Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche.
Author: Fahd Qadir, Mirza Muhammad; Álvarez-Cubela, Silvia; Klein, Dagmar; van Dijk, Jasmijn; Muñiz-Anquela, Rocío; Moreno-Hernández, Yaisa B.; Lanzoni, Giacomo; Sadiq, Saad; Navarro-Rubio, Belén; García, Michael T.; Johnson, Kevin; Sant, David; Ricordi, Camilo; Griswold, Anthony; Pastori, Ricardo Luis; Domínguez-Bendala, Juan
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 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.
Universal identifier: http://hdl.handle.net/10641/2521
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