Physiological pathway of differentiation of hematopoietic stem cell population into mural cells

Endothelial cells (ECs), which are a major component of blood vessels, have been reported to develop in adulthood from hematopoietic cell populations, especially those of the monocyte lineage. Here we show that mural cells (MCs), another component of blood vessels, develop physiologically during embryogenesis from a hematopoietic stem cell (HSC) population, based on the in vitro culture of HSCs and histological examination of acute myeloid leukemia 1 mutant embryos, which lack HSCs. As in the embryo, HSCs in adult bone marrow differentiate into CD45⁺CD11b⁺ cells before differentiating into MCs. Moreover, CD45⁺CD11b⁺ cells are composed of two populations, CD11b^high and CD11b^low cells, both of which can differentiate into MCs as well as ECs. Interestingly, in a murine ischemia model, MCs and ECs derived from the CD11b^low population had a long-term potential to contribute to the formation of newly developed blood vessels in vivo compared with the CD11^high population, which could not. Moreover, injection of the CD11b^high population induced leaky blood vessels, but the CD11b^low population did not. With respect to the permeability of vessels, we found that angiopoietin 1, which is a ligand for Tie2 receptor tyrosine kinase expressed on ECs and is suggested to induce cell adhesion between ECs and MCs, is produced by the CD11b^low population and plays a critical role in the formation of nonleaky vessels. These observations suggested that the CD11^low cell population serves as a good source of cells for in vivo blood vessel regeneration.