Abstract
Vulpinic acid, a naturally occurring methyl ester of pulvinic acid, has been reported to exert anti-fungal, anti-cancer, and anti-oxidative effects. However, its metabolic action has not been implicated yet. Here, we show that vulpinic acid derived from a mushroom, Pulveroboletus ravenelii controls the cell fate of mesenchymal stem cells and preadipocytes by inducing the acetylation of histone H3 and α-tubulin, respectively. The treatment of 10T1/2 mesenchymal stem cells with vulpinic acid increased the expression of Wnt6, Wnt10a, and Wnt10b, which led to osteogenesis inhibiting the adipogenic lineage commitment, through the upregulation of H3 acetylation. By contrast, treatment with vulpinic acid promoted the terminal differentiation of 3T3-L1 preadipocytes into mature adipocytes. In this process, the increase in acetylated tubulin was accompanied, while acetylated H3 was not altered. As excessive generation of adipocytes occurs, the accumulation of lipid drops was not concentrated, but dispersed into a number of adipocytes. Consistently, the expressions of lipolytic genes were upregulated and inflammatory factors were downregulated in adipocytes exposed to vulpinic acid during adipogenesis. These findings reveal the multiple actions of vulpinic acid in two stages of differentiation, promoting the osteogenesis of mesenchymal stem cells and decreasing hypertrophic adipocytes, which can provide experimental evidence for the novel metabolic advantages of vulpinic acid.
Highlights
Mesenchymal stem cells (MSCs), which are present in bone marrow and soft tissues, have the capacity to differentiate into diverse stromal lineages including osteogenic, adipogenic, myogenic, and chondrogenic lineages [1,2]
Since previous studies have reported the cytotoxic effects of vulpinic acid to cancer cells [15,16,17], we evaluated the influence of vulpinic acid on the cell death and morphology of 10T1/2 MSCs and
To estimate the effects of vulpinic acid on the cell fate conversion of 10T1/2 MSCs, we examined the expression of Wnt genes, which are important for the determination of cell lineage during the commitment step of multipotent stem cells [21,22]
Summary
Mesenchymal stem cells (MSCs), which are present in bone marrow and soft tissues, have the capacity to differentiate into diverse stromal lineages including osteogenic (bone), adipogenic (fat), myogenic (muscle), and chondrogenic (cartilage) lineages [1,2]. The determination of MSC fate requires the selective activation or repression of master regulatory genes which are specific for respective lineages, such as peroxisome proliferator-activated receptor (PPAR)γ for adipogenesis, runt-related transcription factor 2 (Runx2) for osteogenesis, and Sox for chondrogenesis [4]. Enhancer of zeste homolog 2 (EZH2)-mediated trimethylation at lysine 27 of histone H3 (H3K27me3) has been reported to promote adipogenesis while inhibiting osteogenesis by enhancing PPARγ and suppressing Runx, which were reversed by lysine-specific demethylase 6A (KDM6A), a demethylase of H3K27me3 [5,6]. HDAC6 is known to promote adipogenesis and to suppress osteogenic differentiation from MSCs [9]. During the control of lineage-associated genes, HATs and HDACs compete for the same promoter region of the genes to precisely adjust the level of histone acetylation [4]
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