Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Mirza Muhammad Fahd Qadir, Silvia Álvarez-Cubela, Dagmar Klein, Jasmijn van Dijk, Rocío Muñiz-Anquela, Yaisa B. Moreno-Hernández, Giacomo Lanzoni, Saad Sadiq, Belén Navarro-Rubio, Michael T. García, Ángela Díaz, Kevin Johnson, David Sant, Camillo Ricordi, Anthony Griswold, Ricardo Luis Pastori, Juan Domínguez-Bendala

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)10876-10887
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number20
DOIs
StatePublished - May 19 2020

Keywords

  • Human pancreatic progenitors
  • Islet regeneration
  • Single-cell RNA sequencing
  • Transplantation
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

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  • Cite this

    Qadir, M. M. F., Álvarez-Cubela, S., Klein, D., van Dijk, J., Muñiz-Anquela, R., Moreno-Hernández, Y. B., Lanzoni, G., Sadiq, S., Navarro-Rubio, B., García, M. T., Díaz, Á., Johnson, K., Sant, D., Ricordi, C., Griswold, A., Pastori, R. L., & Domínguez-Bendala, J. (2020). Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche. Proceedings of the National Academy of Sciences of the United States of America, 117(20), 10876-10887. https://doi.org/10.1073/pnas.1918314117