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

Tissue development and repair throughout life depends on the availability of multipotent mesenchymal stem/progenitor cells capable of differentiating into specialized cell types. How an appropriately sized pool of such multipotent progenitors is maintained under varied signals for tissue growth and repair is unknown. We addressed this question by monitoring fate trajectories of human adipose tissue-derived multipotent progenitor cells using single-cell transcriptomics. Homogenous multipotent progenitors underwent two distinct fate trajectories rapidly upon induction of adipose differentiation- one toward the adipocyte fate, and the other towards a distinct, non-differentiated state characterized by up-regulation of canonical Wnt target genes. Upon isolation, this latter cell population was able to resume proliferation and display multipotency. Using canonical Wnt agonists and antagonists we find Wnt signaling is required for the maintenance of this multipotent pool under differentiation stimulus. In vivo, these cells are retained in adipose tissue developed from human multipotent progenitor cells in immunocompromised mice, and their transcriptomic signature is detected in human adult adipose tissue. Our study reveals a previously unrecognized mechanism for maintaining a functional pool of human mesenchymal progenitor cells under conditions of differentiation pressure, driven by Wnt signaling.