Furuhashi et al. · Nature · 2025
Bone marrow niches orchestrate stem-cell hierarchy and immune tolerance
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
The study
What was asked, and what was found
Furuhashi et al., Nature, 2025 asked whether blood stem cells sit in a hierarchy set by the niche they occupy, and whether that hierarchy also decides which of them the immune system leaves alone. The authors separated bone marrow stem cells by how much nitric oxide they make and found that the high nitric oxide fraction is quiescent, immune privileged and slow to start, yet rebuilds blood robustly over time and survives serial transplantation. Three-dimensional imaging of whole-mount bone showed these cells pressed against a class of fine capillary that carries primary cilia and high levels of the immune checkpoint molecule CD200, not against the sinusoids and type H vessels earlier work had named as the niche.
The mechanism ran through the receptor for that checkpoint molecule. To test it directly, the authors sorted stem cells and treated them with a pool of three self-delivering AUMsilence sdASOs against the coding sequence of Cd200r1, alongside an AUM scramble control, at 2.5 μM in culture medium with no transfection reagent. The sequences were designed to avoid overlap with three related receptor isoforms, and those isoforms were confirmed absent from the cells. Messenger RNA was read 48 hours later, and treated cells were held 22 hours before being transplanted into lethally irradiated recipients at 65 stem cells per animal against 220,000 competitor marrow cells.
Knockdown lowered endothelial nitric oxide synthase in the stem cells and abolished the long-term reconstitution the high nitric oxide cells normally give, read as donor chimerism at 16 weeks. Homing to the marrow was unchanged, which separates the ability to arrive from the ability to rebuild and rules out the simplest alternative explanation. The knockdown is the only arm of the study that tests the receptor on the stem cell itself. The capillary and the nitric oxide synthase ends of the axis rest on conditional knockouts.
Key findings
- Knocking down Cd200r1 in sorted mouse haematopoietic stem cells with a pool of self-delivering AUMsilence sdASOs lowered endothelial nitric oxide synthase in those cells and wiped out the long-term reconstitution the high nitric oxide stem cells normally give, while leaving their homing to marrow untouched.(Results, The IFT20-CD200-eNOS-autophagy axis)
- Because homing was unchanged while reconstitution was lost, the knockdown separated a stem cell's ability to reach the marrow from its ability to rebuild blood once there, which is the distinction the niche model needed.(Extended Data Fig. 9 legend, panel j)
- The oligonucleotides were designed against the coding sequence of Cd200r1 while deliberately avoiding overlap with three related receptor isoforms, and the authors confirmed those isoforms were not expressed in the stem cells they studied.(Supplementary Information, Methods, Down-regulation of Cd200r1 using AntiSense Oligonucleotides)
- The wider study describes a previously unreported layer of hierarchy in blood stem cells, in which the most immune privileged and most potent cells sit against a distinct class of capillary rather than against the sinusoids and type H vessels that earlier work had named as the niche.(Abstract)
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