Single-cell RNA-seq reveals that SLC31A1-dependent copper uptake regulates osteogenic commitment of mouse bone marrow stromal cells

In this study, we identify SLC31A1-mediated copper uptake as a cell-intrinsic metabolic checkpoint for BMSC osteogenic differentiation and skeletal integrity. This single-cell RNA-seq dataset profiles adherent bone marrow stromal cells isolated from wild-type Slc31a1flox/flox mice and mesenchymal lineage-specific Slc31a1 conditional knockout mice (Prrx1-Cre+/-; Slc31a1flox/flox).

Single-cell transcriptomic analysis resolved Prrx1-positive osteogenic-lineage populations, including BMSC subsets and pre-osteoblasts, and revealed that Slc31a1-deficient BMSCs accumulate in an ID1-high progenitor state and fail to efficiently transition toward osteogenic commitment. Together with functional, metabolic, and epigenomic analyses, these data support a copper-mitochondria-NAD-SIRT1-ID1 axis that links trace metal uptake to stem/progenitor cell fate decisions and identifies intracellular copper availability as a reversible metabolic vulnerability in skeletal aging.