Human Pancreatic Microenvironment Promotes β-Cell Differentiation via Non-canonical WNT5A/Jnk and Bmp Signaling

Authors

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

Publication Date

4-12-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-29646-1

PMID

35414140

PMCID

PMC9005503

Published Open-Access

no

Keywords

Bone Morphogenetic Proteins, Cell Differentiation, Humans, MAP Kinase Kinase 4, Pancreas, Wnt Signaling Pathway, Wnt-5a Protein, Endocrinology, Cell signalling, Stem-cell differentiation, Stem-cell niche

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.