Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling

Jolanta Chmielowiec, Wojciech J. Szlachcic, Diane Yang, Marissa A. Scavuzzo, Katrina Wamble, Alejandro Sarrion-Perdigones, Omaima M. Sabek, Koen J.T. Venken, Malgorzata Borowiak

Research output: Contribution to journalArticlepeer-review

Abstract

In vitro derivation of pancreatic β-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent β-cells are still hindered by incomplete understanding of the microenvironment’s role in β-cell development and maturation. Here, we analyze the human mesenchymal and endothelial primary cells from weeks 9-20 fetal pancreas and identify a time point-specific microenvironment that permits β-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human β-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit the BMP pathway during β-cell maturation. Interestingly, we also identify the endothelial-derived Endocan as a SST+ cell promoting factor. Overall, our study shows that the pancreatic microenvironment-derived factors can mimic in vivo conditions in an in vitro system to generate bona fide β-cells for translational applications.

Original languageEnglish (US)
Article number1952
Pages (from-to)1952
JournalNature Communications
Volume13
Issue number1
DOIs
StatePublished - Apr 12 2022

Keywords

  • Cell Differentiation
  • Humans
  • Pancreas/metabolism
  • Wnt Signaling Pathway/physiology
  • Wnt-5a Protein/genetics

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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