PBX1-SIRT1 Positive Feedback Loop Attenuates ROS-Mediated HF-MSC Senescence and Apoptosis

Abstract

Stem cell senescence and depletion are major causes of aging and aging-related diseases. The NAD (Nicotinamide adenine dinucleotide) – SIRT1 (Silent Information Regulator 1) – PARP1 (Poly (ADP-ribose) polymerase-1) axis has gained interest owing to its significant role in regulating stem cell senescence and organismal aging. A recent study from our lab showed that pre-B-cell leukemia transcription factor1 (PBX1) overexpression attenuates hair follicle-derived mesenchymal stem cells (HF-MSCs) senescence and apoptosis by regulating ROS-mediated DNA damage via PARP1 downregulation; thus, suggesting that PARP1 downregulation is a common manifestation of the roles of both PBX1 and SIRT1 in HF-MSCs senescence attenuation, and implying a potential link between PBX1 and SIRT1. To this end, HF-MSCs overexpressing PBX1, overexpressing both PBX1 and PARP1, downregulating SIRT1, and overexpressing PBX1 as well as downregulating SIRT1 were generated, and senescence, apoptosis, DNA damage, and repair biomarkers were analyzed. Our results showed that (1) PBX1 overexpression alleviated HF-MSCs senescence and apoptosis accompanied by SIRT1 upregulation, PARP1 downregulation, and increased intracellular NAD and ATP levels. (2) SIRT1 knockdown enhanced cellular senescence and apoptosis, accompanied by increased ROS accumulation, DNA damage aggravation, and decreased intracellular NAD and ATP levels. (3) PBX1 overexpression rescued HF-MSCs senescence and apoptosis induced by SIRT1 knockdown. (4) PBX1 rescued PARP1 overexpression-mediated ATP and NAD depletion, accompanied by increased SIRT1 expression. Collectively, our results revealed that a positive interaction feedback loop exists between PBX1 and SIRT1. To the best of our knowledge we are the first to report that there is a PBX1-SIRT1-PARP1 axis that plays a critical role in alleviating HF-MSCs senescence and apoptosis. We provide a new perspective on the mechanisms underlying stem cell senescence as well as age-related disease prevention and treatment. Graphical Abstract

Research progress of PBX1 in developmental and regenerative medicine

“…PBX1 rescued ATP and NAD depletion mediated by PARP1 overexpression, accompanied by increased SIRT1 expression. This highlights a critical role of the PBX1-SIRT1-PARP1 axis in alleviating senescence and apoptosis in HF-MSCs 61 .…”

Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

“…Using molecular docking simulations and cell-based studies, we herein demonstrated that both 4-dmH and heliomycin targeted SIRT1 and inhibited its activity and expression, to attenuate the growth of oral cancer cells. Given that SIRT1 contributes to a complex regulatory network, it is of primary importance to understand the fundamental regulatory mechanisms of SIRT1 in cell death regulation ( Wang et al, 2023 ; Wang et al, 2021a ; Lee et al, 2018 ; Zhu et al, 2020 ; Ran et al, 2023 ; Zhang et al, 2020 ).…”

Extracellular vesicle-derived TP53BP1, CD34, and PBX1 from human peripheral blood serve as potential biomarkers for the assessment and prediction of vascular aging

“…Pbx1 mRNA produces two transcripts, Pbx1a and 1b, during variable splicing; and Pbx1 is commonly expressed in embryonic and adult tissues [ 19 ]. Intriguingly, it was shown that enhanced expression of a Pbx1-Sirt1 positive-feedback loop significantly attenuated ROS-induced senescence and apoptosis in hair follicle-derived mesenchymal stem cells [ 26 ], suggesting that Pbx1 expression was negatively correlated with senescence. The above reports are in close agreement with our experimental results and indirectly support our findings and scientific hypotheses.…”