Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department for BioMedical Research, University of Bern, Bern, Switzerland.
Nat Commun. 2021 Feb 16;12(1):1065. doi: 10.1038/s41467-021-21317-x.
The production of blood cells during steady-state and increased demand depends on the regulation of hematopoietic stem cell (HSC) self-renewal and differentiation. Similarly, the balance between self-renewal and differentiation of leukemia stem cells (LSCs) is crucial in the pathogenesis of leukemia. Here, we document that the TNF receptor superfamily member lymphotoxin-β receptor (LTβR) and its ligand LIGHT regulate quiescence and self-renewal of murine and human HSCs and LSCs. Cell-autonomous LIGHT/LTβR signaling on HSCs reduces cell cycling, promotes symmetric cell division and prevents primitive HSCs from exhaustion in serial re-transplantation experiments and genotoxic stress. LTβR deficiency reduces the numbers of LSCs and prolongs survival in a murine chronic myeloid leukemia (CML) model. Similarly, LIGHT/LTβR signaling in human G-CSF mobilized HSCs and human LSCs results in increased colony forming capacity in vitro. Thus, our results define LIGHT/LTβR signaling as an important pathway in the regulation of the self-renewal of HSCs and LSCs.
在稳态和需求增加时，血细胞的生成取决于造血干细胞（HSC）自我更新和分化的调节。同样，白血病干细胞（LSC）自我更新和分化之间的平衡对于白血病的发病机制至关重要。在这里，我们记录了 TNF 受体超家族成员淋巴毒素-β 受体（LTβR）及其配体 LIGHT 调节小鼠和人类 HSC 和 LSC 的静止和自我更新。HSC 上的自主 LIGHT/LTβR 信号会减少细胞周期，促进对称分裂，并防止原始 HSC 在连续再移植实验和遗传毒性应激中衰竭。LTβR 缺陷会减少 LSC 的数量并延长小鼠慢性髓性白血病（CML）模型中的存活时间。同样，在 G-CSF 动员的人类 HSCs 和人类 LSCs 中 LIGHT/LTβR 信号会导致体外集落形成能力增加。因此，我们的结果将 LIGHT/LTβR 信号定义为调节 HSC 和 LSC 自我更新的重要途径。
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