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Cell Metab. 2017 May 2;25(5):1160-1175.e11. doi: 10.1016/j.cmet.2017.04.014.

Pseudotemporal Ordering of Single Cells Reveals Metabolic Control of Postnatal β Cell Proliferation.

Author information

1
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Departments of Medicine and Molecular & Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Medicine, Boston University, School of Medicine, Boston, MA 02118, USA.
3
Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
4
Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, Davis, CA 95616, USA.
5
Department of Cellular & Molecular Medicine and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
6
Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center and Institute for Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: masander@ucsd.edu.

Abstract

Pancreatic β cell mass for appropriate blood glucose control is established during early postnatal life. β cell proliferative capacity declines postnatally, but the extrinsic cues and intracellular signals that cause this decline remain unknown. To obtain a high-resolution map of β cell transcriptome dynamics after birth, we generated single-cell RNA-seq data of β cells from multiple postnatal time points and ordered cells based on transcriptional similarity using a new analytical tool. This analysis captured signatures of immature, proliferative β cells and established high expression of amino acid metabolic, mitochondrial, and Srf/Jun/Fos transcription factor genes as their hallmark feature. Experimental validation revealed high metabolic activity in immature β cells and a role for reactive oxygen species and Srf/Jun/Fos transcription factors in driving postnatal β cell proliferation and mass expansion. Our work provides the first high-resolution molecular characterization of state changes in postnatal β cells and paves the way for the identification of novel therapeutic targets to stimulate β cell regeneration.

KEYWORDS:

Srf; amino acid metabolism; beta cell; catalase; mitochondrial; oxidative phosphorylation; proliferation; reactive oxygen species; single-cell RNA-seq; transcription factor

PMID:
28467932
PMCID:
PMC5501713
DOI:
10.1016/j.cmet.2017.04.014
[Indexed for MEDLINE]
Free PMC Article

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