How mesenchymal stem cells transform into adipocytes: Overview of the current understanding of adipogenic differentiation

Abstract

Mesenchymal stem cells (MSCs) are stem/progenitor cells capable of self-renewal and differentiation into osteoblasts, chondrocytes and adipocytes. The transformation of multipotent MSCs to adipocytes mainly involves two subsequent steps from MSCs to preadipocytes and further preadipocytes into adipocytes, in which the process MSCs are precisely controlled to commit to the adipogenic lineage and then mature into adipocytes. Previous studies have shown that the master transcription factors C/enhancer-binding protein alpha and peroxisome proliferation activator receptor gamma play vital roles in adipogenesis. However, the mechanism underlying the adipogenic differentiation of MSCs is not fully understood. Here, the current knowledge of adipogenic differentiation in MSCs is reviewed, focusing on signaling pathways, noncoding RNAs and epigenetic effects on DNA methylation and acetylation during MSC differentiation. Finally, the relationship between maladipogenic differentiation and diseases is briefly discussed. We hope that this review can broaden and deepen our understanding of how MSCs turn into adipocytes.

Keywords: Adipogenic differentiation; Epigenetic regulation; Mesenchymal stem cell; Noncoding RNA; Signaling pathway.

Figure 1

Morphological changes in differentiating mouse thymic mesenchymal stem cells. Schematic illustration of the adipogenic differentiation protocol and cellular morphological changes that occurred during the differentiation process 33 consecutive days after induction. Typically, mesenchymal stem cell preadipocyte commitment occurred in the first days (days 15), followed by the differentiation of preadipocytes into mature adipocytes with increasing lipid droplets. MSC: Mesenchymal stem cell.

Figure 2

Regulation of adipogenesis and gluconeogenesis by lysine deacetylases, acetyltransferases and noncoding RNAs. Lysine deacetylases (KDACs) and acetyltransferases (KATs) are important regulators of adipocyte differentiation and gluconeogenesis. Peroxisome proliferation activator receptor gamma is acetylated by Gcn5/PCAF, p300/CBP and Tip60 but deacetylated by Sirt1. In addition, Gcn5/PCAF is also regulated Prdm16 expression to influence adipogenesis. Histone deacetylases (HDACs) 1, 2, 3, 5 and 9 redundantly regulate adipogenesis. Moreover, noncoding RNAs cooperatively interact with KDACs to regulate the adipogenic process. H19/miR-675 can inhibit HDAC5 expression. Hence, KDACs and KATs can regulate lipid metabolism. PEPCK-C is acetylated by p300 to induce its degradation and attenuate gluconeogenesis. Conversely, PEPCK-C is deacetylated and stabilized by Sirt2 through Sirt2 deacetylase. HDAC6 also plays an important role in gluconeogenesis regulation. PPARγ: Peroxisome proliferation activator receptor gamma; HDAC: Histone deacetylase; PRDM16: PR domain containing zinc finger protein 16.