Convergent alteration of the mesenchymal stem cell heterogeneity in adipose tissue during aging

Abstract

AbstractAdipose‐derived stem cells (ASCs) from distinct age groups possess different characteristics; however, the age‐associated changes in ASCs heterogenicity remain largely unknown. In this study, several publicly available single‐cell RNA sequencing (RNA‐seq) data cohorts of inguinal adipose tissues, including young (2 weeks), adult (8 weeks), and old (18 months) C57BL/6 mice, were analyzed. Transcriptomic clustering of integrated single‐cell RNA‐seq data from different age groups revealed the existence of five ASCs subtypes. Interestingly, ASCs showed a loss of heterogeneity with aging, and ASCs subtype 4 (ASC‐4) was the dominant subpopulation accounting for more than 98% of aged ASCs converging to the terminal differentiation state. The multidirectional differentiation potentials of different ASCs subtypes were largely distinct while the adipogenic ability of ASC‐4 increased with age persistently. Regulon analysis of ASC subtypes further identified Cebpb as the ASC‐4‐specific transcription factor, which was known as one of the major adipogenic regulators. Analysis of ligand–receptor pairs between ASCs and other cell types in adipose tissue identified age‐associated upregulation of inflammatory responses‐associated factors including CCL2 and CCL7. Treatment with 100 ng/mL CCL2 in vitro could significantly promote the adipogenesis of ASCs through enhanced phosphorylation of AKT and decreased expression of β‐catenin. In addition, supplementation of 100 ng/mL CCL7 could significantly increase the expression of inflammatory genes and ASC‐4‐specific transcriptional factors in 2‐week‐old ASCs, potentially acting as a driver of ASCs convergence. Our findings help to delineate the complex biological processes of ASCs aging and shed light on better regenerative and therapeutic applications of ASCs.