Canonical Wnt Signaling Maintains Human Mesenchymal Progenitor Cell Multipotency During Adult Adipose Tissue Development

Abstract

Human adipose tissue development and repair requires mesenchymal progenitor cells capable of self-renewal and differentiation into adipocytes. These progenitors are within adipose tissue throughout life, and how a progenitor pool is sustained is not well understood. As adipocytes have exceedingly slow turnover rate in vivo, we used a human adult primary adipose tissue-derived progenitor model to study adipogenesis at scale. Initially, single-cell transcriptome profiling of progenitors during early adipogenic induction identified common-origin developmental trajectories toward two fates. One fate is toward adipocyte terminal differentiation, and the other is toward a non-differentiated state characterized by up-regulation of extracellular matrix and canonical Wnt target genes. This latter cell population, herein referred to as Structural Wnt Adipose Tissue resident (SWAT) cells, retains features of progenitors, including the capability to proliferate and to differentiate towards multiple mesenchymal fates, but SWAT cells have a distinct transcriptional profile compared to progenitor cells. We conducted an in-depth investigation of Wnt signaling in SWAT cells. Canonical Wnt signaling reporter assay revealed Wnt activity was rapidly and transiently up-regulated upon adipogenic induction, and perturbation of Wnt activity alters the proportion of differentiated adipocytes. In additional to experimental validations, this research includes meta-analyses of published human adult adipose tissue single-nuclei transcriptome profiles, providing in vivo clinical evidence for expression of Wnt target genes and the transcriptomic signature of the maintained adipose progenitors. Our study identifies canonical Wnt signaling as a critical mechanism for mesenchymal progenitor maintenance and demonstrates its essential role in human adult adipose tissue homeostasis.