Single-cell transcriptomic analyses of pancreatic islets reveals islet cell-type-specific adaptations to pregnancy and the postpartum
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE226788 | GEO | 2023/03/07
REPOSITORIES: GEO
Similar Datasets
Project description:The inability of the beta-cell to meet the demand for insulin brought about by insulin resistance leads to type 2 diabetes. In adults, beta-cell replication is one of the mechanisms thought to cause the expansion of beta-cell mass. Efforts to treat diabetes require knowledge of the pathways that drive facultative beta-cell proliferation in vivo. A robust physiological stimulus of beta-cell expansion is pregnancy, and identifying the mechanisms underlying this stimulus may provide therapeutic leads for the treatment of type 2 diabetes. The peak in beta-cell proliferation during pregnancy occurs on day 14.5 of gestation in mice. Using advanced genomic approaches, we globally characterize the gene expression signature of pancreatic islets on day 14.5 of gestation during pregnancy. We identify a total of 1,907 genes as differentially expressed in the islet during pregnancy. We demonstrate that the islet's ability to compensate for relative insulin deficiency during metabolic stress is associated with the induction of both proliferative and survival pathways. A comparison of the genes induced in three different models of islet expansion suggests that diverse mechanisms can be recruited to expand islet mass. The identification of many novel genes involved in islet expansion during pregnancy provides an important resource for diabetes researchers to further investigate how these factors contribute to the maintenance of not only islet mass, but ultimately beta-cell mass.
2010-06-26 | E-MTAB-120 | biostudies-arrayexpress
Project description:ABSTRACT:Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy. We addressed this question in vitro, by using islet tissue culture with placental lactogen and in vivo, by transplanting male or female islets into female acceptor mice. Additionally, the islet mRNA expression of pregnant prolactin receptor deficient mice was compared with that of their pregnant wild-type littermates. When cultured with placental lactogen, or transplanted in female recipients that became pregnant (day 12.5), male islets induced the ‘islet pregnancy gene signature’, which we defined as the 12 highest induced genes in non-transplanted female islets at day 12.5 of pregnancy. In addition, serotonin immunoreactivity was also induced in these male transplanted islets at day 12.5 of pregnancy. In order to investigate the importance of prolactin receptors in these mRNA changes we used a prolactin receptor deficient mouse model. For the 12 genes of the signature, which are highly induced in control pregnant mice, no significant induction of mRNA transcripts was found at day 9.5 of pregnancy. Together, our results support the key role of placental lactogen as a circulating factor that can trigger the pregnancy mRNA profile in male and female beta cells. The data obtained from the normal islets of pregnant mice (day12.5) was already described in Schraenen et al. 2010 (PMID: 20886204 and PMID: 20938637). Islets and islet grafts were isolated from non-prengant and pregnant mice for RNA extraction and hybridization on Affymetrix microarrays. For every condition, at least 3 biological replicates were used.
2015-03-31 | E-GEOD-59143 | biostudies-arrayexpress
Project description:ABSTRACT:Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy. We addressed this question in vitro, by using islet tissue culture with placental lactogen and in vivo, by transplanting male or female islets into female acceptor mice. Additionally, the islet mRNA expression of pregnant prolactin receptor deficient mice was compared with that of their pregnant wild-type littermates. When cultured with placental lactogen, or transplanted in female recipients that became pregnant (day 12.5), male islets induced the ‘islet pregnancy gene signature’, which we defined as the 12 highest induced genes in non-transplanted female islets at day 12.5 of pregnancy. In addition, serotonin immunoreactivity was also induced in these male transplanted islets at day 12.5 of pregnancy. In order to investigate the importance of prolactin receptors in these mRNA changes we used a prolactin receptor deficient mouse model. For the 12 genes of the signature, which are highly induced in control pregnant mice, no significant induction of mRNA transcripts was found at day 9.5 of pregnancy. Together, our results support the key role of placental lactogen as a circulating factor that can trigger the pregnancy mRNA profile in male and female beta cells. Islets were isolated from non-prengant (NP) and pregnant (day 9.5) PRLR+/+ and PRLR-/- mice for RNA extraction and hybridization on Affymetrix microarrays. For every condition 3 biological replicates were used.
2015-03-31 | E-GEOD-59141 | biostudies-arrayexpress
Project description:ABSTRACT:Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy. We addressed this question in vitro, by using islet tissue culture with placental lactogen and in vivo, by transplanting male or female islets into female acceptor mice. Additionally, the islet mRNA expression of pregnant prolactin receptor deficient mice was compared with that of their pregnant wild-type littermates. When cultured with placental lactogen, or transplanted in female recipients that became pregnant (day 12.5), male islets induced the ‘islet pregnancy gene signature’, which we defined as the 12 highest induced genes in non-transplanted female islets at day 12.5 of pregnancy. In addition, serotonin immunoreactivity was also induced in these male transplanted islets at day 12.5 of pregnancy. In order to investigate the importance of prolactin receptors in these mRNA changes we used a prolactin receptor deficient mouse model. For the 12 genes of the signature, which are highly induced in control pregnant mice, no significant induction of mRNA transcripts was found at day 9.5 of pregnancy. Together, our results support the key role of placental lactogen as a circulating factor that can trigger the pregnancy mRNA profile in male and female beta cells.
