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Single-Cell Transcriptome Profiling Reveals ? Cell Maturation in Stem Cell-Derived Islets after Transplantation.

ABSTRACT: Human pluripotent stem cells differentiated to insulin-secreting ? cells (SC-? cells) in islet organoids could provide an unlimited cell source for diabetes cell replacement therapy. However, current SC-? cells generated in vitro are transcriptionally and functionally immature compared to native adult ? cells. Here, we use single-cell transcriptomic profiling to catalog changes that occur in transplanted SC-? cells. We find that transplanted SC-? cells exhibit drastic transcriptional changes and mature to more closely resemble adult ? cells. Insulin and IAPP protein secretions increase upon transplantation, along with expression of maturation genes lacking with differentiation in vitro, including INS, MAFA, CHGB, and G6PC2. Other differentiated cell types, such as SC-? and SC-enterochromaffin (SC-EC) cells, also exhibit large transcriptional changes. This study provides a comprehensive resource for understanding human islet cell maturation and provides important insights into maturation of SC-? cells and other SC-islet cell types to enable future differentiation strategy improvements.

SUBMITTER: Augsornworawat P

PROVIDER: S-EPMC7491368 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation.

Augsornworawat Punn P Maxwell Kristina G KG Velazco-Cruz Leonardo L Millman Jeffrey R JR

Cell reports 20200801 8

Human pluripotent stem cells differentiated to insulin-secreting β cells (SC-β cells) in islet organoids could provide an unlimited cell source for diabetes cell replacement therapy. However, current SC-β cells generated in vitro are transcriptionally and functionally immature compared to native adult β cells. Here, we use single-cell transcriptomic profiling to catalog changes that occur in transplanted SC-β cells. We find that transplanted SC-β cells exhibit drastic transcriptional changes and ...[more]

PMID: 32846125

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Project description:Newly differentiated pancreatic β cells lack proper insulin secretion profiles of mature functional β cells. The global gene expression differences between paired immature and mature β cells have been studied, but the dynamics of transcriptional events, correlating with temporal development of glucose-stimulated insulin secretion (GSIS), remain to be fully defined. This aspect is important to identify which genes and pathways are necessary for β-cell development or for maturation, as defective insulin secretion is linked with diseases such as diabetes. In this study, we assayed through RNA sequencing the global gene expression across six β-cell developmental stages in mice, spanning from β-cell progenitor to mature β cells. A computational pipeline then selected genes differentially expressed with respect to progenitors and clustered them into groups with distinct temporal patterns associated with biological functions and pathways. These patterns were finally correlated with experimental GSIS, calcium influx, and insulin granule formation data. Gene expression temporal profiling revealed the timing of important biological processes across β-cell maturation, such as the deregulation of β-cell developmental pathways and the activation of molecular machineries for vesicle biosynthesis and transport, signal transduction of transmembrane receptors, and glucose-induced Ca2+ influx, which were established over a week before β-cell maturation completes. In particular, β cells developed robust insulin secretion at high glucose several days after birth, coincident with the establishment of glucose-induced calcium influx. Yet the neonatal β cells displayed high basal insulin secretion, which decreased to the low levels found in mature β cells only a week later. Different genes associated with calcium-mediated processes, whose alterations are linked with insulin resistance and deregulation of glucose homeostasis, showed increased expression across β-cell stages, in accordance with the temporal acquisition of proper GSIS. Our temporal gene expression pattern analysis provided a comprehensive database of the underlying molecular components and biological mechanisms driving β-cell maturation at different temporal stages, which are fundamental for better control of the in vitro production of functional β cells from human embryonic stem/induced pluripotent cell for transplantation-based type 1 diabetes therapy.

Dataset Information

Single-Cell Transcriptome Profiling Reveals ? Cell Maturation in Stem Cell-Derived Islets after Transplantation.

Publications

Single-Cell Transcriptome Profiling Reveals β Cell Maturation in Stem Cell-Derived Islets after Transplantation.

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