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Cell. 2018 May 3;173(4):851-863.e16. doi: 10.1016/j.cell.2018.03.010. Epub 2018 Mar 22.

iPSCs from a Hibernator Provide a Platform for Studying Cold Adaptation and Its Potential Medical Applications.

Author information

1
Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2
State Key Laboratory of Ophthalmology, Guangdong Provincial Key Lab of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China.
3
Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Ophthalmology, The Second Xiang-Ya Hospital, Central South University, Changsha 410011, China.
4
Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Ophthalmology, The Second Affiliated Hospital of Zhejiang University, College of Medicine, Hangzhou 310009, China.
5
Trans-NIH Center for Human Immunology, Autoimmunity, and Inflammation, National Institutes of Health, Bethesda, MD 20892, USA.
6
Department of Biology, University of Wisconsin, Oshkosh, WI 54901, USA.
7
State Key Laboratory of Ophthalmology, Guangdong Provincial Key Lab of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
8
NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
9
Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: liwei2@nei.nih.gov.

Abstract

Hibernating mammals survive hypothermia (<10°C) 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. Using the first iPSC line from a hibernating mammal (13-lined ground squirrel), we uncovered cellular pathways critical for cold tolerance. Comparison between human and ground squirrel iPSC-derived neurons revealed differential mitochondrial and protein quality control responses to cold. In human iPSC-neurons, cold triggered mitochondrial stress, resulting in reactive oxygen species overproduction and lysosomal membrane permeabilization, contributing to microtubule destruction. Manipulations of these pathways endowed microtubule cold stability upon human iPSC-neurons and rat (a non-hibernator) retina, preserving its light responsiveness after prolonged cold exposure. Furthermore, these treatments significantly improved microtubule integrity in cold-stored kidneys, demonstrating the potential for prolonging shelf-life of organ transplants. Thus, ground squirrel iPSCs offer a unique platform for bringing cold-adaptive strategies from hibernators to humans in clinical applications. VIDEO ABSTRACT.

KEYWORDS:

cold adaptation; ground squirrel; hibernation; hypothermia; induced pluripotent stem cells; lysosomal membrane permeabilization; microtubule cold stability; mitochondria; organ storage; retina

PMID:
29576452
PMCID:
PMC5935596
DOI:
10.1016/j.cell.2018.03.010
[Indexed for MEDLINE]
Free PMC Article

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