Abstract
Mesenchymal stem cells have the capacity to give rise to multiple cell types, such as adipocytes, osteoblasts, chondrocytes, and myocytes. However, the molecular events responsible for the lineage specification and differentiation of mesenchymal stem cells remain unclear. Using gene expression profile studies, we determined that Scavenger receptor class A, member 5 (SCARA5) is a novel mediator of adipocyte commitment. SCARA5 was expressed at a higher level in committed A33 preadipocyte cells compared to C3H10T1/2 pluripotent stem cells. Gain- and loss-of-function studies likewise revealed that SCARA5 acts as a mediator of adipocyte commitment and differentiation in both A33 and C3H10T1/2 cells. RNAi-mediated knockdown of SCARA5 in A33 cells markedly inhibited the adipogenic potential, whereas overexpression of SCARA5 enhanced adipocyte differentiation in C3H10T1/2 cells. We also demonstrated that the focal adhesion kinase (FAK) and ERK signaling pathways is associated with the SCARA5-mediated response, thereby modulating adipocyte lineage commitment and adipocyte differentiation. Additionally, glucocorticoids induced the expression of SCARA5 in differentiating adipocytes through glucocorticoids response elements (GRE) in the SCARA5 promoter. Taken together, our study demonstrates that SCARA5 is a positive regulator in adipocyte lineage commitment and early adipogenesis in mesenchymal stem cells.
Highlights
Obesity is a growing health concern and a major risk factor for chronic diseases, including type 2 diabetes, hypertension, and atherosclerosis[1,2]
The A33 cell line, which was cloned from C3H10T1/2 cells treated with 5-azacytidine, was established to study adipocyte commitment[11] and was shown to differentiate into adipocytes in the absence of exogenous BMP2/4 treatment
To identify the molecular mechanisms controlling preadipocyte commitment, we performed preliminary microarray analysis on proliferating A33 and C3H10T1/2 cells and identified SCARA5, a novel gene with increased expression in preadipocyte A33 cells compared to C3H10T1/2 cells (Fig. 1a, Supplementary dataset 1)
Summary
Obesity is a growing health concern and a major risk factor for chronic diseases, including type 2 diabetes, hypertension, and atherosclerosis[1,2]. When treated with differentiation inducers at the growth arrest stage, these cells enter the adipose development pathway, express adipocyte markers, and acquire the adipocyte phenotype. The specific role of SCARA5 in the preadipocyte commitment process, which includes MSC commitment and terminal differentiation into adipocytes, remains undefined. The expression of SCARA5 is enriched in preadipocytes and upregulated during the early stage of MSC adipogenesis These observations suggest that SCARA5 is required for the commitment process, during which it plays an important role in the differentiation of pluripotent stem cells into adipocytes. To this end, we demonstrated that SCARA5 has an essential role in adipocyte lineage commitment via the inactivation of the FAK-ERK signaling pathway. These findings suggest that SCARA5 is a mediator of glucocorticoid effects in adipocyte lineage commitment and adipogenesis
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