Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance

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 and Joji Fujisaki ()
Additional contact information
Kazuhiro Furuhashi: Columbia University Vagelos College of Physicians and Surgeons
Miwako Kakiuchi: Columbia University Vagelos College of Physicians and Surgeons
Ryosuke Ueda: Columbia University Vagelos College of Physicians and Surgeons
Hiroko Oda: Harvard Medical School
Simone Ummarino: Harvard Medical School
Alexander K. Ebralidze: Harvard Medical School
Mahmoud A. Bassal: Harvard Medical School
Chen Meng: Harvard Medical School
Tatsuyuki Sato: Harvard Medical School
Jing Lyu: Harvard Medical School
Min-guk Han: Harvard Medical School
Shoichi Maruyama: Nagoya University Graduate School of Medicine
Yu Watanabe: Nagoya University Graduate School of Medicine
Yuriko Sawa: Nagoya University Graduate School of Medicine
Daisuke Kato: Nagoya University Graduate School of Medicine
Hiroaki Wake: Nagoya University Graduate School of Medicine
Boris Reizis: New York University
John A. Frangos: La Jolla Bioengineering Institute
David M. Owens: Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons
Daniel G. Tenen: Harvard Medical School
Ionita C. Ghiran: Harvard Medical School
Simon C. Robson: Harvard Medical School
Joji Fujisaki: Columbia University Vagelos College of Physicians and Surgeons

Nature, 2025, vol. 638, issue 8049, 206-215

Abstract: Abstract Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1–3. The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NOhi) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NOhi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NOhi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels2–10 co-localize with less immune-privileged and less potent NOlow HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets.

Date: 2025
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DOI: 10.1038/s41586-024-08352-6

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