POT1a deficiency in mesenchymal niches perturbs B-lymphopoiesis

Communications Biology, vol. 6, pp. 996

Abstract

Protection of telomeres 1a (POT1a) is a telomere binding protein. A decrease of POT1a is related to myeloid-skewed haematopoiesis with ageing, suggesting that protection of telomeres is essential to sustain multi-potency. Since mesenchymal stem cells (MSCs) are a constituent of the hematopoietic niche in bone marrow, their dysfunction is associated with haematopoietic failure. However, the importance of telomere protection in MSCs has yet to be elucidated. Here, we show that genetic deletion of POT1a in MSCs leads to intracellular accumulation of fatty acids and excessive ROS and DNA damage, resulting in impaired osteogenic-differentiation. Furthermore, MSC-specific POT1a deficient mice exhibited skeletal retardation due to reduction of IL-7 producing bone lining osteoblasts. Single-cell gene expression profiling of bone marrow from POT1a deficient mice revealed that B-lymphopoiesis was selectively impaired. These results demonstrate that bone marrow microenvironments composed of POT1a deficient MSCs fail to support B-lymphopoiesis, which may underpin age-related myeloid-bias in haematopoiesis.

Authors 15

1. Kentaro Nakashima

   Kyushu University

   Affiliation as printed

   Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

2. Yuya Kunisaki corresponding

   Kyushu University · Kyushu University Hospital

   Affiliation as printed

   Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan. kunisaki.yuya.519@m.kyushu-u.ac.jp

   Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. kunisaki.yuya.519@m.kyushu-u.ac.jp

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kunisaki.yuya.519@m.kyushu-u.ac.jp

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

3. Kentaro Hosokawa

   Kyushu University

   Affiliation as printed

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

4. Kazuhito Gotoh

   Kyushu University

   Affiliation as printed

   Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

5. Hisayuki Yao

   Kyushu University

   Affiliation as printed

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

6. Ryosuke Yuta

   Kyushu University

   Affiliation as printed

   Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

7. Yuichiro Semba

   Kyushu University · Kyushu University Hospital

   Affiliation as printed

   Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

   Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

8. Jumpei Nogami

   Kyushu University · Kyushu University Hospital

   Affiliation as printed

   Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

   Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

9. Yoshikane Kikushige

   Kyushu University · Kyushu University Hospital

   Affiliation as printed

   Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka, Japan

   Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

10. Patrick S. Stumpf Aachen Joint Research Centre for Computational Biomedicine (JRC-COMBINE)

    RWTH Aachen University

    Affiliation as printed

    Joint Research Center for Computational Biomedicine, RWTH Aachen University, Aachen, Germany

11. Ben D. MacArthur

    The Alan Turing Institute · University of Southampton

    Affiliation as printed

    Centre for Human Development, Stem Cells and Regeneration, Faculty of Medicine, University of Southampton, Southampton, UK

    Mathematical Sciences, University of Southampton, Southampton, UK

    The Alan Turing Institute, London, UK

12. Dongchon Kang

    Kyushu University

    Affiliation as printed

    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

13. Koichi Akashi

    Kyushu University

    Affiliation as printed

    Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

14. Shouichi Ohga

    Kyushu University

    Affiliation as printed

    Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

15. Fumio Arai corresponding

    Kyushu University

    Affiliation as printed

    Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. arai.fumio.603@m.kyushu-u.ac.jp

    Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan