Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation
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ABSTRACT:
PROVIDER: PRJNA634768 | ENA |
REPOSITORIES: ENA
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Project description:SC-β cells and native β cells from cadaveric islets have different transcriptome profiles. In this study, we demonstrate that SC-β cells can acquire mature gene signatures via transplantation in mice for 6 months. MAFA, a marker for mature β cells, is expressed and resulted in significant improvements in insulin release and glucose regulation in diabetic mice.
2020-08-25 | GSE151117 | 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 fuel supply and to maintain glucose homeostasis by regulating insulin release and proliferation. Islets from 10-day-old rats (P10) (n=4) or 3-month-old male rat (n=4) were taken. Total RNA was extracted and microRNA profiling was performed with miRNA Agilent arrays.
2014-09-04 | E-GEOD-61090 | biostudies-arrayexpress
Project description:Stem cell-derived β (SC-β) cells are an emerging regenerative therapy to compensate for loss of functional β cell mass in diabetes. Glucose-stimulated insulin secretion in SC-β cells is variable in vitro but stabilizes after transplantation and maturation under the kidney capsule of mice. We identified mechanisms correlated with functional maturation using RNA-sequencing and co-expression network analysis. In vivo maturation enhanced glucose-stimulated but not basal insulin secretion, up-regulated β cell hormones IAPP and ADCYAP1, increased expression of maturation markers MAFA, UCN3, and SIX2, and resolved endocrine identity of incompletely specified polyhormonal cells produced during differentiation. Transplantation promoted calcium signalling, induced exocytotic machinery supporting hormone secretion and improved stimulus-secretion coupling that fine-tunes insulin secretion. Growth hormone signalling emerged as candidate driver of in vivo maturation and was confirmed in vitro. Also, a large co-expression module correlated with HbA1c and was enriched in genes up-regulated during in vivo maturation but down-regulated in hyperglycaemic and palmitate stress conditions, suggesting that transcriptional maturation of SC-β cells in vivo mirrors processes lost in diabetic β cells.
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Project description:Islet transplantation is an attractive treatment for patients with insulin-dependent diabetes mellitus, and currently the liver is the favored transplantation site. However, an alternative site is desirable because of the low efficiency of hepatic transplantation, requiring 2-3 donors for a single recipient, and because the transplanted islets cannot be accessed or retrieved. Here we describe a novel site for islet transplantation, the inguinal subcutaneous white adipose tissue. In this site, transplanted islets are engrafted as clusters and function to reverse diabetes in mice. Importantly, transplanted islets can be visualized by CT and are easily retrievable, and allograft rejection is preventable by blockade of co-stimulatory signals. Of much interest, the efficiency of islet transplantation is superior to the liver, with increased mass of transplanted β cells. Furthermore, transplanted human islets function to reverse diabetes in immunodeficient mice. Thus, this adipose tissue site may be ideal for clinical islet transplantation.
2018-03-01 | GSE95595 | GEO
Project description:Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-bH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno-associated virus (AAV)-mediated PAX6 overexpression in beta cells of streptozotocin-induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV-PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.
2023-10-13 | GSE242338 | GEO
Project description:Islet β-cells from newborn mammals need a maturation process to become mature functional beta cells. The detailed molecular mechanisms were not completely understood. This study was designed to reveal the dynamic gene expression changes during pancreatic beta-cell maturation in postnatal mice. We also want to understand how genetic mutations that impair beta-cell function change the genetic networks involved in the beta-cell maturation process. For these aims, pancreatic beta cells were isolated at P1 islets based on the expression of a MipeGFP transgene in a genetic background with pancreatic specific inactivation of Myt1, Myt1L, and St18 (denoted as MytDelpanc; MipeGFP).
2018-04-01 | E-MTAB-6615 | biostudies-arrayexpress
Project description:Mediator, a co-regulator required for RNA pol II activity, interacts with tissue-specific transcription factors to regulate development and maintain homeostasis. We sought to understand whether Mediator subunit MED15 acts as a node that controls tissue-specific gene expression, using pancreatic insulin-producing β-cell maturation as a model. We found Med15 to be expressed during mouse pancreatic organogenesis and β-cell maturation; moreover, islets from human T2D donors feature reduced MED15 expression. Loss of Med15 in mouse β-cells caused defects in maturation without affecting β-cell mass or insulin expression. ChIP-seq and co-immunoprecipitation analyses determined that Med15 binds β-cell transcription factors Nkx6-1 and NeuroD1 to regulate key β-cell maturation genes. Human embryonic stem cell derived β-like cells, genetically engineered to express high levels of MED15, had increased maturation markers and improved insulin secretion. We provide the first evidence of the importance of Mediator in β-cell maturation and demonstrate an additional layer of control that tunes transcription factor function.
2024-09-10 | GSE137145 | GEO
Project description:SC-beta Cell in vivo Maturation
| PRJNA560712 | ENA
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 ?-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