Each to their bone

Abstract

Skeletal stem cells (SSCs) have been identified in the human fetal growth plate and in regenerating adult bones. Ambrosi et al. now dissect the functional heterogeneity of human SSCs.

The researchers isolated SSCs from ten skeletal sites of the human fetus and performed multiple analyses, including single-cell and spatial transcriptomics, as well as functional assays. SSCs isolated from different bone sites were functionally heterogeneous and each site seemed to enclose its own unique diversity of SSC subtypes. The group identified four different SSC subsets and studied their distinct clonal dynamics. They then expanded their analyses to include samples from adults, healthy individuals or individuals with a disease, and observed a shift towards fibroblast-skewed SSCs in ageing and skeletal pathology. Finally, the authors performed an invariant analysis of Boolean implication relationships to identify the gene regulatory networks that influence SSC identities. On the basis of this analysis, Ambrosi et al. used a small-molecule combinatorial treatment that targeted these networks and helped restore functional SSC diversity.