Patch-Seq Links Single-Cell Transcriptomes to Human Islet Dysfunction in Diabetes

Joan Camunas-Soler; Xiao-Qing Dai; Yan Hang; Austin Bautista; James Lyon; Kunimasa Suzuki; Seung K Kim; Stephen R Quake; Patrick E MacDonald

doi:10.1016/j.cmet.2020.04.005

Patch-Seq Links Single-Cell Transcriptomes to Human Islet Dysfunction in Diabetes

Cell Metab. 2020 May 5;31(5):1017-1031.e4. doi: 10.1016/j.cmet.2020.04.005. Epub 2020 Apr 16.

Authors

Joan Camunas-Soler¹, Xiao-Qing Dai², Yan Hang³, Austin Bautista², James Lyon⁴, Kunimasa Suzuki⁴, Seung K Kim⁵, Stephen R Quake⁶, Patrick E MacDonald⁷

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94518, USA.
² Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.
³ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada.
⁵ Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA. Electronic address: seungkim@stanford.edu.
⁶ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94518, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA 94305, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA. Electronic address: steve@quake-lab.org.
⁷ Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2E1, Canada; Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address: pmacdonald@ualberta.ca.

Abstract

Impaired function of pancreatic islet cells is a major cause of metabolic dysregulation and disease in humans. Despite this, it remains challenging to directly link physiological dysfunction in islet cells to precise changes in gene expression. Here we show that single-cell RNA sequencing combined with electrophysiological measurements of exocytosis and channel activity (patch-seq) can be used to link endocrine physiology and transcriptomes at the single-cell level. We collected 1,369 patch-seq cells from the pancreata of 34 human donors with and without diabetes. An analysis of function and gene expression networks identified a gene set associated with functional heterogeneity in β cells that can be used to predict electrophysiology. We also report transcriptional programs underlying dysfunction in type 2 diabetes and extend this approach to cryopreserved cells from donors with type 1 diabetes, generating a valuable resource for understanding islet cell heterogeneity in health and disease.

Keywords: T1D; T2D; alpha cell; beta cell; cryopreservation; diabetes; islet; pancreas; patch-seq; single-cell RNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 1 / metabolism*
Diabetes Mellitus, Type 2 / genetics
Diabetes Mellitus, Type 2 / metabolism*
Humans
Islets of Langerhans / metabolism*
Sequence Analysis, RNA
Single-Cell Analysis*
Transcriptome

Abstract

Publication types

MeSH terms

Grants and funding