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Cell Stem Cell. 2018 May 3;22(5):713-725.e8. doi: 10.1016/j.stem.2018.04.002. Epub 2018 Apr 26.

Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress.

Author information

1
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: tadokoro@staff.kanazawa-u.ac.jp.
2
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
3
Laboratory of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
4
Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
5
Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin 300020, China.
6
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
7
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
8
Division of Cancer Biology, Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan; Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
9
Department of Human Pathology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8640, Japan.
10
WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
11
Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka 812-8582, Japan.
12
Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
13
Laboratory of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Electronic address: nakauchi@stanford.edu.
14
Division of Molecular Genetics, Cancer and Stem Cell Research Program, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: ahirao@staff.kanazawa-u.ac.jp.

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.

KEYWORDS:

ERK activation; Rho kinase; actin polymerization; hematopoietic stem cell; high-fat diet; microbiota; myeloproliferative neoplasm; self-renewal

PMID:
29706577
DOI:
10.1016/j.stem.2018.04.002

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