Werner syndrome induced pluripotent stem cells, a study of pathologic aging

Werner syndrome (WS) is a premature aging disease in adults. Symptoms related to aging or age-associated disease appears in early adulthood. WS patients develop a senile appearance in middle adulthood, and usually die before 60 years of age. The genetic basis for WS was identified to be due to mutation in a single gene encoding a RecQ DNA helicase WRN. WRN is multifunctional nuclear protein which participates in DNA metabolic events such as DNA replication, repair, recombination and other processes such as transcriptional regulation and telomere maintenance. Loss of the WRN protein or its catalytic activity was proposed to result in increased apoptosis, premature senescence, mitotic arrest, and genomic instability causing the disease phenotype. The disease pathogenesis remains elusive and techniques examining the “aging” phenotypes in different cell types differentiated from WS iPSC or ESC have been investigated as model systems. Systematic examination of the in vivo requirement of WRN protein for maintaining genome stability and integrity in different cell types is lacking. Additionally, examination of the disease phenotype in a single cell type does not permit the study of trophic interactions and paracrine action between different cell types. The most recent development in stem cell biology, the use of derived organoids may open new vistas for studying the pathogenesis of WS.