Characterisation of the intestinal epithelium and adult stem cell dynamics in the naked mole rats

Thesis

Naked mole rats (Heterocephalus glaber) are the longest-living rodents on earth that exhibit a low incidence of ageing-associated complexities (e.g. cancer, osteoarthritis, neurodegenerative diseases etc.). These subterranean eusocial mammals live in an arid, hypoxic environment with high oxidative stress. Evolution in such a damage-prone environment has made NMR an ideal model to study the adaptations of adult stem cells for long-term healthy tissue maintenance. In this study, we have characterised the intestinal epithelia, including the Lgr5+ stem cells, in NMRs in a cross-species histological comparison with mice and humans. NMR intestines possess higher numbers of differentiated cells (enterocytes, goblet cells, and enteroendocrine cells) than mice, facilitating efficient nutrient absorption and protection against damage. Using in vivo cumulative DNA labelling, we show that intestinal Lgr5+ cells in NMRs cycle slower than mice. However, these cells in the NMR colon have a similar cycling rate to humans. Additionally, we demonstrate that NMR intestines are more resistant to epithelial damage induced by Dextran Sodium Sulphate (DSS) than mice. However, despite not succumbing to any DSS-mediated tissue damage, Lgr5+ cells in NMR intestines are hypersensitive to this colitogen and undergo apoptosis. In summary, the expanded pool of stem and differentiated cells in NMR intestines, along with the slow turnover rate of Lgr5+ cells and their hypersensitivity to damage are a few adaptations we report here in this thesis that may allow these animals to maintain a healthy intestinal tissue for longer.

Authors: Montazid, S

• DOI: 10.5287/ora-yr8prenb6
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: long-lived mammals; Lgr5+ cells; stem cell kinetics
• Subjects: Intestines; Naked mole rat; Adult stem cells