2015-03-31 | GSE59141 | GEO
Project description:During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.
2019-11-20 | GSE138494 | GEO
Project description:ABSTRACT:Pregnancy requires a higher functional beta cell mass and this is associated with profound changes in the gene expression profile of pancreatic islets. Taking Tph1 as a sensitive marker for pregnancy-related islet mRNA expression in female mice, we previously identified prolactin receptors and placental lactogen as key signalling molecules. Since beta cells from male mice also express prolactin receptors, the question arose whether male and female islets have the same phenotypic resilience at the mRNA level during pregnancy. We addressed this question in vitro, by using islet tissue culture with placental lactogen and in vivo, by transplanting male or female islets into female acceptor mice. Additionally, the islet mRNA expression of pregnant prolactin receptor deficient mice was compared with that of their pregnant wild-type littermates. When cultured with placental lactogen, or transplanted in female recipients that became pregnant (day 12.5), male islets induced the ‘islet pregnancy gene signature’, which we defined as the 12 highest induced genes in non-transplanted female islets at day 12.5 of pregnancy. In addition, serotonin immunoreactivity was also induced in these male transplanted islets at day 12.5 of pregnancy. In order to investigate the importance of prolactin receptors in these mRNA changes we used a prolactin receptor deficient mouse model. For the 12 genes of the signature, which are highly induced in control pregnant mice, no significant induction of mRNA transcripts was found at day 9.5 of pregnancy. Together, our results support the key role of placental lactogen as a circulating factor that can trigger the pregnancy mRNA profile in male and female beta cells. The data obtained from the normal islets of pregnant mice (day12.5) was already described in Schraenen et al. 2010 (PMID: 20886204 and PMID: 20938637).
2015-03-31 | GSE59143 | GEO
Project description:During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta-cells. However, the exact mechanisms by which the lactogenic hormones drive beta-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive beta-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in beta-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes. Analysis of poly(A)+ RNA from 3 biological replicates of pancreatic islets isolated from normal female and pregnant female mice
2010-07-01 | E-GEOD-21860 | biostudies-arrayexpress
Project description:It is known that the stresses encountered during islet isolation have deleterious effects on beta-cell physiology. The nature of these effects, however, is incompletely known, partly due to the heterogeneity of islet preparations. The objective was to assess the genome-wide effect of islet isolation and in-vitro culture on beta-cell transcriptome. Beta cells identified by their intrinsic autofluorescence, were captured from donor pancreas and isolated islets using Laser Capture Microdissection. Beta cells from donor pancreas serve as the control. Our results indicated induction of a strong inflammatory response induced by islet isolation which continues during in vitro culture manifested by upregulation of several cytokines, chemokines and their receptors. IL-8 was induced by 3.6-fold and 56-fold in fresh and 3-days cultured islets respectively. Concordantly, several pancreatic progenitor cell-specific transcription factors like were upregulated in cultured islets, suggesting progressive transformation of mature beta-cell phenotype toward an immature endocrine cell phenotype. There are three sample types in our experiment; 1) beta-cells captured from the frozen sections of donor pancreas n=8, 2) beta cells extracted from islets frozen immediately after isolation (d0 islets) n=8 and, 3) beta cells extracted from isolated islets frozen after culturing for 3 days (d3 islets) n=5. For the analysis, beta cells from pancreas were considered as the reference point.
2012-02-12 | E-GEOD-29113 | biostudies-arrayexpress
Project description:Pancreatic islets adapt to insulin resistance of pregnancy by up regulating beta-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr+/-) mice are glucose intolerant, had a lower number of beta cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its beta-cell-specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, i.e. bPrlR-/- mice, allowing conditional deletion of Prlr from beta cells in adult mice. In this study, we found that beta-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mice with global Prlr reduction, beta-cell-specific Prlr loss led to a lower beta-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus beta-cell-specific Prlr reduction, we found differences in expression of genes that regulate apoptosis, synaptic vesicle function and neuronal development. Indeed, islets from pregnant Prlr+/- mice are more susceptible glucolipotoxicity than bPrlR+/- islets. These observations suggest that Prlr has both cell-autonomous and non-cell-autonomous effect on beta cells, beyond its regulation of pro-proliferative genes.
2020-08-25 | GSE156774 | GEO
Project description:Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet endocrine cell differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature and innervation, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion. Examination of RNA profiles from isolated whole islets from RIP-rtTA; TetO-VEGF-A mice with no doxycycline (Dox) treatment (3 samples) and after 1 week of Dox (3 sample); and islet-derived macrophages (3 samples) and endothelial cells (3 samples) isolated from dispersed purified islets from RIP-rtTA; TetO-VEGF-A mice after 1 week Dox treatment by fluorescence-activated cell sorting using antibodies against CD11b and CD31, respectively.
2015-09-01 | E-GEOD-72546 | biostudies-arrayexpress