MRAP mediated adipocyte differentiation by thymic MSCs contributes to thymic adipose involution

Abstract Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution, but the underlying cellular and molecular mechanisms remain unknown. We show here that thymic mesenchymal stromal cells (tMSCs) are differentiated into adipocytes through melanocortin-2 receptor accessory protein (MRAP). Specifically, we found that in contrast to bone-forming MSCs isolated from dental pulp tissues, tMSCs were more susceptible to differentiate into adipocytes under adipogenic condition, but hardly to differentiate into bone tissues in osteogenic medium. We identified MRAP as a potential factor to drive tMSCs adipogenesis by global RNA-seq analysis and confirmed its key role by knockdown of Mrap in tMSCs in vitro and null mutation of Mrap in mice. The aged Mrap-knockout mice had enhanced thymic size and increased thymic weight with less adipocytes accumulation in the thymus. We further uncovered that thymosin-α1 promoted MRAP expression in tMSCs through FoxO1 signaling pathway. Moreover, tMSCs proportion increased in old mice compared to young mice. Importantly, human thymic MSCs also required MRAP to differentiate into adipocytes in response to thymosin-a1. Thus, we have revealed MRAP as a key factor in promoting thymic MSCs adipogenesis triggered by thymosin- α1 and FoxO1 pathway, which may serve as potential target to hinder adiposity in age- related thymic involution.