Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Proc Natl Acad Sci U S A. 2020 May 19;117(20):10876-10887. doi: 10.1073/pnas.1918314117. Epub 2020 Apr 30.


We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII- cells) differentiate into all pancreatic lineages, including functional β-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII- progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

Keywords: human pancreatic progenitors; islet regeneration; single-cell RNA sequencing; transplantation; type 1 diabetes.

Publication types

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

MeSH terms

  • Activins / metabolism
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / metabolism
  • Cell Differentiation
  • Diabetes Mellitus, Type 1
  • Diabetes Mellitus, Type 2
  • Female
  • Humans
  • Insulin-Secreting Cells
  • Islets of Langerhans Transplantation
  • Male
  • Mice
  • Models, Animal
  • Pancreas / cytology*
  • Pancreatic Ducts / cytology*
  • Receptors, Purinergic P2Y1 / metabolism
  • Single-Cell Analysis / methods*
  • Stem Cells / cytology*
  • Transcriptome


  • P2RY1 protein, human
  • Receptors, Purinergic P2Y1
  • Activins
  • BMPR1A protein, human
  • Bone Morphogenetic Protein Receptors, Type I