Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Development. 2020 Jun 22;147(12):dev189977. doi: 10.1242/dev.189977.
Retinoic acid (RA) signaling is essential for multiple developmental processes, including appropriate pancreas formation from the foregut endoderm. RA is also required to generate pancreatic progenitors from human pluripotent stem cells. However, the role of RA signaling during endocrine specification has not been fully explored. In this study, we demonstrate that the disruption of RA signaling within the NEUROG3-expressing endocrine progenitor population impairs mouse β cell differentiation and induces ectopic expression of crucial δ cell genes, including somatostatin. In addition, the inhibition of the RA pathway in hESC-derived pancreatic progenitors downstream of NEUROG3 induction impairs insulin expression. We further determine that RA-mediated regulation of endocrine cell differentiation occurs through Wnt pathway components. Together, these data demonstrate the importance of RA signaling in endocrine specification and identify conserved mechanisms by which RA signaling directs pancreatic endocrine cell fate.
视黄酸（RA）信号对于多个发育过程是必不可少的，包括从前肠内胚层形成适当的胰腺。RA 也需要从人类多能干细胞中产生胰腺祖细胞。然而，RA 信号在内分泌特化过程中的作用尚未得到充分探索。在这项研究中，我们证明了在表达 NEUROG3 的内分泌祖细胞群体中破坏 RA 信号会损害小鼠 β 细胞分化，并诱导关键 δ 细胞基因（包括生长抑素）的异位表达。此外，在诱导 NEUROG3 后，在 hESC 衍生的胰腺祖细胞中抑制 RA 途径会损害胰岛素的表达。我们进一步确定 RA 介导的内分泌细胞分化的调节是通过 Wnt 途径成分发生的。总之，这些数据表明 RA 信号在内分泌特化中的重要性，并确定了 RA 信号指导胰腺内分泌细胞命运的保守机制。
