Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance

• 成果类型: Article
• 署名作者: Furuhashi, Kazuhiro; Kakiuchi, Miwako; Ueda, Ryosuke; Oda, Hiroko; Ummarino, Simone; Ebralidze, Alexander K.; Bassal, Mahmoud A.; Meng, Chen; Sato, Tatsuyuki; Lyu, Jing; Han, Min-guk; Maruyama, Shoichi; Watanabe, Yu; Sawa, Yuriko; Kato, Daisuke; Wake, Hiroaki; Reizis, Boris; Frangos, John A.; Owens, David M.; Tenen, Daniel G.; Ghiran, Ionita C.; Robson, Simon C.; Fujisaki, Joji
• 署名单位: Columbia University; Columbia University; Nagoya University; Nagoya University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; National University of Singapore; Hubei University of Medicine; Nagoya University; New York University; La Jolla Bioengineering Institute; Columbia University; NewYork-Presbyterian Hospital; NewYork-Presbyterian Hospital; Columbia University; Harvard University; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; Harvard Medical School
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3231
• DOI: 10.1038/s41586-024-08352-6
• 发表日期: 2025-02-01
• 页码: 206-+
• 关键词: hematopoietic stem; nitric-oxide; engraftment; quiescence; privilege; cilia

摘要

Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues(1, 2-3). 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 vessels(2, 3, 4, 5, 6, 7, 8, 9-10) 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.