Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche
Open Access
- 30 April 2020
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 117 (20), 10876-10887
- https://doi.org/10.1073/pnas.1918314117
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.Keywords
Funding Information
- American Diabetes Association Research Foundation (#1-19-ICTS-078)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (U01DK120393)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (1R43DK105655-01)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (2R44 DK105655-02)
- Diabetes Research Institute Foundation (NO GRANT NUMBER)
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