MRAP mediated adipocyte differentiation by thymic mesenchymal stromal cells contributes to thymic involution

Dandan Wang, Xiang Fang, Yujun Deng, Xin Wen, Ousheng Liu, Junji Xu, Fudong Fan, Dongjin Wang, Yichen Han, Peter Zanvit, Sang A. Park, Wenwen Jin, Hongbo Hu, Lingyun Sun () and WanJun Chen ()
Additional contact information
Dandan Wang: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Xiang Fang: the Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Emergency Medicine
Yujun Deng: Sichuan University, Center for Immunology and Hematology, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital
Xin Wen: the Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Rheumatology and Immunology
Ousheng Liu: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Junji Xu: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Fudong Fan: the Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Cardiothoracic Surgery
Dongjin Wang: the Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Cardiothoracic Surgery
Yichen Han: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Peter Zanvit: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Sang A. Park: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Wenwen Jin: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research
Hongbo Hu: Sichuan University, Center for Immunology and Hematology, Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital
Lingyun Sun: the Affiliated Drum Tower Hospital of Nanjing University Medical School, Department of Rheumatology and Immunology
WanJun Chen: National Institutes of Health, Mucosal Immunology Section, National Institute of Dental and Craniofacial Research

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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) have a higher tendency to differentiate into adipocytes and melanocortin-2 receptor accessory protein (MRAP) is a potential driver of tMSCs adipogenesis. Furthermore, we discover that thymosin-α1 promotes MRAP expression in tMSCs through FoxO1 signaling pathway. Additionally, the proportion of tMSCs increase in older mice compared to young mice. Importantly, MRAP is also necessary for human thymic MSCs to differentiate into adipocytes when exposed to thymosin-α1. Single-cell RNA-seq analysis of human thymus revealed an accumulation of tMSCs and adipocytes during aging, indicating a strong potential for adipogenic differentiation in age-related thymic involution. 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.

Date: 2025
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DOI: 10.1038/s41467-025-64973-z

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