Mouse islet cells were transplanted onto kidney sections following long-term cold storage and treatment with KPT-330 and protease inhibitors to protect them from cold damage (arrows upper left). Confocal images show the grafted cells produced insulin (green) and glucagon (pink), indicating the cells’ ability to function following transplantation.
Newswise — Research led by scientists at the National Eye Institute and Sun Yat-sen University, Guangzhou, China points to a potential strategy for extending the cold storage shelf life of donor cells and tissues, such as those of the pancreas, an organ crucial for making insulin. If the strategy proves clinically successful, it could help increase access to transplantable cells and tissues for the treatment of diabetes and other conditions. The findings published online in Nature Communications.
The cold preservation strategy was conceived in the course of ongoing research aimed at understanding how hibernating animals survive long periods near freezing without tissue injury. Seeking treatments for blinding diseases, vision researchers studying hibernators have focused specifically on the light-sensing retinal tissues of the eye. The retina survives winter months despite its high energy requirements. This ability for the retina to adapt to cold temperatures and energy deprivation, they say, may hold clues for treating diseases that affect the retina such as age-related macular degeneration.
For this latest study, researchers compared the responses of cells to cold from animals that hibernate versus those that don’t. They observed that a protein called FOXO1 tends to accumulate in the nuclei of hibernator tissues exposed to cold.
FOXO1 is a transcription factor, meaning it regulates gene activity. It functions similarly across species; however, in hibernators adapting to cold temperatures it migrates into the cell nucleus by way of a nuclear pore complex (RANBP2), a type of opening/transport system that appears to arise as part of cold adaptation. Once inside the nucleus, FOXO1 accumulates and turns on several genes. When the animals begin warming up, the accumulated FOXO1 appears to kickstart a different set of genes that seems to facilitate the warming process while avoiding cell damage.
The researchers investigated whether inducing FOXO1 accumulation in non-hibernator cells/tissues might protect them from low temperatures.
To explore this question, they treated insulin-producing pancreatic islet cells from mice with a drug called KPT-330, approved by Food and Drug Administration for treating multiple myeloma. Islets are among cells/tissues with the shortest shelf life. KPT-330 promotes the accumulation of FOXO1 in the nucleus of many tissue/cell types and the survival of mice exposed to cold.
The researchers found that pre-treating mouse islets with KPT-330 plus a protease inhibitor—a type of antiviral drug—significantly reduced cold-triggered cell death. The preservation strategy extended the cold storage shelf life of islets from 2 to 14 days. Meanwhile, control experiments using mouse islets engineered to have low FOXO1 levels confirmed that FOXO1 plays a key role in maintaining the viability of cold-stored islets. Furthermore, blood glucose levels dropped in diabetic mice that had received previously cold-stored transplanted islets protected by the KPT-330 formula, demonstrating the functional recovery of the islets to produce insulin.
Transplantation of pancreatic islets is currently an experimental treatment for type 1 diabetes provided only as part of an FDA-allowed clinical trial.
More research will be needed to determine if this preservation strategy will work in human transplants and other transplantable tissues such as cornea.
“Our findings provide a practical solution to extend the shelf life of pancreatic islets for treatment of diabetes via transplantation. This is just one example of how basic science of hibernation could help medicine,” said Wei Li, NEI Retinal Neurophysiology Section. Li, who co-led the study and collaborated with former postdoctoral fellow Jingxing Ou, Ph.D., now a principal investigator at Sun Yat-sen University, Guangzhou, China.
Funding was provided in part by the Intramural Research Program of the NEI, part of the National Institutes of Health.
Reference:
Zhang, X., Ge, L., Jin, G. et al. Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage. Nat Commun 15, 2859 (2024). https://doi.org/10.1038/s41467-024-47095-w
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