Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche
Mirza Muhammad Fahd Qadir, Silvia Álvarez-Cubela, Dagmar Klein, Jasmijn van Dijk, Rocío Muñiz-Anquela, Yaisa Moreno-Hernández, Giacomo Lanzoni, Saad Sadiq, Belén Navarro-Rubio, Michael T. García, Ángela Blanco Díaz, Kevin B. Johnson, David Sant, Camillo Ricordi, Anthony J. Griswold, Ricardo L. Pastori, Juan Domínguez‐Bendala
Abstract
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.