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      Endocrine lineage biases arise in temporally distinct endocrine progenitors during pancreatic morphogenesis

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          Abstract

          Decoding the molecular composition of individual Ngn3 + endocrine progenitors (EPs) during pancreatic morphogenesis could provide insight into the mechanisms regulating hormonal cell fate. Here, we identify population markers and extensive cellular diversity including four EP subtypes reflecting EP maturation using high-resolution single-cell RNA-sequencing of the e14.5 and e16.5 mouse pancreas. While e14.5 and e16.5 EPs are constantly born and share select genes, these EPs are overall transcriptionally distinct concomitant with changes in the underlying epithelium. As a consequence, e16.5 EPs are not the same as e14.5 EPs: e16.5 EPs have a higher propensity to form beta cells. Analysis of e14.5 and e16.5 EP chromatin states reveals temporal shifts, with enrichment of beta cell motifs in accessible regions at later stages. Finally, we provide transcriptional maps outlining the route progenitors take as they make cell fate decisions, which can be applied to advance the in vitro generation of beta cells.

          Abstract

          Endocrine progenitors form early in pancreatic development but the diversity of this cell population is unclear. Here, the authors use single cell RNA sequencing of the mouse pancreas at e14.5 and e16.5 to show that endocrine progenitors are temporally distinct and those formed later are more likely to become beta cells

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          Generation of functional human pancreatic β cells in vitro.

          The generation of insulin-producing pancreatic β cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation therapy in diabetes. However, insulin-producing cells previously generated from human pluripotent stem cells (hPSC) lack many functional characteristics of bona fide β cells. Here, we report a scalable differentiation protocol that can generate hundreds of millions of glucose-responsive β cells from hPSC in vitro. These stem-cell-derived β cells (SC-β) express markers found in mature β cells, flux Ca(2+) in response to glucose, package insulin into secretory granules, and secrete quantities of insulin comparable to adult β cells in response to multiple sequential glucose challenges in vitro. Furthermore, these cells secrete human insulin into the serum of mice shortly after transplantation in a glucose-regulated manner, and transplantation of these cells ameliorates hyperglycemia in diabetic mice. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Molecular Diversity of Midbrain Development in Mouse, Human, and Stem Cells

            Summary Understanding human embryonic ventral midbrain is of major interest for Parkinson’s disease. However, the cell types, their gene expression dynamics, and their relationship to commonly used rodent models remain to be defined. We performed single-cell RNA sequencing to examine ventral midbrain development in human and mouse. We found 25 molecularly defined human cell types, including five subtypes of radial glia-like cells and four progenitors. In the mouse, two mature fetal dopaminergic neuron subtypes diversified into five adult classes during postnatal development. Cell types and gene expression were generally conserved across species, but with clear differences in cell proliferation, developmental timing, and dopaminergic neuron development. Additionally, we developed a method to quantitatively assess the fidelity of dopaminergic neurons derived from human pluripotent stem cells, at a single-cell level. Thus, our study provides insight into the molecular programs controlling human midbrain development and provides a foundation for the development of cell replacement therapies.
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              SeeDB: a simple and morphology-preserving optical clearing agent for neuronal circuit reconstruction.

              We report a water-based optical clearing agent, SeeDB, which clears fixed brain samples in a few days without quenching many types of fluorescent dyes, including fluorescent proteins and lipophilic neuronal tracers. Our method maintained a constant sample volume during the clearing procedure, an important factor for keeping cellular morphology intact, and facilitated the quantitative reconstruction of neuronal circuits. Combined with two-photon microscopy and an optimized objective lens, we were able to image the mouse brain from the dorsal to the ventral side. We used SeeDB to describe the near-complete wiring diagram of sister mitral cells associated with a common glomerulus in the mouse olfactory bulb. We found the diversity of dendrite wiring patterns among sister mitral cells, and our results provide an anatomical basis for non-redundant odor coding by these neurons. Our simple and efficient method is useful for imaging intact morphological architecture at large scales in both the adult and developing brains.
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                Author and article information

                Contributors
                jfmartin@bcm.edu
                borowiak@bcm.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 August 2018
                22 August 2018
                2018
                : 9
                : 3356
                Affiliations
                [1 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Program in Developmental Biology, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [2 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Center for Cell and Gene Therapy, Texas Children’s Hospital, and Houston Methodist Hospital, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [3 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Stem Cell and Regenerative Medicine Center, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [4 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Molecular and Cellular Biology Department, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [5 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Integrative Molecular and Biomedical Sciences Graduate Program, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [6 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Molecular and Human Genetics, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [7 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Dan L Duncan Comprehensive Cancer Center, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [8 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children’s Hospital, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [9 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, McNair Medical Institute, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [10 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Department of Molecular Physiology and Biophysics, , Baylor College of Medicine, ; Houston, TX 77030 USA
                [11 ]ISNI 0000 0004 4656 4290, GRID grid.416470.0, The Texas Heart Institute, ; Houston, TX 77030 USA
                [12 ]ISNI 0000 0001 2160 926X, GRID grid.39382.33, Cardiovascular Research Institute, , Baylor College of Medicine, ; Houston, TX 77030 USA
                Author information
                http://orcid.org/0000-0002-6415-7731
                Article
                5740
                10.1038/s41467-018-05740-1
                6105717
                30135482
                9ce2bb26-1a6f-48ff-a3c9-fee3c55a3643
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 2 March 2018
                : 20 July 2018
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