Impaired LEF1 Activation Accelerates iPSC-Derived Keratinocytes Differentiation in Hutchinson-Gilford Progeria Syndrome

    February 2022 in “ bioRxiv (Cold Spring Harbor Laboratory) ”
    Xiaojing Mao, Zheng‐Mei Xiong, Huijing Xue, Markus Brown, Yantenew Gete, Reynold Yu, Linlin Sun, Kan Cao
    TLDR Impaired LEF1 activation speeds up skin cell development in Hutchinson-Gilford Progeria Syndrome.
    The study investigated the molecular mechanisms of skin development in Hutchinson-Gilford Progeria Syndrome (HGPS) by differentiating patient-derived induced pluripotent stem cells (iPSCs) into keratinocytes. It was found that HGPS iPSCs showed accelerated differentiation into keratinocytes compared to normal controls. The research focused on the WNT signaling pathway and discovered that the expression of the transcription factor LEF1 was diminished early in the differentiation process, despite normal β-catenin activity. LEF1 was shown to bind strongly to early epithelial developmental markers K8 and K18, and its silencing reduced their transcription. Partial correction of the HGPS mutation using Adenine base editing (ABE) partially rescued the accelerated differentiation phenotype and reduced cell death in HGPS iPSCs-derived keratinocytes. These findings provided new insights into the molecular basis of skin abnormalities in HGPS and potential therapeutic applications.
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