Abstract
Aging is identified by a progressive decline of physiological integrity leading to age-related degenerative diseases, but its causes is unclear. Human dental pulp stem cells (hDPSCs) has a remarkable rejuvenated capacity that relies on its resident stem cells. However, because of the lack of proper senescence models, exploration of the underlying molecular mechanisms has been hindered. Here, we established a cellular model utilizing a hydroxyurea (HU) treatment protocol and effectively induced Human dental pulp stem cells to undergo cellular senescence. Age-related phenotypic changes were identified by augmented senescence-associated-β-galactosidase (SA-β-gal) staining, declined proliferation and differentiation capacity, elevated G0/G1 cell cycle arrest, increased apoptosis and reactive oxygen species levels. Furthermore, we tested the expression of key genes in various DNA repair pathways including nonhomologous end-joining (NHEJ) and homologous recombination (HR) pathways. In addition, our results showed that Dental pulp stem cells from young donors are more resistant to apoptosis and exhibit increased non-homologous end joining activity compared to old donors. Further transcriptome analysis demonstrate that multiple pathways are involved in the HU-induced Dental pulp stem cells ageing, including genes associated with DNA damage and repair, mitochondrial dysfunction and increased reactive oxygen species levels. Taken together, the cellular model have important implications for understanding the molecular exploration of Dental pulp stem cells senescence and aging.
Highlights
Aging generally experience a gradual loss in physiological integrity and rejuvenated capacities within adult tissues [1], which lead to impaired function, increased susceptibility to disease and elevated risk of death [2]
The sites of DNA damage was stained by γH2AX foci to quantify the extent of DNA double-strand breaks
Human DFSCs were treated with 8mM hydroxyurea for 12 h and an increased cell senescence model was successfully established
Summary
Aging generally experience a gradual loss in physiological integrity and rejuvenated capacities within adult tissues [1], which lead to impaired function, increased susceptibility to disease and elevated risk of death [2]. The general mechanism of aging is widely considered as the chronic accumulation of cellular damage [4, 5]. Damaged DNA accumulation in aged stem cells may constantly arise from internal and external factors including DNA replication, transcription, recombination errors, repair, spontaneous chemical reactions and assaults metabolism-derived agents [7]. The mechanistic basis by which increased levels of DNA damage in aged stem cell can decrease stem cell dysfunction are still being illustrated. Genetic assaults may increase stem cell ageing or apoptosis and may directly trigger gene regulation, causing alterations in stem cell differentiation and self-renewal
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