Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress
Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress
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DOI：
10.1016/j.stem.2018.04.002
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发表时间：
2018-05-03
期刊：
影响因子：
23.9
通讯作者：
Hirao, Atsushi
中科院分区：
文献类型：
--
作者：
Tadokoro, Yuko;Hoshii, Takayuki;Hirao, Atsushi
干细胞的自我更新对于组织的稳态是至关重要的，其失调可导致器官衰竭或肿瘤发生。虽然肥胖可以诱导骨髓成分的各种异常，但尚不清楚饮食如何影响造血干细胞（HSC）的自我更新。在这里，我们表明，Spread 1，RAS-MAPK信号的负调节，保障HSC的稳态在高脂饮食（HFD）的动物。在稳态条件下，Spread 1负调控HSC自我更新和适应性，部分通过Rho激酶活性。Spread 1缺陷减轻感染模拟物诱导的HSC衰竭和延长HSC寿命，但由于Spread 2的代偿性上调，它不会引发白血病发生。相反，HFD诱导ERK过度活化和Spread 1缺陷HSC的异常自我更新，导致功能性HSC衰竭、严重贫血和骨髓增生性肿瘤样疾病。HFD诱导的造血异常部分是通过肠道微生物群的改变介导的。总之，这些发现表明，饮食诱导的应激破坏了Spread 1介导的信号的微调，以控制HSC的稳态。
Stem cell self-renewal is critical for tissue homeostasis, and its dysregulation can lead to organ failure or tumorigenesis. While obesity can induce varied abnormalities in bone marrow components, it is unclear how diet might affect hematopoietic stem cell (HSC) self-renewal. Here, we show that Spred1, a negative regulator of RAS-MAPK signaling, safeguards HSC homeostasis in animals fed a high-fat diet (HFD). Under steady-state conditions, Spred1 negatively regulates HSC self-renewal and fitness, in part through Rho kinase activity. Spred1 deficiency mitigates HSC failure induced by infection mimetics and prolongs HSC lifespan, but it does not initiate leukemogenesis due to compensatory upregulation of Spred2. In contrast, HFD induces ERK hyperactivation and aberrant self-renewal in Spred1-deficient HSCs, resulting in functional HSC failure, severe anemia, and myeloproliferative neoplasm-like disease. HFD-induced hematopoietic abnormalities are mediated partly through alterations to the gut microbiota. Together, these findings reveal that diet-induced stress disrupts fine-tuning of Spred1-mediated signals to govern HSC homeostasis.