Universal fibroblasts across tissues can differentiate into niche cells for hematopoietic stem cells

Hematopoietic stem cells (HSCs) generating all blood cells are maintained by their niche cells, termed CXCL12-abundant reticular (CAR) cells, which strongly overlap with leptin-receptor-expressing (LepR⁺) cells in the bone marrow. A meta-analysis of single-cell RNA sequencing datasets across tissues hypothesized that universal fibroblasts present in all organs give rise to distinct tissue-specific fibroblast subsets designated as specialized fibroblasts, including CAR/LepR⁺ cells. However, there is no direct evidence that universal fibroblasts can differentiate into specialized fibroblasts at a distant location. Here, we demonstrated that CD248⁺ universal fibroblasts from the lung and colon outside the skeletal system, as well as from muscle, generated CAR/LepR⁺ cells characterized by HSC niche functions and expression of cytokines and transcription factors essential for HSC maintenance during ectopic bone formation or after intra-bone marrow transplantation. These results demonstrate that universal fibroblasts with the potential to differentiate into bone marrow-specific HSC niche cells are scattered throughout the entire body.