Abstract
BackgroundThe naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear.MethodsNeural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR.ResultsNMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs.ConclusionsNMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.
Highlights
The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of Naked mole-rats (NMRs) are highly capable of maintaining homeostasis
Immunohistochemistry showed that the subventricular zone (SVZ) of the neonatal NMR brain contained many cells positive for the Neural stem cell (NSC) markers SRY-box transcription factor 2 (SOX2), NES, and musashi RNA-binding protein 1 (MSI1), as well as a small population of BrdU-positive cells (Fig. 1b, c, Supplementary Fig. 1a)
The dissected SVZ was dissociated by gentle pipetting after treatment with trypsin and hyaluronidase, suspended in NSC culture medium supplemented with B27, basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF), as previously used in other species [31], and cultured in neurosphere culture conditions
Summary
The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. NMRs exhibit extraordinary resistance to cancer; spontaneous carcinogenesis was seldom observed in more than 2000 necropsies of captive NMR colonies [4,5,6]. Tian et al reported that compared with shortlived rodent species, fibroblasts from various long-lived rodent species including NMRs have a high DNA double-strand break (DSB) repair capacity and high activity of Sirtuin 6, which acts as a DSB sensor [14, 15]. In addition to their high DSB repair capacity, NMRs have high DNA excision repair activity [16]
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