Adult stem cell activity in naked mole rats for long-term tissue maintenance

Montazid, Shamir; Bandyopadhyay, Sheila; Hart, Daniel W.; Gao, Nan; Johnson, Brian; Thrumurthy, Sri G.; Penn, Dustin J.; Wernisch, Bettina; Bansal, Mukesh; Altrock, Philipp M.; Rost, Fabian; Gazinska, Patrycja; Ziolkowski, Piotr; Hayee, Bu’Hussain; Liu, Yue; Han, Jiangmeng; Tessitore, Annamaria; Koth, Jana; Bodmer, Walter F.; East, James E.; Bennett, Nigel C.; Tomlinson, Ian; Irshad, Shazia

doi:10.1038/s41467-023-44138-6

Cited by 4 publications

References 90 publications

(113 reference statements)

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Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

Aguilera-Lizarraga,

Ritoux,

Bulmer

et al. 2024

Preprint

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The intestinal barrier plays a crucial role in homeostasis, both by facilitating absorption of nutrients and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues such as the liver, fat, skeletal muscle, and brain. Hence, a deeper understanding of physiological aspects related to an enhanced barrier function is of great clinical relevance. The naked mole-rat (Heterocephalus glaber) has many unusual biological features, including impaired colonic neuron sensitivity to acid and bradykinin, and resistance to chemically induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable differences in intestinal tissue structure between naked mole-rats and mice, especially in the ileum. This was characterised by thicker muscularis and submucosa layers, longer villi and larger crypts. In measuring gut permeability, naked mole-rats showed reduced permeability compared to mice, especially in the small intestine (ileum). Furthermore, intestinal anion secretion induced by serotonin, bradykinin, histamine and capsaicin was significantly impaired in naked mole-rats compared to mice, despite the expression of receptors for all these agonists. Collectively, these findings indicate that naked mole-rats possess a robust gastrointestinal barrier, that is hard to penetrate and is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier related to different pathological conditions and set the stage for the development of innovative and effective therapies.

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Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

Aguilera-Lizarraga,

Ritoux,

Bulmer

et al. 2024

Preprint

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Human spermatogonial stem cells retain states with a foetal-like signature

Bush,

Nikola,

Han

et al. 2024

Preprint

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Spermatogenesis involves a complex process of cellular differentiation maintained by spermatogonial stem cells (SSCs). Being critical to male reproduction, it is generally assumed that spermatogenesis starts and ends in equivalent transcriptional states in related species. Based on single-cell gene expression profiling it has been proposed that undifferentiated human spermatogonia can be sub-classified into four heterogenous subtypes, termed states 0, 0A, 0B, and 1. To increase the resolution of the undifferentiated compartment and trace the origin of the spermatogenic trajectory, we re-analysed the single-cell (sc)RNA-seq libraries of 34 post-pubescent human testes to generate an integrated atlas of germ cell differentiation. We then used this atlas to perform comparative analyses of the putative SSC transcriptome both across human development (using 28 foetal and pre-pubertal scRNA-seq libraries) and across species (including data from sheep, pig, buffalo, rhesus and cynomolgus macaque, rat and mouse). Alongside its detailed characterisation, we show that the transcriptional heterogeneity of the undifferentiated spermatogonial cell compartment varies not only between species but across development. Our findings associate 'state 0B' with a suppressive transcriptomic program that, in adult humans, acts to functionally oppose proliferation and maintain cells in a ready-to-react state. Consistent with this conclusion, we show that human foetal germ cells - which are mitotically arrested - can be characterised solely as state 0B. While germ cells with a state 0B signature are also present in foetal mouse (and are likely conserved at this stage throughout mammals), they are not maintained into adulthood. We conjecture that in rodents, the foetal-like state 0B differentiates at birth into the renewing SSC population, whereas in humans it is maintained as a reserve population, supporting testicular homeostasis over a longer reproductive life while reducing mutagenic load. Together, these results suggest that SSCs adopt differing evolutionary strategies across species to ensure fertility and genome integrity over vastly differing life histories and reproductive timeframes.

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Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

Aguilera-Lizarraga,

Ritoux,

Bulmer

et al. 2024

American Journal of Physiology-Gastrointestinal and Liver Physi

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The intestinal barrier plays a crucial role in homeostasis, both by facilitating absorption of nutrients and fluids, and providing a tight shield to prevent the invasion by either pathogen or commensal microorganisms. Intestinal barrier malfunction is associated with systemic inflammation, oxidative stress, and decreased insulin sensitivity, which may lead to the dysregulation of other tissues. Therefore, a deeper understanding of physiological aspects related to an enhanced barrier function is of significant scientific and clinical relevance. The naked mole-rat has many unusual biological features, including attenuated colonic neuron sensitivity to acid and bradykinin, and resistance to chemical-induced intestinal damage. However, insight into their intestinal barrier physiology is scarce. Here, we observed notable macroscopic and microscopic differences in intestinal tissue structure between naked mole-rats and mice. Moreover, naked mole-rats showed increased number of larger goblet cells and elevated mucus content. In measuring gut permeability, naked mole-rats showed reduced permeability compared to mice, measured as transepithelial electrical resistance, especially in ileum. Furthermore, intestinal ion secretion induced by serotonin, bradykinin, histamine, and capsaicin was significantly reduced in naked mole-rats compared to mice, despite the expression of receptors for all these agonists. In addition, naked mole-rats exhibited reduced pro-secretory responses to the non-selective adenylate cyclase activator forskolin. Collectively, these findings indicate that naked mole-rats possess a robust and hard-to-penetrate gastrointestinal barrier, that is resistant to environmental and endogenous irritants. Naked mole-rats may therefore provide valuable insights into the physiology of the intestinal barrier and set the stage for the development of innovative and effective therapies.

show abstract

Adult stem cell activity in naked mole rats for long-term tissue maintenance

Cited by 4 publications

References 90 publications

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

Human spermatogonial stem cells retain states with a foetal-like signature

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

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