Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

HPAP Consortium

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Objective: Dedifferentiation of pancreatic β-cells may reduce islet function in type 2 diabetes (T2D). However, the prevalence, plasticity and functional consequences of this cellular state remain unknown. Methods: We employed single-cell RNAseq to detail the maturation program of α- and β-cells during human ontogeny. We also compared islets from non-diabetic and T2D individuals. Results: Both α- and β-cells mature in part by repressing non-endocrine genes; however, α-cells retain hallmarks of an immature state, while β-cells attain a full β-cell specific gene expression program. In islets from T2D donors, both α- and β-cells have a less mature expression profile, de-repressing the juvenile genetic program and exocrine genes and increasing expression of exocytosis, inflammation and stress response signalling pathways. These changes are consistent with the increased proportion of β-cells displaying suboptimal function observed in T2D islets. Conclusions: These findings provide new insights into the molecular program underlying islet cell maturation during human ontogeny and the loss of transcriptomic maturity that occurs in islets of type 2 diabetics.

Original languageAmerican English
Article number101057
JournalMolecular Metabolism
Volume42
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
We thank Olga Smirnova for excellent technical support and Ran Avrahami for his critical help with data analysis. We thank Yuval Dor and Agnes Klochendler for critical reading of the manuscript. This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN, RRID:SCR_014393; https://hirnetwork.org; UC4-DK104119 to KHK and BG). BG was supported by The BIRAX Regenerative Medicine Initiative (14BX14NHBG); Israel Science Foundation (ISF)?Juvenile Diabetes Research Foundation Joint Program in Type 1 Diabetes Research 1506/12; ISF grant 1782/18; EFSD award supported by EFSD/JDRF/Lilly Program on Type 1 Diabetes Research and the EU's Horizon 2020 research and innovation programme No 874710. This manuscript used data acquired from the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202) Database (https://hpap.pmacs.upenn.edu), a Human Islet Research Network (RRID:SCR_014393) consortium (UC4-DK-112217, U01-DK-123594, UC4-DK-112232, and U01-DK-123716). We thank the University of Pennsylvania Diabetes Research Centre (DRC) for the use of the Functional Genomics, (P30-DK19525). We owe special gratitude to the pancreatic islet donors and their families. Without their altruistic contribution in times of great personal tragedy, human islet research would not be possible.

Funding Information:
We thank Olga Smirnova for excellent technical support and Ran Avrahami for his critical help with data analysis. We thank Yuval Dor and Agnes Klochendler for critical reading of the manuscript. This research was performed using resources and/or funding provided by the NIDDK-supported Human Islet Research Network (HIRN, RRID:SCR_014393 ; https://hirnetwork.org ; UC4-DK104119 to KHK and BG). BG was supported by The BIRAX Regenerative Medicine Initiative ( 14BX14NHBG ); Israel Science Foundation (ISF)—Juvenile Diabetes Research Foundation Joint Program in Type 1 Diabetes Research 1506/12; ISF grant 1782/18; EFSD award supported by EFSD/JDRF/Lilly Program on Type 1 Diabetes Research and the EU's Horizon 2020 research and innovation programme No 874710. This manuscript used data acquired from the Human Pancreas Analysis Program (HPAP-RRID:SCR_016202) Database ( https://hpap.pmacs.upenn.edu ), a Human Islet Research Network (RRID:SCR_014393) consortium (UC4-DK-112217, U01-DK-123594, UC4-DK-112232, and U01-DK-123716). We thank the University of Pennsylvania Diabetes Research Centre (DRC) for the use of the Functional Genomics, (P30-DK19525). We owe special gratitude to the pancreatic islet donors and their families. Without their altruistic contribution in times of great personal tragedy, human islet research would not be possible.

Publisher Copyright:
© 2020 The Author(s)

Keywords

  • Human islet
  • Ontogeny
  • Single cell RNAseq
  • Type 2 diabetes
  • α-Cell
  • β-Cell

Fingerprint

Dive into the research topics of 'Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D'. Together they form a unique fingerprint.

Cite this