Correction to Supporting Information for Qadir et al., Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche
| Autor: | Anthony J. Griswold, Giacomo Lanzoni, Camillo Ricordi, Kevin R. Johnson, Michael T. García, Juan Domínguez-Bendala, Ángela Díaz, Mirza Muhammad Fahd Qadir, Silvia Álvarez-Cubela, Dagmar Klein, Ricardo L. Pastori, Saad Sadiq, David W. Sant, Jasmijn van Dijk, Belén Navarro-Rubio, Yaisa B. Moreno-Hernández, Rocío Muñiz-Anquela |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
type 1 diabetes Cell Niche Islets of Langerhans Transplantation islet regeneration Biology single-cell RNA sequencing Mice Receptors Purinergic P2Y1 Insulin-Secreting Cells medicine Animals Humans Pancreatic carcinoma Progenitor cell Pancreas Bone Morphogenetic Protein Receptors Type I Multidisciplinary Stem Cells Resolution (electron density) Pancreatic Ducts Cell Differentiation Cell Biology Biological Sciences Activins medicine.anatomical_structure Diabetes Mellitus Type 1 SI Correction Diabetes Mellitus Type 2 Models Animal human pancreatic progenitors Cancer research Female Single-Cell Analysis Transcriptome transplantation |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America |
| Popis: | Significance The existence of progenitors within pancreatic ducts has been studied for decades, but the hypothesis that they may help regenerate the adult endocrine compartment (chiefly insulin-producing β-cells) remains contentious. Here, we examine the single-cell transcriptome of the human ductal tree. Our data confirm the paradigm-shifting notion that specific lineages, long thought to be cast in stone, are in fact in a state of flux between differentiation stages. In addition to pro-ductal and pro-acinar transcriptomic gradients, our analysis suggests the existence of a third (ducto-endocrine) differentiation axis. Such prediction was experimentally validated by transplanting sorted progenitor-like cells, which revealed their tri-lineage differentiation potential. Our findings further indicate that progenitors might be activated in situ for therapeutic purposes. 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. |
| Databáze: | OpenAIRE |
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