Fahd Qadir, Mirza MuhammadÁlvarez-Cubela, SilviaKlein, Dagmarvan Dijk, JasmijnMuñiz-Anquela, RocíoMoreno-Hernández, Yaisa B.Lanzoni, GiacomoSadiq, SaadNavarro-Rubio, BelénGarcía, Michael T.Johnson, KevinSant, DavidRicordi, CamiloGriswold, AnthonyPastori, Ricardo LuisDomínguez-Bendala, Juan2021-10-272021-10-2720200027-8424http://hdl.handle.net/10641/2521We 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.engAtribución-NoComercial-SinDerivadas 3.0 Españahttp://creativecommons.org/licenses/by-nc-nd/3.0/es/human pancreatic progenitorstype 1 diabetesislet regenerationtransplantationsingle-cell RNAsequencingjournal articleopen access10.1073/pnas.1918314117