Single-cell multiomics of pediatric BM reveals age-dependent differences in lineage differentiation linked to stromal cell heterogeneity

Childhood is critical for hematopoietic development and the onset of hematologic diseases. To explore hematopoietic changes from infancy through adolescence, we generated a multi-modal single-cell atlas capturing mRNA and surface protein expression of 90.710 bone marrow (BM) cells. This includes hematopoietic stem/progenitor cells and mesenchymal stromal cells, from seven pediatric individuals and two young adults. We demonstrate that young pediatric BM is distinct from adolescents/young adults (AYA), shifting from B-lineage dominance in early childhood to myeloid and T-lineage bias in adolescence. We uncover two distinct lymphoid progenitors (LyPs) subsets regulating this shift: CD127-positive LyPs with B-lineage output, most abundant in early childhood, and CD127-negative LyPs with lymphoid and myeloid features, more common in AYAs. Age-related changes in stromal composition and signaling, mediated by IL-7 and TGF-β1, correspond with this lineage shift. This study provides an in-depth resource for understanding healthy hematologic development and potential early-life perturbations underlying pediatric hematologic diseases.