SPOCK2 controls the proliferation and function of immature pancreatic β-cells through MMP2.
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ABSTRACT:
PROVIDER: PRJNA786870 | ENA |
REPOSITORIES: ENA
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Project description:Human pluripotent stem cell-derived β-cells (SC-β-cells) represent an alternative cell source for transplantation in diabetic patients. While mitogens could in theory be employed to expand β-cells, adult β-cells very rarely replicate. Conversely, newly formed β-cells, including SC-β-cells, display higher proliferative capacity and distinct transcriptional and functional profiles. Through bidirectional expression modulation and single-cell RNA-seq, we identified SPOCK2, an ECM protein, as inhibitor of immature β-cell proliferation. Human β-cells lacking SPOCK2 demonstrated elevated MMP2 expression and activity, leading to β-integrin-FAK-c-JUN pathway activation. Treatment with MMP2 protein resulted in pronounced short- and long-term SC-β-cell expansion, significantly, increasing glucose-stimulated insulin secretion in vitro and in vivo. This suggests that SPOCK2 mediates fetal β-cell proliferation and maturation. Together, we identified molecular mechanism that specifically regulates SC-β-cell proliferation and function, highlighting a unique signaling milieu of SC-β-cells with promising potential for robust derivation of fully functional cells for transplantation.
2025-02-12 | GSE190361 | GEO
Project description:CD81 marks immature and dedifferentiated pancreatic β-cells
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Project description:Transcriptional profiling of a directed differentiation time course converting human embryonic stem cells (hES) into immature pancreatic beta cell precursors.
2012-10-11 | E-MTAB-817 | biostudies-arrayexpress
Project description:miRNA transcript profiling of a directed differentiation time course converting human embryonic stem cells (hES) into immature pancreatic beta cell precursors.
2012-10-11 | E-MTAB-818 | biostudies-arrayexpress
Project description:Replenishing insulin-producing pancreatic β cell mass will benefit both type I and type II diabetics. In adults, pancreatic β cells are generated primarily by self-duplication. We report on a mouse model of insulin resistance that induces dramatic pancreatic β cell proliferation and β cell mass expansion. Using this model, we identify a hormone, betatrophin, that is primarily expressed in liver and fat. Expression of betatrophin correlates with β cell proliferation in other mouse models of insulin resistance and during gestation. Transient expression of betatrophin in mouse liver significantly and specifically promotes pancreatic β cell proliferation, expands β cell mass, and improves glucose tolerance. Thus, betatrophin treatment could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.
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Project description:This submission comprises RNA-Seq profiling of in vivo differentiated pancreatic beta cells types and primary islet-derived pancreatic beta cell sources. The study reports that re-aggregation of immature beta-like cells (d20Beta) and removal of progenitor cells leads to further maturation in vitro resulting in beta-cells (eBCBeta) that are closer to human primary islet-derived beta-cells(IsletBeta). As a control stem cell derived spheres were dissocated, reassociated and taken through till the end of the protocol (NECBeta).
2019-02-01 | GSE109795 | GEO
Project description:AIMS/HYPOTHESIS: Manoeuvres aimed at increasing beta cell mass have been proposed as regenerative medicine strategies for diabetes treatment. Raf-1 kinase inhibitor protein 1 (RKIP1) is a common regulatory node of the mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB) pathways and therefore may be involved in regulation of beta cell homeostasis. The aim of this study was to investigate the involvement of RKIP1 in the control of beta cell mass and function. METHODS: Rkip1 (also known as Pebp1) knockout (Rkip1 (-/-)) mice were characterised in terms of pancreatic and glucose homeostasis, including morphological and functional analysis. Glucose tolerance and insulin sensitivity were examined, followed by assessment of glucose-induced insulin secretion in isolated islets and beta cell mass quantification through morphometry. Further characterisation included determination of endocrine and exocrine proliferation, apoptosis, MAPK activation and whole genome gene expression assays. Capacity to reverse a diabetic phenotype was assessed in adult Rkip1 (-/-) mice after streptozotocin treatment. RESULTS: Rkip1 (-/-) mice exhibit a moderately larger pancreas and increased beta cell mass and pancreatic insulin content, which correlate with an overall improvement in whole body glucose tolerance. This phenotype is established in young postnatal stages and involves enhanced cellular proliferation without significant alterations in cell death. Importantly, adult Rkip1 (-/-) mice exhibit rapid reversal of streptozotocin-induced diabetes compared with control mice. CONCLUSIONS/INTERPRETATION: These data implicate RKIP1 in the regulation of pancreatic growth and beta cell expansion, thus revealing RKIP1 as a potential pharmacological target to promote beta cell regeneration. Pancreatic gene expression of Rkip-1 (Raf kinase inhibitor 1) knockout (KO) and wild type (WT) mice, including three biological replicates in each group.
2012-11-19 | E-GEOD-31150 | biostudies-arrayexpress
Project description:We investigated the pancreatic beta cell proteome changes in NOD-LIRKO vesus NOD where beta cell mass was enhanced early in life. Proteomics data is derived from FACS-sorted beta cells at 8 weeks and 12 weeks.
2019-03-14 | MSV000083576 | MassIVE
Project description:A small molecule, AT7867, is a proliferation-promoting factor of human iPS cell-derived pancreatic progenitor cells; yet how it promotes cell proliferation is not known. AT7867 induces proliferation of pancreatic progenitor cells, but not that of definitive endoderm cells or primitive gut tube cells suggesting a cell type-specific effect. Our aim is to perform RNA-seq of cells obtained during a three stage differentiation of hiPS cells to the endodermal cell lineage in addition to pancreatic progenitor cells treated with AT7867, and analyze signaling pathways altered by the compound treatment.
2020-07-06 | GSE153806 | GEO
Project description:ObjectiveIslets of Langerhans contain heterogeneous populations of insulin-producing β-cells. Surface markers and respective antibodies for isolation, tracking, and analysis are urgently needed to study β-cell heterogeneity and explore the mechanisms to harness the regenerative potential of immature β-cells.MethodsWe performed single-cell mRNA profiling of early postnatal mouse islets and re-analyzed several single-cell mRNA sequencing datasets from mouse and human pancreas and islets. We used mouse primary islets, iPSC-derived endocrine cells, Min6 insulinoma, and human EndoC-βH1 β-cell lines and performed FAC sorting, Western blotting, and imaging to support and complement the findings from the data analyses.ResultsWe found that all endocrine cell types expressed the cluster of differentiation 81 (CD81) during pancreas development, but the expression levels of this protein were gradually reduced in β-cells during postnatal maturation. Single-cell gene expression profiling and high-resolution imaging revealed an immature signature of β-cells expressing high levels of CD81 (CD81high) compared to a more mature population expressing no or low levels of this protein (CD81low/-). Analysis of β-cells from different diabetic mouse models and in vitro β-cell stress assays indicated an upregulation of CD81 expression levels in stressed and dedifferentiated β-cells. Similarly, CD81 was upregulated and marked stressed human β-cells in vitro.ConclusionsWe identified CD81 as a novel surface marker that labels immature, stressed, and dedifferentiated β-cells in the adult mouse and human islets. This novel surface marker will allow us to better study β-cell heterogeneity in healthy subjects and diabetes progression.
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