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 - 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
UR - http://www.scopus.com/inward/record.url?scp=85128139815&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85128139815&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-29646-1
DO - 10.1038/s41467-022-29646-1
M3 - Article
C2 - 35414140
AN - SCOPUS:85128139815
SN - 2041-1723
VL - 13
SP - 1952
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1952
ER -