Hematopoietic stem and progenitor cells use podosomes to transcellularly cross the bone marrow endothelium

Bone marrow endothelium plays an important role in the homing of hematopoietic stem and progenitor cells (HSPC) upon transplantation, but surprisingly little is known on how the bone marrow (BM) endothelial cells regulate local permeability and hematopoietic stem and progenitor cells transmigration. We show that temporal loss of vascular endothelial-cadherin function promotes vascular permeability in BM, even upon low-dose irradiation. Loss of vascular endothelial-cadherin function also enhances homing of transplanted HSPC to the BM of irradiated mice although engraftment is not increased. Intriguingly, stabilizing junctional vascular endothelial-cadherin in vivo reduced BM permeability, but did not prevent HSPC cells migration into the BM, suggesting that HSPC use the transcellular migration route to enter BM. Indeed, using an in vitromigration assay, we show that human HSPC cells predominantly cross BM endothelium in a transcellular manner in homeostasis by inducing podosome-like structures. Taken together, vascular endothelial-cadherin is crucial for BM vascular homeostasis but dispensable for the homing of HSPC. These findings are important in the development of potential therapeutic targets to improve HSPC homing strategies.