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 and Malgorzata Borowiak ()
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Jolanta Chmielowiec: Baylor College of Medicine
Wojciech J. Szlachcic: Adam Mickiewicz University
Diane Yang: Baylor College of Medicine
Marissa A. Scavuzzo: Baylor College of Medicine
Katrina Wamble: Baylor College of Medicine
Alejandro Sarrion-Perdigones: Baylor College of Medicine
Omaima M. Sabek: The Methodist Hospital
Koen J. T. Venken: Baylor College of Medicine
Malgorzata Borowiak: Baylor College of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29646-1

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