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Combinatorial transcription factor profiles predict mature and functional human islet α and β cells
Shristi Shrestha, … , Alvin C. Powers, Marcela Brissova
Shristi Shrestha, … , Alvin C. Powers, Marcela Brissova
Published August 24, 2021
Citation Information: JCI Insight. 2021;6(18):e151621. https://doi.org/10.1172/jci.insight.151621.
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Resource and Technical Advance Cell biology Endocrinology

Combinatorial transcription factor profiles predict mature and functional human islet α and β cells

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Abstract

Islet-enriched transcription factors (TFs) exert broad control over cellular processes in pancreatic α and β cells, and changes in their expression are associated with developmental state and diabetes. However, the implications of heterogeneity in TF expression across islet cell populations are not well understood. To define this TF heterogeneity and its consequences for cellular function, we profiled more than 40,000 cells from normal human islets by single-cell RNA-Seq and stratified α and β cells based on combinatorial TF expression. Subpopulations of islet cells coexpressing ARX/MAFB (α cells) and MAFA/MAFB (β cells) exhibited greater expression of key genes related to glucose sensing and hormone secretion relative to subpopulations expressing only one or neither TF. Moreover, all subpopulations were identified in native pancreatic tissue from multiple donors. By Patch-Seq, MAFA/MAFB-coexpressing β cells showed enhanced electrophysiological activity. Thus, these results indicate that combinatorial TF expression in islet α and β cells predicts highly functional, mature subpopulations.

Authors

Shristi Shrestha, Diane C. Saunders, John T. Walker, Joan Camunas-Soler, Xiao-Qing Dai, Rachana Haliyur, Radhika Aramandla, Greg Poffenberger, Nripesh Prasad, Rita Bottino, Roland Stein, Jean-Philippe Cartailler, Stephen C.J. Parker, Patrick E. MacDonald, Shawn E. Levy, Alvin C. Powers, Marcela Brissova

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Figure 1

Bulk RNA-Seq and immunohistochemistry data highlight unique expression patterns of transcription factors ARX, MAFA, and MAFB in human α and β cells.

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Bulk RNA-Seq and immunohistochemistry data highlight unique expression p...
(A–D) Normalized expression values (A, C, and D) and fold change (B) of ARX, MAFA, and MAFB in previously published bulk RNA-Seq data sets from α cells (green) and β cells (blue). Data in A is from Brissova et al. (17) and Saunders et al. (27) (n = 5 donors); additional data sets from Arda et al. (10) (n = 5 donors) and Blodgett et al. (26) (n = 7 donors) are included in B. See also Supplemental Figure 1, A and B. (C) Expression of ARX and MAFB is decreased (ARX fold change: –2.7; MAFB: –3.4) in α cells from donors with type 1 diabetes (T1D) compared with nondiabetic (ND) donors (17). (D) Expression of MAFA is increased (fold change: 7.1) in adult β cells compared with fetal β cells, while MAFB is decreased (fold change: –2.0) (26). All data shown as mean + SEM; symbols represent individual donors (A, C, and D) or average value per data set (B). Asterisks indicate significant (adjusted P value < 0.05) fold change of α versus β in A and B, T1D versus ND in C, and adult versus fetal in D. (E) Immunohistochemical staining of pancreatic sections from a nondiabetic adult (55 years, Supplemental Table 4), showing specificity of ARX, MAFA, and MAFB (red) in α cells (GCG; green) and β cells (CPEP; blue). Arrowheads indicate cells negative (white) or positive (purple) for transcription factors; scale bar: 50 μm. See also Supplemental Figure 1, C and D.

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