The proliferation of human pancreatic progenitor cells (PPCs) is critical for developing cell therapies for diabetes. Here, using transcriptome analysis combined with small interfering RNA (siRNA) screening, we revealed that WNT7B is a downstream growth factor of AT7867, a compound known to promote the proliferation of PPCs generated from human pluripotent stem cells. Feeder cell lines stably expressing mouse Wnt7a or Wnt7b, but not other Wnts, enhanced PPC proliferation in the absence of AT7867. Importantly, Wnt7a/b ligands did not activate the canonical Wnt pathway, and PPC proliferation depended on the non-canonical Wnt/PKC pathway. A comparison of the phosphoproteome in response to AT7867 or a newly synthesized AT7867 derivative uncovered the function of YY1 as a transcriptional regulator of WNT7B. Overall, our data highlight unknown roles of non-canonical WNT7B/PKC signaling and YY1 in human PPC proliferation and will contribute to the stable supply of a cell source for pancreatic disease modeling and therapeutic applications.

人胰腺祖细胞（PPC）的增殖对于开发用于糖尿病的细胞疗法至关重要。在这里，使用转录组分析与小干扰RNA（siRNA）筛选相结合，我们发现WNT7B是AT7867的下游生长因子，AT7867是一种已知能促进人多能干细胞生成的PPC增殖的化合物。在不存在AT7867的情况下，稳定表达小鼠Wnt7a或Wnt7b而不是其他Wnts的饲养细胞系增强了PPC增殖。重要的是，Wnt7a / b配体不会激活经典的Wnt途径，而PPC的增殖取决于非经典的Wnt / PKC途径。磷酸化蛋白质组对AT7867或新合成的AT7867衍生物的响应比较发现YY1作为WNT7B的转录调节因子。总体而言，我们的数据突显了非经典WNT7B / PKC信号传导和YY1在人PPC增殖中的未知作用，并将有助于为胰腺疾病建模和治疗应用稳定地提供细胞来源。