Regulation of hematopoietic stem cell homeostasis by Spred1

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  • TADOKORO Yuko
    Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University
  • HIRAO Atsushi
    Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University

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Other Title
  • 造血幹細胞の恒常性維持におけるSpred1の役割
  • 第78回日本血液学会学術集会 学会奨励賞受賞論文 造血幹細胞の恒常性維持におけるSpred1の役割
  • ダイ78カイ ニホン ケツエキ ガッカイ ガクジュツ シュウカイ ガッカイ ショウレイショウ ジュショウ ロンブン ゾウケツ カンサイボウ ノ コウジョウセイ イジ ニ オケル Spred1 ノ ヤクワリ

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Abstract

<p>Various types of stresses account for the dysregulation of the self-renewal activity of stem cells, resulting in the functional failure of tissues or tumorigenesis promotion. Although diets also affect our health, the effect of harmful dietary stresses on the tissue or stem cell homeostasis remains unclear. Recent research has revealed that Spred1, which negatively regulates RAS-MAPK signaling, protects hematopoietic stem cell (HSC) homeostasis against high-fat diet (HFD) -induced systemic stress. In steady-state conditions, Spred1 negatively regulates HSC self-renewal in a manner supported by the Rho kinase (ROCK) activity. In addition, Spred1 deficiency in mice mitigates HSC dysfunction induced by aging or lipopolysaccharide treatment, enhances the HSC self-renewal capacity, and prolongs HSC lifespan, but does not induce leukemia because of the compensatory upregulation of Spred2—the other Spred family member. Conversely, HFD triggers ERK hyperactivation and aberrant self-renewal in Spred1-deficient HSCs, resulting in HSC dysfunction, severe anemia, and the development of lethal myeloproliferative neoplasm-like disease. The depletion of the gut microbiota by antibiotics restored myeloproliferation, anemia, and HSC reconstitution ability in HFD-fed Spred1-deficient mice, suggesting that HFD-induced hematopoietic abnormalities were partially because of alterations in the gut microbiota composition. Thus, HFD-induced systemic stress affects the regulation of HSC self-renewal, and Spred1 safeguards HSC homeostasis against the diet-induced systemic stress.</p>

Journal

  • Rinsho Ketsueki

    Rinsho Ketsueki 59 (11), 2441-2448, 2018

    The Japanese Society of Hematology

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