Yang Wendy, Lampe Paul D, Kensel-Hammes Patricia, Hesson Jennifer, Ware Carol B, Crisa Laura, Cirulli Vincenzo
Department of Medicine, UW Diabetes Institute, University of Washington, 850 Republican Street, S475, Seattle, WA 98109, USA.
Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
iScience. 2019 Sep 27;19:450-460. doi: 10.1016/j.isci.2019.07.033. Epub 2019 Jul 24.
Efficient stem cell differentiation into pancreatic islet cells is of critical importance for the development of cell replacement therapies for diabetes. Here, we identify the expression pattern of connexin 43 (Cx43), a gap junction (GJ) channel protein, in human embryonic stem cell (hESC)-derived definitive endoderm (DE) and primitive gut tube cells, representing early lineages for posterior foregut (PF), pancreatic progenitors (PP), pancreatic endocrine progenitors (PE), and islet cells. As the function of GJ channels is dependent on their gating status, we tested the impact of supplementing hESC-derived PP cell cultures with AAP10, a peptide that promotes Cx43 GJ channel opening. We found that this treatment promotes the expression of DE markers FoxA2 and Sox17, leads to a more efficient derivation of DE, and improves the yield of PF, PP, and PE cells. These results demonstrate a functional involvement of GJ channels in the differentiation of embryonic stem cells into pancreatic cell lineages.
高效地将干细胞分化为胰岛细胞对于开发糖尿病细胞替代疗法至关重要。在此，我们确定了连接蛋白43（Cx43）（一种间隙连接（GJ）通道蛋白）在人胚胎干细胞（hESC）来源的定形内胚层（DE）和原始肠管细胞中的表达模式，这些细胞代表了前肠后部（PF）、胰腺祖细胞（PP）、胰腺内分泌祖细胞（PE）和胰岛细胞的早期谱系。由于GJ通道的功能取决于其门控状态，我们测试了用促进Cx43 GJ通道开放的肽AAP10补充hESC来源的PP细胞培养物的影响。我们发现这种处理促进了DE标志物FoxA2和Sox17的表达，导致DE的衍生更有效，并提高了PF、PP和PE细胞的产量。这些结果证明了GJ通道在胚胎干细胞向胰腺细胞谱系分化中的功能参与。
