Abstract
Infantile-onset Pompe disease (IOPD) is a life-threatening multi-organ disease caused by an inborn defect of lysosomal acid α-glucosidase (GAA), which can degrade glycogen into glucose. Lack of GAA causes abnormal accumulation of glycogen in the lysosomes, particularly in the skeletal muscle, liver, and heart. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is the only available treatment; however, its effect varies by organ. Thus, to fully understand the pathomechanism of IOPD, organ-specific disease models are necessary. We previously generated induced pluripotent stem cells (iPSCs) from three unrelated patients with IOPD and establish a skeletal muscle model of IOPD. Here, we used the same iPSC lines as the previous study and differentiated them into hepatocytes. As a result, hepatocytes differentiated from iPSC of IOPD patients showed abnormal accumulation of lysosomal glycogen, the hallmark of Pompe disease. Using this model, we also demonstrated that glycogen accumulation was dose-dependently restored by rhGAA treatment. In conclusion, we have successfully established an in vitro liver model of IOPD using patient-specific iPSCs. This model can be a platform to elucidate the underlying disease mechanism or to be applied to drug-screening. Moreover, our study also suggest that an iPSC-based approach is suitable for modeling of diseases that affect multiple organs like Pompe disease.
Highlights
Pompe disease (OMIM 232300, glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disease, caused by an inborn defect of lysosomal acid α-glucosidase (GAA; Hers, 1963)
The cytoplasm was uniformly stained in hepatocytes derived from Ctr-induced pluripotent stem cells (iPSCs); in contrast, many strongly Periodic Acid-Schiff (PAS)-positive round structures occupied the cytoplasm of hepatocytes derived from Pom-iPSCs (Figure 1C)
In Infantile-onset Pompe disease (IOPD), one of the most serious clinical problems is the insufficient effect of recombinant human GAA (rhGAA) on skeletal muscle symptoms compared to those on the other organs including heart and liver
Summary
Pompe disease (OMIM 232300, glycogen storage disease type II or acid maltase deficiency) is an autosomal recessive disease, caused by an inborn defect of lysosomal acid α-glucosidase (GAA; Hers, 1963). GAA breaks down glycogen into glucose in the lysosomes, and the lack of GAA causes abnormal accumulation of glycogen within the lysosomes, in the skeletal muscle, heart, and liver (Kishnani and Howell, 2004). ERT is very effective on cardiac and hepatic symptoms; in contrast, its effect on skeletal muscle symptoms is quite limited (Kishnani et al, 2009; Nicolino et al, 2009). This suggests the possibility that each organ has its own pathomechanism. Organ-specific disease models are necessary to fully understand the pathomechanism of IOPD and develop a better therapeutic approach
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