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

In vitro differentiation of pancreatic beta cells offers a potential therapeutic approach for diabetes. Here they show human pluripotent stem cell derived pancreatic progenitors differentiate into insulin-secreting cells by crosstalk of WNT5A and BMP signaling. In vitro derivation of pancreatic beta-cells from human pluripotent stem cells holds promise as diabetes treatment. Despite recent progress, efforts to generate physiologically competent beta-cells are still hindered by incomplete understanding of the microenvironment's role in beta-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 beta-cell differentiation. Further, we uncover unique factors that guide in vitro development of endocrine progenitors, with WNT5A markedly improving human beta-cell differentiation. WNT5A initially acts through the non-canonical (JNK/c-JUN) WNT signaling and cooperates with Gremlin1 to inhibit the BMP pathway during beta-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 beta-cells for translational applications.