Abstract
Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications.
Highlights
Werner syndrome (WS) is a rare human autosomal recessive disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition (Goto, 1997, 2000)
Since embryoid body (EB)-derived differentiated cells include a variety of cell types originating from the three germ layers, these results suggest that EB-mediated induced pluripotent stem cells (iPSCs) differentiation could provide a simple and rapid method for the identification of cell lineages other than the mesenchymal stem cells (MSCs) in WS
Recent findings including ours, demonstrate that reprogramming bypasses premature senescence and suppresses genomic instability in WS cells, leading to sustained undifferentiated states with the ability to differentiate into three embryonic germ layers over the long term
Summary
Werner syndrome (WS) is a rare human autosomal recessive disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition (Goto, 1997, 2000). These findings demonstrate that activation of telomerase during reprogramming plays a pivotal role in telomere elongation with chromatin state characteristic of ESCs, and in the restoration and maintenance of the protective functions of the telomere at the chromosomal ends, in order to suppress DNA damage responses.
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