Specialized blood vessels and nitric oxide found to be key to stem cell survival and immune evasion

An international group of researchers led by Kazuhiro Furuhashi (Nagoya University and Columbia University) and Joji Fujisaki (Harvard University and Columbia University) has identified an important mechanism that enables stem cells to evade immune rejection. Their research, published in Nature, sheds light on how these specialized cells create an “immune-privileged” environment—areas in the body where stem cells survive and function without being attacked by the immune system.

Stem cells are special cells in the body that can divide and turn into different types of cells. This functionality allows them to play roles in the growth, healing, and development of tissues and organs.

Stem cells in immune-privileged sites in the body use multiple mechanisms to inhibit or prevent immune responses against them. This protection is necessary because if the immune system recognizes them as foreign, it may attack them—a common occurrence in autoimmune diseases.

The researchers focused on hematopoietic stem cells (HSCs), which generate blood cells and are often used by clinicians to treat leukemia and inherited blood disorders. Being able to transfer these cells without triggering the patient’s immune response or requiring large amounts of immune-suppressing medicine would be a valuable way to increase their effectiveness.

Scientists have long proposed a ‘hierarchy’ in HSCs that is related to their survivability. At the top of the hierarchy are specialized stem cells that produce nitric oxide (NO), which they use to manipulate the immune response to ensure safe reproduction.

The researchers identified a unique subset of HSCs that express high levels of NO (termed “NOhi HSCs”) and discovered these cells also contain high levels of the immunomodulatory receptor CD200R—a protein that plays a critical role in immune suppression and tolerance.

They also identified that survival of these NOhi HSCs depended on their location near specialized blood vessels that have a distinctive hairpin-curve shape. The scientists concluded that the curved nature of these capillaries affects blood flow dynamics, creating increased shear stress—the force of blood moving along vessel walls. Shear stress regulates the behavior of stem cells by increasing NO levels, which plays an important role in the maintenance, survival, and function of stem cells by modulating cellular signaling pathways.

Combining shear stress and higher NO levels in these specialized capillaries creates an optimal microenvironment. These findings may explain how NOhi HSCs can survive and proliferate while evading immune detection.

Beyond providing insights into stem cell survival, these findings reshape our understanding of blood vessels. They reveal that blood vessels function as “gatekeepers” regulating stem cell activity and immune responses within surrounding tissues—a role that extends far beyond simply transporting blood.

This research should pave the way for advances in regenerative medicine and immunotherapy, highlighting the critical role of blood vessels in maintaining stem cell function and immune balance.

“Understanding how shear stress and immune regulatory molecules influence stem cells could inform the development of new immunosuppressive and anti-inflammatory treatments,” Furuhashi said. “In addition, these findings may revolutionize cancer treatment, as similar mechanisms involving CD200 have been identified in tumor-associated blood vessels, potentially leading to targeted cancer therapies.”

The study, “Bone marrow niches orchestrate stem cell hierarchy and immune tolerance,” was published in Nature on January 1, 2025, at DOI: 10.1038/s41586-024-08352-6.

Authors:

Kazuhiro Furuhashi, Miwako Kakiuchi, Ryosuke Ueda, Hiroko Oda, Simone Ummarino, Alexander K. Ebralidze, Mahmoud A. Bassal, Chen Meng, Tatsuyuki Sato, Jing Lyu, Min-guk Han, Shoichi Maruyama, Yu Watanabe, Yuriko Sawa, Daisuke Kato, Hiroaki Wake, Boris Reizis, John A. Frangos, David M. Owens, Daniel G. Tenen, Ionita C. Ghiran, Simon C. Robson, Joji Fujisaki