Hibernating mammals survive profound hypothermia without injury, a remarkable feat of cellular preservation that bears significance for potential medical applications. However, mechanisms imparting cold-resistance, such as cytoskeleton stability, remain elusive. Here we report for the first time the establishment of iPSCs from a hibernating mammal (GS) to study their hibernation-specific features, inspiring novel pharmacological strategies to bestow cold adaptability to cells and organs from non-hibernating mammals. We found that neurons differentiated from GS-iPSCs retain intrinsic cold-resistant features such as the microtubule stability exhibited by GS primary neurons and neural tissues. This enabled us to identify the cellular pathways linking mitochondria-initiated oxidative stress and dysfunctional lysosomes with microtubule instability in cold. Using drugs targeting these pathways, we demonstrate that human iPSC-derived neurons and rat retinal neurons can acquire the cold-resistant feature that is unique to GS neurons. Remarkably, these treatments functionally rescued cold-exposed rat retinal tissues that otherwise would have sabotaged their structure and function. Furthermore, the same treatments prevented cold-induced microtubule and other damages in kidneys undergoing conventional transplantation storage. Prospectively, GS-iPSCs can serve as a valuable platform for exploring the unique mechanisms of metabolic adaptation and stress responses in hibernators, facilitating the translation of hibernation research to medical applications.
