Abstract
Mesenchymal stem cells have emerged as an important tool that can be used for tissue regeneration thanks to their easy preparation, differentiation potential and immunomodulatory activity. However, an extensive culture of stem cells in vitro prior to clinical use can lead to oxidative stress that can modulate different stem cells properties, such as self-renewal, proliferation, differentiation and senescence. The aim of this study was to investigate the aging process occurring during in vitro expansion of stem cells, obtained from amniotic fluids (AFSC) at similar gestational age.The analysis of 21 AFSC samples allowed to classify them in groups with different levels of stemness properties. In summary, the expression of pluripotency genes and the proliferation rate were inversely correlated with the content of reactive oxygen species (ROS), DNA damage signs and the onset premature aging markers, including accumulation of prelamin A, the lamin A immature form. Interestingly, a specific source of ROS, the NADPH oxidase isoform 4 (Nox4), can localize into PML nuclear bodies (PML-NB), where it associates to prelamin A. Besides, Nox4 post translational modification, involved in PML-NB localization, is linked to its degradation pathway, as it is also for prelamin A, thus possibly modulating the premature aging phenotype occurrence.
Highlights
Stem cells are implicated in preserving tissue homeostasis throughout life, by replacing damaged or lost cells
The presence of NADPH oxidase isoform 4 (Nox4), a reactive oxygen species (ROS) enzymatic source, increased in the sumoylated form into the nuclei localizing in promyelocytic leukemia (PML)
Www.aging-us.com bodies and interacting with immature lamin A. This localization is a way to sequester and favour proteasome degradation, with the possible protecting meaning to modulate ROS content, limit DNA damage and induce senescence
Summary
Stem cells are implicated in preserving tissue homeostasis throughout life, by replacing damaged or lost cells. The excessive generation of endogenous ROS and the imbalance between ROS and antioxidant systems, and the culture of stem cells with various extracellular sources of ROS can lead to oxidative stress. This is the case of MSCs, whose low number requires ex vivo expansion prior to clinical use. Most of the expansion procedures of MSCs are performed under atmospheric O2 concentration (20% O2), which is approximately 4–10 times higher than the concentration of O2 in their natural niches [3] This higher O2 concentration might cause environmental stress to the in vitro cultured MSCs, due to the increased ROS concentration. The review by Choi et al [4] reported studies demonstrating that hypoxia has a greater ability to preserve the stemness of human Adipose SCs, (ASC) as indicated by the increased expression of stemness genes (e.g., NANOG, SOX-2, OCT4, and REX-1)
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