期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 20, 页码 10876-10887出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1918314117
关键词
human pancreatic progenitors; type 1 diabetes; islet regeneration; transplantation; single-cell RNA sequencing
资金
- Network for Pancreatic Organ Donors with Diabetes (nPOD) [RRID:SCR 014641]
- Juvenile Diabetes Research Foundation [nPOD:5-SRA-2018-557-Q-R]
- Leona M. & Harry B. Helmsley Charitable Trust [2018PG-T1D053]
- Diabetes Research Institute Foundation
- Inserra family
- Fred and Mabel R. Parks Foundation
- Tonkinson Foundation
- American Diabetes Association [1-19-ICTS-078]
- NIH [1R43DK105655-01, 2R44 DK105655-02, U01 DK120393]
- Foreign Fulbright Scholarship Board
- International Institute of Education
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 (CAll). 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 P-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1(+)/ALK3(+)/CAll(-) 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.
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