PDF(Pubmed)
Abstract：
Mesenchymal stem cells (MSCs) hold immense potential as multipotent stem cells and serve as a primary source of adipocytes. The process of MSC adipogenesis plays a crucial role in maintaining systemic metabolic homeostasis and has garnered significant attention in tissue bioengineering. N6-methyladenosine (m6A), the most prevalent RNA modification, is known to regulate cell fate and disease. However, the precise involvement of m6A readers in MSC adipogenesis remains unclear. In this study, we investigated the impact of IGF2BP3, a prominent m6A reader, on MSC adipogenesis. Our findings revealed a decrease in IGF2BP3 expression during the natural adipogenic differentiation of MSCs. Furthermore, IGF2BP3 was found to repress MSC adipogenesis by augmenting the levels of MYLK, a calcium/calmodulin-dependent kinase. Mechanistically, IGF2BP3 interacted with MYLK mRNA in an m6A-dependent manner, extending its half-life and subsequently inhibiting the phosphorylation of the ERK1/2 pathway, thereby impeding the adipogenic differentiation of MSCs. Additionally, we successfully achieved the overexpression of IGF2BP3 through intraperitoneal injection of adeno-associated virus serotype Rec2, which specifically targeted adipose tissue. This intervention resulted in reduced body weight and improved insulin resistance in high-fat diet mice. Overall, our study provides novel insights into the role of IGF2BP3 in MSC adipogenesis, shedding light on adipocyte-related disorders and presenting potential targets for related biomedical applications.
摘要：
间充质干细胞(MSC)具有作为多能干细胞的巨大潜力,并且充当脂肪细胞的主要来源。MSC脂肪形成过程在维持全身代谢稳态中起着至关重要的作用，并在组织生物工程中引起了广泛关注。N6-甲基腺苷（m6A），最普遍的RNA修饰，已知调节细胞命运和疾病。然而,m6A阅读器在MSC脂肪形成中的确切参与尚不清楚.在这项研究中,我们调查了IGF2BP3的影响，IGF2BP3是一款著名的M6A阅读器，关于MSC脂肪生成。我们的发现揭示了在MSCs自然成脂分化过程中IGF2BP3表达的降低。此外，发现IGF2BP3通过增加MYLK的水平来抑制MSC的脂肪形成，钙/钙调蛋白依赖性激酶。机械上,IGF2BP3以m6A依赖性方式与MYLKmRNA相互作用，延长其半衰期并随后抑制ERK1/2途径的磷酸化，从而阻碍MSC的成脂分化。此外,我们通过腹腔注射特异性靶向脂肪组织的腺相关病毒血清型Rec2成功实现了IGF2BP3的过表达。这种干预导致高脂肪饮食小鼠的体重减轻和胰岛素抵抗改善。总的来说,我们的研究为IGF2BP3在MSC脂肪形成中的作用提供了新的见解，揭示脂肪细胞相关疾病，并提出相关生物医学应用的潜在目标。
