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

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

  • Nat Commun. 2025 Oct 7;16(1):8434. doi: 10.1038/s41467-025-62670-5.
Randy B Kang 1,  Miguel Varela 1,  Eunjin Oh 1,  Jungeun Lee 1,  Tuo Zhang 2,  Esra Karakose 3,  Andrew F Stewart 3,  Donald K Scott 3,  Debbie C Thurmond 1,  Adolfo Garcia-Ocana # 4,  Geming Lu # 5
Affiliations

Affiliations

  • 1 Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA.
  • 2 Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY, 10065, USA.
  • 3 Diabetes, Obesity and Metabolism Institute, and Division of Endocrinology, Diabetes and Bone Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  • 4 Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA. agarciaocana@coh.org.
  • 5 Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, CA, 91010, USA. gelu@coh.org.
  • # Contributed equally.
PMID: 41057332 DOI: 10.1038/s41467-025-62670-5
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.

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