Backgroud: Familial amyloidotic polyneuropathy (FAP) is an autosomal-dominant hereditary systemic amyloidosis induced by amyloidogenic transthyretin (ATTR). Because most transthyretin (TTR) in serum is synthesized by the liver, liver transplantation (LT) is today the only treatment available to halt the progression of FAP, even though LT is associated with several problems. Despite the urgent need to develop alternatives to LT, the detailed pathogenesis of FAP is still unknown; also, no model fully represents the relevant processes in patients with FAP. The induction of induced pluripotent stem (iPS) cells has allowed development of pluripotent cells specific for patients and has led to useful models of human diseases. Because of the need for a tool to elucidate the molecular pathogenesis of FAP, in this study we sought to establish heterozygous ATTR mutant iPS cells.

Methods: Dermal fibroblasts were obtained from heterozygotic FAP Val30Met patients, and were reprogrammed by using Sendai virus (SeV) vectors mixture containing four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc). SeV vector does not integrate into the host genome and has a low risk of tumorigenicity. Moreover, FAP-specific iPS sells were differentiated into hepatocyte-like cells.

Result: By introduction of four reprogramming factors into the dermal fibroblasts via SeV vector infection, FAP-specific iPS cells were generated from FAP Val30Met patients. Expression of ES cell-markers, such as NANOG and TERT, were comfirmed in FAP-specific iPS cells by RT-PCR. SeV vectors used for gene transduction were diluted and disappeared during cell growth. Moreover, FAP-specific iPS cells had the potential to differentiate into hepatocyte-like cells and indeed expressed ATTR and wild-type TTR at mRNA levels.

Conclusion: FAP-specific iPS cells demonstrated the possibility of serving as a model that will contribute to understanding the pathogenesis of FAP and development of FAP treatments.

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