美国哥伦比亚大学Joji Fujisaki研究团队发现，骨髓微环境调控干细胞层级与免疫耐受性。相关论文于2025年1月1日在线发表在《自然》杂志上。

研究人员描述了在造血干细胞（HSC）和骨髓微环境中之前未知的新层级排列，这些排列决定了再生潜力和免疫特权。高水平的生成一氧化氮（NO^hi）HSC对免疫攻击具有抵抗力，并展现出延迟但强劲的长期重建能力。这些高度免疫特权的原始NO^hi HSC与具有原生纤毛内皮和高水平免疫检查点分子CD200的独特毛细血管共同定位。

这些毛细血管通过纤毛蛋白IFT20以及CD200、内皮一氧化氮合酶和自噬信号调控NO^hi HSC的再生功能，从而进一步介导免疫保护。值得注意的是，先前描述的栖息地成分，如窦状细胞和H型血管，与免疫特权较低且功能较弱的NO^low HSC共同定位。

总的来说，研究人员识别了具有高度免疫特权的、晚期上升的原始HSC，并表征了其免疫保护栖息地，这些栖息地包括特化的血管区域。这些研究结果表明，栖息地在干细胞层级和免疫耐受性中起着调控作用，并强调了未来免疫治疗的潜在靶点。

研究人员表示，干细胞栖息在组织中多个不同位置的特化微环境中，这些微环境被称为“栖息地”。干细胞和栖息地的不同功能变得尤为重要，因为干细胞移植和免疫疗法的临床应用日益增多。不同栖息地中的干细胞是否存在层级结构，并进一步调控免疫耐受性，目前尚不清楚。

附：英文原文

Title: Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance

Author: 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

Issue&Volume: 2025-01-01

Abstract: Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues1,2,3. 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 vessels2,3,4,5,6,7,8,9,10 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.

DOI: 10.1038/s41586-024-08352-6

Source: https://www.nature.com/articles/s41586-024-08352-6