Researchers at Kobe University's Graduate School of Medicine have developed the world's first congenital pituitary hypoplasia (CPH) model using patient-derived iPS cells. The research group consisting of Associate Professor TakahashiYutaka, medical researcher Matsumoto Ryusaku and Professor AOI Takashi et al. succeeded in using the model to illuminate the mechanisms underlying CPH. The team has been attempting to apply this model to other pituitary diseases and drug discovery.
The results of this study were published in the American Scientific Journal ' J Clinical Investigation ' on December 17, 2019. Main points: Successfully created the world's first model of pituitary disease using human iPS cells. iPS cells were generated from a patient with CPH. These iPS cells enabled the recapitulation of the disease in vitro ; an impaired differentiation into the pituitary. The causal gene mutation was identified in the patient by exome sequencing analysis. Using this disease model, it was revealed that a deficiency in the FGF10 produced in the neighboring hypothalamus caused CPH. Expected application of this model to other pituitary diseases, leading to the clarification of the underlying mechanisms and drug discovery. Research background
Hypopituitarism caused by CPH is not uncommon and it is sometimes life-threating. Patients with this disease require lifelong hormone replacement therapy. The causes and underlying mechanisms are not well understood.
Prior research on pituitary diseases has been mainly conducted using animal models, such as knock out mouse. However, sometimes there are differences in the phenotypes between animal and human. This means that human models are necessary in order to fully understand the mechanisms of such diseases.
In recent years, iPS (induced pluripotent stem) cells have been utilized in the development of disease models, regenerative medicine, and drug discovery. In addition, a method using iPS cells to induce differentiation of both the pituitary and hypothalamus in vitro has been developed; however it had yet to be applied to pituitary disease modeling.
With this in mind, researchers at Kobe University's Graduate School of Medicine have applied this strategy to develop a human model of CPH in vitro using iPS cells to understand the pathophysiology and causes of the disease. Research methodology
iPS cells were generated from blood samples taken from a patient with CPH. This patient exhibited congenital pituitary hypoplasia and was undergoing pituitary hormone replacement therapy. These patient-derived iPS cells were utilized to elucidate the underlying mechanisms in vitro . Interestingly, control iPS cells differentiated into hormone-producing cells, however, the CPH patient-derived iPS cells were not able to differentiate into these cells. Further analysis of the differentiation process revealed that the transcription factor LHX3, which is essential for pituitary differentiation, was not expressed in the pituitary progenitor from patient-derived iPS cells (Figure 2). Exome sequencing analysis revealed a mutation in the OTX2 gene and that its function was impaired. Correction of the OTX2 mutation in patient-derived iPS cells restored the pituitary differentiation ability, demonstrating that the OTX2 mutation was responsible. Related Stories
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