Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress

Yuko Tadokoro, Takayuki Hoshii, Satoshi Yamazaki, Koji Eto, Hideo Ema, Masahiko Kobayashi, Masaya Ueno, Kumiko Ohta, Yuriko Arai, Eiji Hara, Kenichi Harada, Masanobu Oshima, Hiroko Oshima, Fumio Arai, Akihiko Yoshimura, Hiromitsu Nakauchi, Atsushi Hirao

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Tadokoro et al. show that Spred1 negatively regulates HSC self-renewal in a manner supported by ROCK activity and that Spred1 safeguards HSC homeostasis under high-fat diet (HFD) conditions by regulating HSC self-renewal. The gut microbiota dysbiosis induced by HFD disrupts the fine-tuning of Spred1-mediated signals that govern HSC homeostasis.

Original languageEnglish
Pages (from-to)713-725.e8
JournalCell stem cell
Volume22
Issue number5
DOIs
Publication statusPublished - May 3 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Cell Biology

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  • Cite this

    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. (2018). Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress. Cell stem cell, 22(5), 713-725.e8. https://doi.org/10.1016/j.stem.2018.04.002