CAR cells drive hematopoiesis

Kyoto, Japan -

It is an established fact that administration of bone marrow hematopoietic cells systemically leads to their homing to the recipient bone marrow due in part to constitutive secretion of the cytokine SDF-1, otherwise known as CXCL12, by the bone marrow stroma. It is also known that tissue injury, whether by a pathological event such as a heart attack, or stroke, also results in bone marrow derived stem cells to home to the area of injury, in part due to a gradient of CXCL-12 secreted by the injured tissue.

A recent paper (Sugiyama et al. Maintenance of the Hematopoietic Stem Cell Pool by CXCL12-CXCR4 Chemokine Signaling in Bone Marrow Stromal Cell Niches. Immunity. 2006 Dec;25(6):977-88) examined the importance of CXCL-12, and its receptor, CXCR-4 in the mouse hematopoietic system.

Using an elegant model of "induced deletion" (that is the gene was deleted after the animal reached a certain age), it was demonstrated that ablation of CXCR4 resulted in a substantial fall in numbers of hematopoietic stem cells, as well as made the mice more sensitive to injury of the myeloid compartment. This finding, perhaps is not that surprising since the hematopoietic stem cells need to stay in the bone marrow microenvironment to be active.

What was surprising, was the discovery of a special cell population that surrounds the marrow sinusoidal endothelial cell, which the investigators called "CXCL12-abundant reticular (CAR) cells". It appears that these cells are the main reason why peripherally injected hematopoietic stem cells always home to the bone marrow.

In all cases the early hematopoietic stem cells were found to be residing in direct contact with CAR cells. Additionally, the CAR cells were by far the highest producers of CXCL12 of all the bone marrow cells.

Understanding methods of expanding and using these CAR cells may lead to novel means of accelerating stem cell engraftment, as well as selectively guiding stem cells to injured tissue.