Biochemistry Biokhimiia · Oct 2026
Accelerated Senescence of Fibroblast-Like Cells Derived from Induced Pluripotent Stem Cells of a Patient with Wiedemann-Rautenstrauch Progeroid Syndrome
By Orlova EA, Shchukina AA, Kalmykova AI
The study of senescence dynamics in cells obtained from patients with accelerated aging syndromes provides a model for understanding the fundamental mechanisms of cellular senescence and for the search for approaches to slowing it down. Wiedemann-Rautenstrauch progeroid syndrome, caused by a mutation in the gene encoding the catalytic subunit of RNA polymerase III POLR3A, is a poorly studied syndrome with the earliest manifestation of accelerated aging features. Previously, we obtained induced pluripotent stem cells (iPSCs) from the fibroblasts of a patient with this syndrome. These iPSCs displayed changes in nucleolar structure, genome instability, and impairments in telomere maintenance mechanisms, as a result of which the telomeres did not elongate during reprogramming of the patient's fibroblasts into iPSCs. During iPSC differentiation, we obtained fibroblast-like cells (secondary fibroblasts), which were used to study dynamics of accelerated senescence. Expression of the mutant POLR3A was decreased in the secondary fibroblasts compared with the iPSCs; however, features of accelerated senescence were already detectable at early passages, manifested as increased β-galactosidase activity and increased expression of the cell-cycle inhibitor p16. Differentiation was accompanied by a pronounced shortening of telomere length, which had not been restored during the reprogramming of the patient's cells into iPSCs. The data obtained demonstrate that genomic instability of stem cells exerts an accelerating effect on the development of progeroid features during cellular differentiation.