Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging

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.

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

“…They argued that mtROS activates Nrf2 based on the fact that NOX4 and SOD2, but not NOX2 and SOD1, are induced by AES. Although different NOX4 subcellular localization has been reported, including in the nucleus and endoplasmic reticulum [76,77], NOX4 has been shown to mainly localize in mitochondria, especially in the heart Metabolic stress, such as caloric restriction and exercise, causes a decline in ATP levels and an increase in the NAD + /NADH ratio that is sensed by downstream pathways that promote mitochondrial function and increase ATP synthesis [50,55]. An increase in AMP/ATP activates AMPK, which induces mitochondrial biogenesis via PGC1α activation and enhances autophagy via mTOR inhibition.…”

“…They argued that mtROS activates Nrf2 based on the fact that NOX4 and SOD2, but not NOX2 and SOD1, are induced by AES. Although different NOX4 subcellular localization has been reported, including in the nucleus and endoplasmic reticulum [76,77], NOX4 has been shown to mainly localize in mitochondria, especially in the heart [78][79][80]. Indeed, several beneficial effects of exercise in the vasculature and skeletal muscle, such as increased physical activity, are diminished in NOX4-knockout mice [81].…”

Crucial Role of Lamin A/C in the Migration and Differentiation of MSCs in Bone

“…In MSCs, alterations in lamin A protein have been described to disrupt nuclear organization, leading to the sequestration of transcription factors to the nuclear periphery [ 115 , 116 , 117 , 118 ]. This pathological entrapment of transcription factors leads to an impaired homeostasis in MSCs, affecting their fate [ 116 , 119 ]. This is the case of PPARs, which are essential regulators of MSCs’ differentiation [ 120 ].…”

Psychological Stress and Cellular Aging in Cancer: A Meta-Analysis

“…Comprehensive experimental studies over the past decade have shown OS can impair stem cells' redox homeostasis in hematopoietic, neural, and muscle stem cell compartments [100]. Stem cells are involved in preserving tissue homeostasis and the repair of damaged DNA through replacing damaged/lost cells; thus, they play an important role for functional tissue and organ maintenance [101]. Therefore, the regulation of balance between quiescence, self-renewal, and differentiation is crucial for stem cell functioning during early development and cell homeostasis [100–102].…”

“…The response mechanism of stem cells on OS is not well recognized, but accelerated telomere shortening, increased double-stranded DNA breaks, and nuclear A-type prelamin accumulation, followed by stem cell senescence or premature aging and cell death, have been reported [103]. An important role of A-type prelamins, i.e., the proteins responsible for the structural and functional integrity of the cell nucleus, is the ability to modulate intracellular redox homeostasis [101]. The experimental study of aging processes during in vitro expansion of stem cells from amniotic fluids (hAFSCs cultures) by Casciaro et al showed low levels of intracellular ROS prevented nuclear A-type prelamin accumulation and Nox4 nuclear activity towards ROS production [101].…”