential cellular features. Additionally, in entirely hiPSC-derived LOs consisting of HSCs, hepatic endoderm, and endothelial cells, hiPSC-HSCs play a vital role in LO maturation and vascularization, both in vitro and in vivo. This work represents a significant advancement in understanding HSC roles in human liver development, and LOs containing non-activated hiPSC-HSCs hold potential in modeling congenital human liver diseases.

2026-03-20 | GSE289592 | GEO

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