Publications by authors named "Eric E Xu"

5 Publications

  • Page 1 of 1

Single-Cell Transcriptome Profiling of Mouse and hESC-Derived Pancreatic Progenitors.

Stem Cell Reports 2018 12;11(6):1551-1564

Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; Departments of Surgery and Cellular and Physiological Sciences, University of British Columbia, 950 28(th) Avenue West, Vancouver, BC V5Z4H4, Canada. Electronic address:

Human embryonic stem cells (hESCs) are a potential unlimited source of insulin-producing β cells for diabetes treatment. A greater understanding of how β cells form during embryonic development will improve current hESC differentiation protocols. All pancreatic endocrine cells, including β cells, are derived from Neurog3-expressing endocrine progenitors. This study characterizes the single-cell transcriptomes of 6,905 mouse embryonic day (E) 15.5 and 6,626 E18.5 pancreatic cells isolated from Neurog3-Cre; Rosa26 embryos, allowing for enrichment of endocrine progenitors (yellow; tdTomato + EGFP) and endocrine cells (green; EGFP). Using a NEUROG3-2A-eGFP CyT49 hESC reporter line (N5-5), 4,462 hESC-derived GFP+ cells were sequenced. Differential expression analysis revealed enrichment of markers that are consistent with progenitor, endocrine, or previously undescribed cell-state populations. This study characterizes the single-cell transcriptomes of mouse and hESC-derived endocrine progenitors and serves as a resource (https://lynnlab.shinyapps.io/embryonic_pancreas) for improving the formation of functional β-like cells from hESCs.
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http://dx.doi.org/10.1016/j.stemcr.2018.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294286PMC
December 2018

Maternal folic acid supplementation with vitamin B deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet.

FASEB J 2018 09 17;32(9):5039-5050. Epub 2018 Apr 17.

Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Epidemiologic studies have reported relationships between maternal high folate and/or low B status during pregnancy and greater adiposity and insulin resistance in children. The goal of this study was to determine the effects of maternal folic acid supplementation (10 mg/kg diet), with (50 μg/kg diet) and without B, on adult female offspring adiposity and glucose homeostasis. Female C57BL/6J mice were fed 1 of 3 diets from weaning and throughout breeding, pregnancy, and lactation: control (2 mg/kg diet folic acid, 50 μg/kg diet B), supplemental folic acid with no B (SFA-B), or supplemental folic acid with adequate B (SFA+B). Female offspring were weaned onto the control diet or a Western diet (45% energy fat, 2 mg/kg diet folic acid, 50 μg/kg diet B) for 35 wk. After weaning, control diet-fed offspring with SFA-B dams had fasting hyperglycemia, glucose intolerance, lower β cell mass, and greater islet hepatocyte nuclear factor 1 homeobox α and nuclear receptor subfamily 1 group H member 3 mRNA than did offspring from control dams. In Western diet-fed offspring, those with SFA-B dams had lower fasting blood glucose and plasma insulin concentrations, and were smaller than control offspring. Our findings suggest that maternal folic acid supplementation with B deficiency during pregnancy/lactation programs the metabolic health of adult female offspring but is dependent on offspring diet.-Henderson, A. M., Tai, D. C., Aleliunas, R. E., Aljaadi, A. M., Glier, M. B., Xu, E. E., Miller, J. W., Verchere, C. B., Green, T. J., Devlin, A. M. Maternal folic acid supplementation with vitamin B deficiency during pregnancy and lactation affects the metabolic health of adult female offspring but is dependent on offspring diet.
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http://dx.doi.org/10.1096/fj.201701503RRDOI Listing
September 2018

SOX4 Allows Facultative β-Cell Proliferation Through Repression of .

Diabetes 2017 08 11;66(8):2213-2219. Epub 2017 May 11.

BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada

The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in are associated with an increased risk of developing type 2 diabetes. We used an inducible β-cell knockout mouse model to test the hypothesis that is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease in β-cell mass in knockout mice that was caused by a 39% reduction in β-cell proliferation. Gene expression studies revealed that induction of the cell cycle inhibitor was responsible for the decreased proliferation in the knockout animals. Altogether, this study demonstrates that SOX4 is necessary for adult β-cell replication through direct regulation of the β-cell cycle.
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http://dx.doi.org/10.2337/db16-1074DOI Listing
August 2017

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation.

Cell Metab 2016 Jan 25;23(1):179-93. Epub 2015 Nov 25.

Department of Cellular and Physiological Sciences, Diabetes Research Group, Life Sciences Institute, University of British Columbia, BC V6T1Z3, Canada. Electronic address:

Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia. Transcriptome, proteome, and network analysis revealed alleviation of chronic endoplasmic reticulum (ER) stress, indicated by reduced Ddit3, Trib3, and Atf4 expression; reduced Xbp1 splicing; and reduced phospho-eIF2α. This state was associated with hyper-phosphorylation of Akt, which is negatively regulated by Trib3, and with cyclinD1 upregulation. Remarkably, β cell proliferation was increased 2-fold after reduced insulin production independently of hyperglycemia. Eventually, recombined cells mis-expressed glucagon in the hyperglycemic state. We conclude that the normally high rate of insulin production suppresses β cell proliferation in a cell-autonomous manner.
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http://dx.doi.org/10.1016/j.cmet.2015.10.016DOI Listing
January 2016

SOX4 cooperates with neurogenin 3 to regulate endocrine pancreas formation in mouse models.

Diabetologia 2015 May 5;58(5):1013-23. Epub 2015 Feb 5.

Diabetes Research Program, Child and Family Research Institute, A4-184, 950 West 28 Ave, Vancouver, BC, V5Z 4H4, Canada.

Aims/hypothesis: The sex-determining region Y (SRY)-related high mobility group (HMG) box (SOX) family of transcription factors is essential for normal organismal development. Despite the longstanding knowledge that many SOX family members are expressed during pancreas development, a role for many of these factors in the establishment of insulin-producing beta cell fate remains to be determined. The aim of this study is to elucidate the role of SOX4 during beta cell development.

Methods: We used pancreas and endocrine progenitor mouse knockouts of Sox4 to uncover the roles of SOX4 during pancreas development. Lineage tracing and in vitro models were used to determine how SOX4 regulates beta cell formation and understand the fate of Sox4-null endocrine lineage cells.

Results: This study demonstrates a progenitor cell-autonomous role for SOX4 in regulating the genesis of beta cells and shows that it is required at multiple stages of the process. SOX4 deletion in the multipotent pancreatic progenitors resulted in impaired endocrine progenitor cell differentiation. Deletion of SOX4 later in the Neurog3-expressing cells also caused reductions in beta cells. Lineage studies showed loss of Sox4 in endocrine progenitors resulted in a block in terminal islet cell differentiation that was attributed to reduction in the production of key beta cell specification factors.

Conclusions/interpretation: These results demonstrate that SOX4 is essential for normal endocrine pancreas development both concomitant with, and downstream of, the endocrine fate decision. In conclusion, these studies position Sox4 temporally in the endocrine differentiation programme and provide a new target for improving in vitro differentiation of glucose-responsive pancreatic beta cells.
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http://dx.doi.org/10.1007/s00125-015-3507-xDOI Listing
May 2015
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