PDF(Pubmed)
Abstract：
Dysfunction of pancreatic δ cells contributes to the etiology of diabetes. Despite their important role, human δ cells are scarce, limiting physiological studies and drug discovery targeting δ cells. To date, no directed δ-cell differentiation method has been established. Here, we demonstrate that fibroblast growth factor (FGF) 7 promotes pancreatic endoderm/progenitor differentiation, whereas FGF2 biases cells towards the pancreatic δ-cell lineage via FGF receptor 1. We develop a differentiation method to generate δ cells from human stem cells by combining FGF2 with FGF7, which synergistically directs pancreatic lineage differentiation and modulates the expression of transcription factors and SST activators during endoderm/endocrine precursor induction. These δ cells display mature RNA profiles and fine secretory granules, secrete somatostatin in response to various stimuli, and suppress insulin secretion from in vitro co-cultured β cells and mouse β cells upon transplantation. The generation of human pancreatic δ cells from stem cells in vitro would provide an unprecedented cell source for drug discovery and cell transplantation studies in diabetes.
摘要：
胰腺δ细胞的功能障碍是糖尿病的病因。尽管发挥了重要作用,人类δ细胞很少，限制了针对δ细胞的生理学研究和药物发现。迄今为止,没有建立直接的δ细胞分化方法。这里,我们证明成纤维细胞生长因子（FGF）7促进胰腺内胚层/祖细胞分化，而FGF2通过FGF受体1将细胞偏向胰腺δ细胞谱系。我们开发了一种分化方法，通过将FGF2与FGF7组合来从人干细胞中产生δ细胞，该方法在内胚层/内分泌前体诱导过程中协同指导胰腺谱系分化并调节转录因子和SST激活剂的表达。这些δ细胞表现出成熟的RNA谱和细小的分泌颗粒，分泌生长抑素以响应各种刺激，并抑制移植后体外共培养的β细胞和小鼠β细胞的胰岛素分泌。体外从干细胞产生人δ胰腺细胞将为糖尿病中的药物发现和细胞移植研究提供前所未有的细胞来源。
