Human pancreatic α-cell heterogeneity and trajectory inference analyses reveal SMOC1 as a β-cell dedifferentiation gene

Randy B. Kang, Miguel Varela, Eunjin Oh, Jungeun Lee, Tuo Zhang, Esra Karakose, Andrew F. Stewart, Donald K. Scott, Debbie C. Thurmond, Adolfo Garcia-Ocana () and Geming Lu ()
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Randy B. Kang: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Miguel Varela: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Eunjin Oh: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Jungeun Lee: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Tuo Zhang: Weill Cornell Medicine
Esra Karakose: Icahn School of Medicine at Mount Sinai
Andrew F. Stewart: Icahn School of Medicine at Mount Sinai
Donald K. Scott: Icahn School of Medicine at Mount Sinai
Debbie C. Thurmond: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Adolfo Garcia-Ocana: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope
Geming Lu: Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract β-cell dysfunction and dedifferentiation towards an α-cell-like phenotype are hallmarks of type 2 diabetes. However, the cell subtypes involved in β-to-α-cell transition are unknown. Using single-cell and single-nucleus RNA-seq, RNA velocity, PAGA/cell trajectory inference, and gene commonality, we interrogated α-β-cell fate switching in human islets. We found five α-cell subclusters with distinct transcriptomes. PAGA analysis showed bifurcating cell trajectories in non-diabetic while unidirectional cell trajectories from β-to-α-cells in type 2 diabetes islets suggesting dedifferentiation towards α-cells. Ten genes comprised the common signature genes in trajectories towards α-cells. Among these, the α-cell gene SMOC1 was expressed in β-cells in type 2 diabetes. Enhanced SMOC1 expression in β-cells decreased insulin expression and secretion and increased β-cell dedifferentiation markers. Collectively, these studies reveal differences in α-β-cell trajectories in non-diabetes and type 2 diabetes human islets, identify signature genes for β-to-α-cell trajectories, and discover SMOC1 as an inducer of β-cell dysfunction and dedifferentiation.

Date: 2025
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DOI: 10.1038/s41467-025-62670-5

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