Discovery of a New Mechanism Regulating Hematopoietic Stem Cell Function

A research group led by Lecturer Kazuhiro Furuhashi from the Department of Nephrology at Nagoya University Hospital has revealed that “hematopoietic stem cells that express high amounts of NO (nitric oxide)” (NO^hiHSCs) present in the hairpin-shaped capillary regions within bone marrow evade attacks from immune cells while remaining dormant under physiological conditions, yet exhibit high long-term regenerative capacity upon transplantation. Furthermore, through 3D imaging of the bone marrow, the group became the first in the world to demonstrate that the hairpin-shaped capillary endothelial cells, where NO^hiHSCs predominantly reside, highly express the immune regulatory molecule CD200, and that this CD200 expression is regulated by stimulating primary cilia, which are shear stress sensors. They showed that vascular endothelium with high CD200 expression creates a special place that sustains NO^hiHSC function.

These findings indicate that blood vessels are not merely pathways for blood, but actively utilize the fluid mechanical stimuli of blood flow to create an environment that appropriately maintains stem cells. The results are promising for applications in regenerative medicine and immunosuppressive therapies.

The Mystery of Hematopoietic Stem Cell Location and Immune Privilege

Hematopoietic stem cells are the cells responsible for producing all blood cells, including red blood cells and white blood cells, and their existence within bone marrow has long been established. However, bone marrow has a complex, spongy architecture, and no unified consensus had been reached regarding the precise regions where hematopoietic stem cells are located.

Furthermore, hematopoietic stem cells are notably more resistant to elimination by immune cells. This is regarded as one of the key reasons why hematopoietic stem cells can be protected over extended periods in so-called “immune-privileged” sites, enabling them to regenerate blood when needed. Nevertheless, the specific reasons why immune cells do not attack them, the non-immunological effects exerted by immune cells on stem cells, and the specific mechanisms that enable this protection were unresolved

Identification of NO^hi HSCs as a subset of primitive HSCs and their specific regulatory mechanisms

NO^hiHSCs present in hairpin-shaped capillary regions

The research group focused on the observation that, when hematopoietic stem cells were transplanted into allogeneic mice that lacked transplant compatibility, a portion of these stem cells survived in the bone marrow without eliciting rejection responses. Upon examining the regions where surviving hematopoietic stem cells were abundant, they determined that these were predominantly the hairpin-shaped capillary areas located at the bone ends (Fig. 1).

These vessels are considered sites exposed to strong shear stress^*1, and because the hematopoietic stem cells located there showed high expression of NO (nitric oxide), the research group designated these cells as NO^hiHSCs.

*1 Shear stress
The mechanical force exerted by flowing fluid as it rubs against cells or tissue

NO^hiHSCs possess high regenerative capability

NO^hiHSCs constitute 10 to 15% of the total hematopoietic stem cell population and were found to express high levels of immune regulatory molecules such as CD39 and PD-L1, along with the receptor CD200R that binds to CD200. Furthermore, NO^hiHSCs typically remain in a dormant state and evade immune cell attacks under physiological conditions, but upon transplantation, they demonstrate the ability to regenerate blood cells over an extended period.

Vascular endothelium serves as a place for maintaining hematopoietic stem cells

Hairpin-shaped capillaries are abundant around the ends of bones and exhibit particularly high expression of CD200. These CD200-positive vessels express primary cilia that sense shear stress (Fig. 2).

In contrast, analysis of mouse vascular endothelium that was deficient in either primary cilia or CD200 showed that NO^hiHSC properties were not maintained. These findings indicate that primary cilia receive shear stress, thereby inducing CD200 expression in vessels. Furthermore, these vessels are shown to maintain the NO expression and stem cell properties of NO^hiHSCs through the CD200.

Applications in Research on Regenerative Medicine, Cancer Stem Cells, and Immune Regulation

This study has demonstrated that shear stress caused by blood flow creates an environment appropriate for the maintenance of hematopoietic stem cells, thereby regulating their dormancy and regenerative potential. These findings extend beyond hematopoietic stem cells and are applicable to a wide range of other stem cell types. Novel therapeutic strategies that promote tissue regeneration by manipulating the perivascular microenvironment are anticipated. Furthermore, cancer stem cells are known to reside close to blood vessels within tumor tissues, and the mechanisms shown in this study may inform the development of targeted therapies against cancer stem cells. Additionally, the observation that immune regulatory molecules are highly expressed in vessels exposed to strong shear stress is expected to contribute to new pharmacological developments for inflammation control and the preservation of healthy tissue.