Induced pluripotent stem cells as a tool for comparative physiology: lessons from the thirteen-lined ground squirrel

Comparative physiologists are often interested in adaptive physiological phenomena found in unconventional model organisms; however, research on these species is frequently constrained by the limited availability of investigative tools. Here, we propose that induced pluripotent stem cells (iPSCs) from unconventional model organisms may retain certain species-specific features that can consequently be investigated in depth in vitro; we use hibernating mammals as an example. Many species (including ground squirrels, bats and bears) can enter a prolonged state of physiological dormancy known as hibernation to survive unfavorable seasonal conditions. Our understanding of the mechanisms underpinning the rapid transition and adaptation to a hypothermic, metabolically suppressed winter torpor state remains limited partially because of the lack of an easily accessible model. To address the fascinating unanswered questions underlying hibernation biology, we have developed a powerful model system: iPSCs from a hibernating species, the thirteen-lined ground squirrel (Ictidomys tridecemlineatus). These stem cells can potentially be differentiated into any cell type, and can be used for the analysis of cell-autonomous mechanisms that facilitate adaptation to hibernation and for comparisons with non-hibernators. Furthermore, we can manipulate candidate molecular and cellular pathways underlying relevant physiological phenomena by pharmacological or RNAi-based methods, and CRISPR/Cas9 gene editing. Moreover, iPSC strategies can be applied to other species (e.g. seals, naked mole rats, humming birds) for in vitro studies on adaptation to extreme physiological conditions. In this Commentary, we discuss factors to consider when attempting to generate iPSCs from unconventional model organisms, based on our experience with the thirteen-lined ground squirrel.