RRC ID 52683
著者 Tadokoro Y, Hoshii T, Yamazaki S, Eto K, Ema H, Kobayashi M, Ueno M, Ohta K, Arai Y, Hara E, Harada K, Oshima M, Oshima H, Arai F, Yoshimura A, Nakauchi H, Hirao A.
タイトル Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress.
ジャーナル Cell Stem Cell
Abstract 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.
巻・号 22(5)
ページ 713-725.e8
公開日 2018-5-3
DOI 10.1016/j.stem.2018.04.002
PII S1934-5909(18)30164-4
PMID 29706577
MeSH Adaptor Proteins, Signal Transducing Animals Diet, High-Fat / adverse effects* Hematopoietic Stem Cells / metabolism* Homeostasis* Mice Mice, Inbred Strains Mice, Knockout Oxidative Stress* Repressor Proteins / deficiency Repressor Proteins / metabolism*
IF 20.86
引用数 5
リソース情報
ヒト・動物細胞 OP9(RCB1124)