Abstract
BackgroundPluripotent stem cells that are capable of differentiating into different cell types and develop robust hallmark cellular features are useful tools for clarifying the impact of developmental events on neurodegenerative diseases such as Huntington's disease. Additionally, a Huntington's cell model that develops robust pathological features of Huntington's disease would be valuable for drug discovery research.ResultsTo test this hypothesis, a pluripotent Huntington's disease monkey hybrid cell line (TrES1) was established from a tetraploid Huntington's disease monkey blastocyst generated by the fusion of transgenic Huntington's monkey skin fibroblast and a wild-type non-transgenic monkey oocyte. The TrES1 developed key Huntington's disease cellular pathological features that paralleled neural development. It expressed mutant huntingtin and stem cell markers, was capable of differentiating to neural cells, and developed teratoma in severely compromised immune deficient (SCID) mice. Interestingly, the expression of mutant htt, the accumulation of oligomeric mutant htt and the formation of intranuclear inclusions paralleled neural development in vitro , and even mutant htt was ubiquitously expressed. This suggests the development of Huntington's disease cellular features is influenced by neural developmental events.ConclusionsHuntington's disease cellular features is influenced by neural developmental events. These results are the first to demonstrate that a pluripotent stem cell line is able to mimic Huntington's disease progression that parallels neural development, which could be a useful cell model for investigating the developmental impact on Huntington's disease pathogenesis.
Highlights
Pluripotent stem cells that are capable of differentiating into different cell types and develop robust hallmark cellular features are useful tools for clarifying the impact of developmental events on neurodegenerative diseases such as Huntington’s disease
Characterization of Huntington’s disease (HD) monkey skin fibroblast Skin cells were isolated from a miscarried male transgenic HD monkey at four months of gestation. rHD was confirmed transgenic with mutant htt and green fluorescent protein (GFP) gene by PCR (Figure 1A)
Oligomeric mutant htt was presented in the peripheral tissues (Figure 1B) and brain (Figure 1B) of rHD but not in wild-type non-transgenic (WT)-monkeys
Summary
Pluripotent stem cells that are capable of differentiating into different cell types and develop robust hallmark cellular features are useful tools for clarifying the impact of developmental events on neurodegenerative diseases such as Huntington’s disease. A Huntington’s cell model that develops robust pathological features of Huntington’s disease would be valuable for drug discovery research. Huntington’s disease (HD) is an autosomal dominant neurological disorder caused when the CAG expansions encode the polyglutamine (polyQ) stretches at the Nterminus of the huntingtin (htt) protein [1]. HD patients progress to their death 15 to 20 years after the onset of symptoms at mid-life. Unique HD pathology is characterized by the accumulation of oligomeric mutant htt, the formation of intranuclear inclusions (NIs), neuropil aggregates and progressive neuronal death
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