Identification and removal of unexpected proliferative off-target cells emerging after implantation of iPSC-derived pancreatic islet cells
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ABSTRACT:
PROVIDER: PRJNA881936 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21622112_1.fastq.gz | Fastqsanger.gz | |||
| SRR21622112_2.fastq.gz | Fastqsanger.gz | |||
| SRR21622113_1.fastq.gz | Fastqsanger.gz | |||
| SRR21622113_2.fastq.gz | Fastqsanger.gz | |||
| SRR21622114_1.fastq.gz | Fastqsanger.gz |
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Project description:The differentiation of pancreatic endocrine cells from human pluripotent stem cells (PSC) has been thoroughly investigated for their application in cell therapy against diabetes. However, there is little information available on the long-term safety of these differentiated cells. Here we show that implantation of induced PSC-derived pancreatic islet cells (iPIC) results in the appearance of unexpected proliferative off-target cells via in vivo maturation. Since the unexpected cells have characteristics of both mesenchymal stem cells (MSC) and uterine tissue, we named these cells proliferative MSC and uterus like cells (PMUC). To detect PMUC without implantation, we developed four-week-extended culture system and found that PMUC can be reduced by compound treatment, especially a taxane Docetaxel. Indeed, when we implanted Docetaxel-treated iPIC, the appearance of PMUC disappeared. The present study provides useful insights into identifying and resolving safety issues which is particularly important in the field of cell-based medicine using PSC.
2024-04-22 | GSE213617 | GEO
Project description:Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential1-5, thus understanding the mechanisms underlying this functional heterogeneity might allow novel regenerative approaches. Here we discovered Flattop (Fltp) as a biomarker that distinguishes proliferative from mature β-cells. Genetic lineage tracing revealed that these β-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- β-cells undergo compensatory proliferation, whereas Fltp-lineage+ β-cells account for islet cell hypertrophy commonly associated with cytotoxic stress. The expression of the Wnt/planar cell polarity (PCP) effector gene Fltp increases when naïve β-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs6-8. We show that dispersed early postnatal islet cells, insulinoma cells and human β-cells all have the intrinsic ability to form polarized pseudo-islets in 3D cultures. Compaction and polarization correlates with the induction of maturation markers and can be enhanced by Wnt/PCP pathway activation. Finally, we show that Fltp is not only a marker for mature β-cells, but is also functionally required for proper insulin secretion in mouse and human. We conclude that planar cell polarity and 3D architecture underlie functional β-cell heterogeneity and report that Fltp is a biomarker that separates proliferative from mature β-cells. These findings establish novel molecular underpinnings of β-cells and enable targeting of subpopulations for the regeneration of functional β-cell mass in diabetic patients. We performed gene expression microarray analysis on two FACS-sorted pancreatic islet cell populations: flattop-positive and flattop-negative.
2016-06-02 | E-GEOD-68853 | biostudies-arrayexpress
Project description:Age-related Islet Inflammation Marks the Proliferative Decline of Pancreatic Beta-cells in Zebrafish
| PRJNA418467 | ENA
Project description:Insulin-dependent diabetes is a complex multifactorial disorder characterized by loss or dysfunction of β-cells. Pancreatic β-cells differ in size, glucose responsiveness, insulin secretion and precursor cell potential, thus understanding the mechanisms underlying this functional heterogeneity might allow novel regenerative approaches. Here we discovered Flattop (Fltp) as a biomarker that distinguishes proliferative from mature β-cell subpopulations with distinct molecular, physiological and ultrastructural features. Genetic lineage tracing revealed that these β-cell subpopulations react differentially to environmental changes. Upon insulin resistance Fltp- β-cells undergo compensatory proliferation, whereas Fltp-lineage+ β-cells account for islet cell hypertrophy commonly associated with cytotoxic stress. The expression of the Wnt/planar cell polarity (PCP) effector gene Fltp increases when naïve β-cells cluster together to form polarized and mature three-dimensional (3D) islet mini-organs. We show that 3D architecture and Wnt/PCP ligands are sufficient to trigger mouse and human β-cell maturation. Finally, we show that Fltp is not necessary for β-cell development, proliferation, or maturation, but is required for proper glucose-stimulated insulin secretion in mature β-cells. We conclude that 3D architecture and Wnt/PCP signaling underlie functional β-cell heterogeneity and induce β-cell maturation. The identification of Fltp as a biomarker for mature β-cells establish novel molecular underpinnings of β-cells and enable targeting of subpopulations for the regeneration of functional β-cell mass in diabetic patients.
2016-06-02 | GSE68853 | GEO
Project description:This is an Affy experiment that was conducted on human derived pancreatic islet cells that were expanded in serum-containing medium to produce hIPC cells (human Islet-derived Precursor Cells). These cells, when subjected to 1 day of serum starvation, transition into hormone-expressing ICAs (Islet-like Cell Aggregates). In this experiment, proliferative hIPCs were trypsin-harvested and transferred in either serum-containing media (C) or serum-free media (F). After 24 hours, cells from both conditions were harvested and RNA was extracted. This experiment was meant to identify gene expression changes between hIPC early differentiation (condition F) and hIPC proliferation (condition C) with cells being in culture for the same amount of time. There were 3 replicates each for each of the two conditions, of which the 3rd was a pool of the first 2 replicates.
2014-09-22 | E-MTAB-2936 | biostudies-arrayexpress
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during ?-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature ?-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn ?-cells, suggesting that they contribute to the limited proliferative capacity of adult ?-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=5) or 3-month-old male rat (n=6) were taken. Total RNA was extracted and microRNA profiling was performed using the Illumina TruSeq small RNA kit and single-end sequencing.
2014-09-06 | E-GEOD-61180 | biostudies-arrayexpress
Project description:Dll4-Notch signaling is required for cell fate decisions and neoplasias. However, emerging evidence suggests a role for Dll4-Notch signaling in metabolic and immune diseases. To date, there is no evidence of a direct effect of Dll4-Notch signaling inhibition on pancreatic islet function and insulin secretion.
2018-08-13 | PXD005333 | Pride
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=3) or 3-month-old male rat (n=3) were taken. Total RNA was extracted and mRNA profiling via Illumina single-end sequencing of mRNA-seq libraries was performed.
2014-09-06 | E-GEOD-61179 | biostudies-arrayexpress
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation.
2014-09-06 | GSE61180 | GEO
Project description:We found that in rodents, postnatal beta-cell maturation is associated with changes in the expression of several islet microRNAs and discovered that these modifications are driven by changes in the nutrient supply. Mimicking the microRNA changes observed during β-cell maturation in newborn rat islet cells was sufficient to promote glucose-induced insulin release and to achieve a mature β-cell secretory phenotype. Moreover, the modifications in the level of some of these microRNAs reduced the proliferation of newborn β-cells, suggesting that they contribute to the limited proliferative capacity of adult β-cells. These findings demonstrated that miRNAs contribute to postnatal beta-cell maturation and development. Their role is likely to promote beta-cell adaptation to fule supply and to maintain glucose homeostasis by regulating insulin release and proliferation.
2014-09-06 | GSE61179 | GEO