TY - JOUR
T1 - Human pancreatic microenvironment promotes β-cell differentiation via non-canonical WNT5A/JNK and BMP signaling
AU - Chmielowiec, Jolanta
AU - Szlachcic, Wojciech J.
AU - Yang, Diane
AU - Scavuzzo, Marissa A.
AU - Wamble, Katrina
AU - Sarrion-Perdigones, Alejandro
AU - Sabek, Omaima M.
AU - Venken, Koen J.T.
AU - Borowiak, Malgorzata
N1 - Funding Information:
We thank Catherine Gillespie for critical comments on the manuscript. We thank Drs. Hoang Nguyen, Xiang Zhang, Stephanie Pangas, Kenneth Chien, Lei Bu and Joanne Richards for sharing reagents. We thank Anna Jedrzejak and all Borowiak lab members for helpful comments and discussion. This project was supported in part by the Genomic and RNA Profiling Core at Baylor College of Medicine with funding from the NIH NCI grant (P30CA125123) and the expert assistance of Dr Lisa D. White. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the NIH (P30 AI036211, P30 CA125123, and S10 RR024574) and the expert assistance of Joel M. Sederstrom. This work was supported by funding from Brown Foundation and Vivian L. Smith Foundation to O.M.S. This work was supported by the Baylor College of Medicine start-up, McNair Medical Institute, and the National Health Institute (P30-DK079638, 5 R01 AI120989, and 5T32HL092332-13), TEAM program from the Foundation for Polish Science and EU (POIR.04.04.00-00-20C5/16-00), the National Science Centre (OPUS UMO-2O19/33/B/NZ3/01226 and UMO-2020/39/B/NZ3/01408) to M.B. Research in the lab of KV was supported by start-up funds kindly provided by Baylor College of Medicine, the Albert and Margaret Alkek Foundation, and the McNair Medical Institute, as well as contributions from grants from the March of Dimes Foundation (#1-FY14-315), the Foundation For Angelman Syndrome Therapeutics (FT2016-002), the Cancer Prevention and Research Institute of Texas (R1313), and the National Institutes of Health (1R21OD022981, R01GM109938, and R01GM138781).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/4/12
Y1 - 2022/4/12
N2 - 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.
AB - 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.
KW - Cell Differentiation
KW - Humans
KW - Pancreas/metabolism
KW - Wnt Signaling Pathway/physiology
KW - Wnt-5a Protein/genetics
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U2 - 10.1038/s41467-022-29646-1
DO - 10.1038/s41467-022-29646-1
M3 - Article
C2 - 35414140
AN - SCOPUS:85128139815
VL - 13
SP - 1952
JO - Nat Commun
JF - Nat Commun
SN - 2041-1723
IS - 1
M1 - 1952
ER -