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

• DOI: 10.1073/pnas.1918314117
• Publication Date: 2020-05-01T01:36:27Z
• Authors: Mirza Muhammad Fa...; Silvia Álvarez-Cu...; Dagmar Klein; Jasmijn van Dijk; Rocío Muñiz-Anquela; Yaisa B. Moreno-H...; Giacomo Lanzoni; Saad Sadiq; Belén Navarro-Rubio; Michael T. García; Ángela Díaz; Kevin Johnson; David Sant; Camillo Ricordi; Anthony Griswold; Ricardo Luis Pastori; Juan Domínguez-Be...
• Keywords: Male; 0303 health sciences; Stem Cells; Islets of Langerhans Transplantation; Pancreatic Ducts; Cell Differentiation; Biological Sciences; Activins; Mice; Receptors, Purinergic P2Y1; 03 medical and health sciences; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Models, Animal; Animals; Humans; Female; Single-Cell Analysis; Transcriptome; Pancreas; Bone Morphogenetic Protein Receptors, Type I

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 ALK3 bright+ -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 ALK3 bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1 + /ALK3 bright+ 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.