Abstract
BackgroundThis study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrow-derived mesenchymal stem cells (BMSCs) and its potential mechanism.MethodsThe acetylation level and KAT6A expression of BMSCs from the young (YBMSCs) and the old (OBMSCs) were examined. Gain- and loss-of-function experiments were performed to determine the effect of KAT6A on BMSC proliferation, colony formation, and osteogenic differentiation. The effect of KAT6A on Nrf2/ARE signaling pathway was investigated after KAT6A inhibition in YBMSCs or overexpression in OBMSCs, and the role of Nrf2/ARE signaling pathway on stemness was examined by investigating proliferation, colony formation, and osteogenic differentiation. Further in vivo study was performed to explore osteogenesis ability of OBMSCs after modulation of KAT6A and Nrf2/ARE pathway through cell sheet technology.ResultsThe acetylation level and KAT6A expression of OBMSCs were decreased, and KAT6A downregulation resulted in decreased proliferation, colony formation, and osteogenic differentiation of OBMSCs. Mechanically, KAT6A was found to regulate Nrf2/ARE signaling pathway and inhibit ROS accumulation in OBMSCs, thus promoting proliferation, colony formation, and osteogenic differentiation of OBMSCs. Further study demonstrated that KAT6A could promote osteogenesis of OBMSCs by regulating Nrf2/ARE signaling pathway.ConclusionsDownregulation of KAT6A resulted in the decreased stemness of OBMSCs by inhibiting the Nrf2/ARE signaling pathway.Graphical abstractKAT6A was downregulated in aging bone marrow-derived mesenchymal stem cells (BMSCs), and downregulation of KAT6A resulted in Nrf2/ARE signaling pathway inhibition and ROS accumulation, thus leading to decreased stemness of aging BMSCs.
Highlights
This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrowderived mesenchymal stem cells (BMSCs) and its potential mechanism
QRTPCR and alizarin red staining confirmed the decreased osteogenesis ability of BMSCs from the old (OBMSCs) than that of BMSCs from the young (YBMSCs) (Figure S1C and S1D). These results indicated that OBMSCs exhibited lower stemness than YBMSCs
The levels of acetylated lysine in YBMSCs and OBMSCs were explored, and the acetylation levels of lysine were found to be decreased in OBMSCs compared to those in YBMSCs (Fig. 1a), indicating that histone acetylation may be involved in the decreased stemness of OBMSCs
Summary
This study aimed to explore the effect of KAT6A on the decreased stemness of aging bone marrowderived mesenchymal stem cells (BMSCs) and its potential mechanism. Bone marrow-derived mesenchymal stem cells (BMSCs) are essential for bone formation, and decreased stemness of BMSCs has been regarded as one important factor contributing to age-related osteoporosis [1, 2]. Histone acetyltransferases (HATs), such as KAT2A, elongator complex protein 3, and KAT6A, are enzymes responsible for histone lysine residues acetylation. They have numerous functions including DNA repair and transcriptional regulation [5]. The KAT6A gene, which can acetylate lysine residues in histone H3, is required for hematopoiesis [9] and skeletogenesis, as well as the regulation of many genes. Several studies reported that KAT6A could regulate the self-renewal, proliferation, and differentiation of hematopoietic stem cells [9]; whether and how KAT6A regulated the decreased stemness of aging BMSCs remains unknown
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