Adaptive changes of the ground squirrel retina during hibernation

National Eye Institute

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Abstract

Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in ground squirrel iPSCs and human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for cell autonomous cold adaptation. FOXO1 in Cold Adaptation: our work demonstrates that FOXO1, a transcription factor, plays a crucial role in autonomous cold adaptation. It undergoes a nonconventional, temperature-sensitive nuclear trans-localization involving the nuclear pore complex protein RANBP2, the SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1 itself. We used ground squirrel tissue, ground squirrel iPSCs, human stem cells, zebrafish larvae, and pre-diabetic obese mice as models to explore the mechanisms of cold adaptation and the potential therapeutic applications of modulating FOXO1 activity. Cold survival experiments with human stem cell models and zebrafish larvae showed that promoting FOXO1 nuclear entry by inhibiting Exportin-1 enhances cold tolerance. This was further supported by evidence from pre-diabetic obese mice, where such intervention improved their survival under cold exposure. Implications for Organ Preservation: The work extends its findings to the preservation of human and mouse pancreatic tissues and islets. It demonstrates that targeting the XPO1-FOXO1 axis not only enhances cold survival in vivo but also significantly prolongs the shelf-life of pancreatic tissues and islets. This suggests a novel approach to improving organ preservation techniques. Similar effects have been observed in cornea preserved with such treatment. Mechanistic Insights: The work elucidates a detailed mechanism involving the SUMOylation-dependent temperature-sensing transport system that governs FOXO1 cellular localization and its transcriptional activities, which are pivotal for cellular and organismal cold adaptation. Potential Therapeutic Applications: The findings uncover a regulatory network and potential therapeutic targets to enhance natural cold adaptation. This has implications for improving hypothermic therapies, organ preservation, and possibly the treatment of conditions related to impaired cold adaptation. The study integrates advanced genomic and proteomic analyses, animal models, and practical applications in organ preservation to offer a comprehensive understanding of the role of FOXO1 in cold adaptation and its potential therapeutic implications. It demonstrates the significance of leveraging natural adaptive strategies, such as hibernation.