Abstract
Domestic dogs are superior models for translational medicine due to greater anatomical and physiological similarities with humans than rodents, including hereditary diseases with human equivalents. Particularly with respect to neurodegenerative medicine, dogs can serve as a natural, more relevant model of human disease compared to transgenic rodents. Herein we report attempts to develop a canine-derived in vitro model for neurodegenerative diseases through the generation of induced pluripotent stem cells from a 14-year, 9-month-old female West Highland white terrier with mild cognitive impairment (MCI). Canine induced pluripotent stem cells-like cells (ciPSCLC) were generated using human OSKM and characterized by positive expression of pluripotency markers. Due to inefficient viral vector silencing we refer to them as ciPSCLCs. Subsequently, the ciPSCLC were subjected to neural induction according to two protocols both yielding canine neural progenitor cells (cNPCs), which expressed typical NPC markers. The cNPCs were cultured in neuron differentiation media for 3 weeks, resulting in the derivation of morphologically impaired neurons as compared to iPSC-derived human counterparts generated in parallel. The apparent differences encountered in this study regarding the neural differentiation potential of ciPSCLC reveals challenges and new perspectives to consider before using the canine model in translational neurological studies.
Highlights
Neurodegenerative diseases represent a substantial unmet medical need, notably as the population ages worldwide
Previous studies report the generation of ciPSCs from embryonic, fetal, and adult canine tissues, with the adult donor ages ranging from 7 months to 7-year-old, using integrative reprogramming systems or non-integrative sendai viruses [47]
Even tough very recently one study generated a ciPSC line using episomal vectors in specific conditions [48], episomal reprogramming did not succeeded with our adult canine fibroblasts
Summary
Neurodegenerative diseases represent a substantial unmet medical need, notably as the population ages worldwide. All attempts to develop drugs to intervene into neuronal degeneration have failed in stage one and two clinical trials The majority of these potential drugs have been tested for their efficacy using transgenic mouse models, which artificially express human genes containing mutations identified in early onset familiar AD (fAD). It would be more appropriate to study neurodegenerative diseases as e.g., AD in animal model species, which develop age depended cognitive decline comparable to AD in man (natural models) Such species would have longer life-spans and be exposed to similar environmental conditions as their human counterparts. Dogs with CCD exhibit signs comparable to AD patients, including slowly progressing changes in social interactions, signs of disorientation, impaired memory and learning as well as changes in the level of activity [21]
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