Disease Modeling of Pituitary Adenoma Using Human Pluripotent Stem Cells

Simple Summary Pituitary adenoma pathophysiology has been studied mainly using murine cell lines, animal models, and pituitary tumor samples. However, the lack of human pituitary cell line is a significant limiting factor in studying the molecular mechanisms of human pituitary tumors. Recently, pituitary induction methods from human-induced pluripotent stem cells (hiPSCs) have been established. These methods can induce human pituitary hormone-producing cells that retain physiological properties. hiPSCs in which tumor-causing gene mutations are introduced using genome-editing techniques, such as CRISPR/Cas9 systems, provide great opportunities to establish in vitro human pituitary adenoma disease models. The models will be a novel platform to discover novel drugs and investigate tumorigenesis and pathophysiology. The purpose of this review is to provide an overview of the applications of iPSCs for pituitary and neoplastic disorder research and genome-editing technologies to create strategies for developing pituitary adenoma models using iPSCs. Pituitary adenomas are characterized by abnormal growth in the pituitary gland. Surgical excision is the first-line treatment for functional (hormone-producing) pituitary adenomas, except for prolactin-producing adenomas; however, complete excision is technically challenging, and many patients require long-term medication after the treatment. In addition, the pathophysiology of pituitary adenomas, such as tumorigenesis, has not been fully understood. Pituitary adenoma pathophysiology has mainly been studied using animal models and animal tumor-derived cell lines. Nevertheless, experimental studies on human pituitary adenomas are difficult because of the significant differences among species and the lack of reliable cell lines. Recently, several methods have been established to differentiate pituitary cells from human pluripotent stem cells (hPSCs). The induced pituitary hormone-producing cells retain the physiological properties already lost in tumor-derived cell lines. Moreover, CRISPR/Cas9 systems have expedited the introduction of causative gene mutations in various malignant tumors into hPSCs. Therefore, hPSC-derived pituitary cells have great potential as a novel platform for studying the pathophysiology of human-specific pituitary adenomas and developing novel drugs. This review presents an overview of the recent progresses in hPSC applications for pituitary research, functional pituitary adenoma pathogenesis, and genome-editing techniques for introducing causative mutations. We also discuss future applications of hPSCs for studying pituitary adenomas.