Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging.
Del Toro, Raquel
Cell stem cell
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Ho, Y., Del Toro, R., Rivera-Torres, J., Rak, J., Korn, C., García-García, A., Macías, D., et al. (2019). Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging.. Cell stem cell, 25 (3), 407-418.e6. https://doi.org/10.1016/j.stem.2019.06.007
Hematopoietic stem cells (HSCs) residing in the 32 bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem/niche cells is unknown. Here we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes -adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced - AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with -agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
Hematopoietic Stem Cells, Megakaryocytes, Myeloid Cells, Bone Marrow, Animals, Humans, Mice, Progeria, Disease Models, Animal, Aging, Premature, Receptors, Adrenergic, beta-2, Adrenergic Agonists, Interleukin-6, Signal Transduction, Cell Differentiation, Cell Proliferation, Aging, Nitric Oxide Synthase Type I, Stem Cell Niche, Cell Encapsulation
We thank A.R. Green for advice and support; M. García-Fernández, C. Fielding, C. Kapeni, X. Langa, and other current and former members of the S.M.-F group for help and discussions; A. Barettino and A. Macías (CNIC), D. Pask, T. Hamilton, the Central Biomedical Services and Cambridge NIHR BRC Cell Phenotyping Hub for technical assistance; H. Jolin and A.N.J. McZenzie (MRC Laboratory of Molecular Biology, Cambridge, UK) for help with milliplex analyses. Y.-H.O. received fellowships from Alborada Scholarship (University of Cambridge), Trinity-Henry Barlow Scholarship (University of Cambridge) and R.O.C. Government Scholarship to Study Abroad (GSSA) A.G.G. received fellowships from Ramón Areces and LaCaixa Foundations. C.K. was supported by Marie Curie Career Integration grant H2020-MSCA-IF-2015-70841. S.M.F., by Red TerCel (ISCIII-Spanish Cell Therapy Network). VA is supported by grants from the Spanish Ministerio de Economía, Industria y Competitividad (MEIC) with cofunding from the Fondo Europeo de Desarrollo Regional (FEDER, “Una manera de hacer Europa”) (SAF2016-79490-R), the Instituto de Salud Carlos III (AC16/00091), the Fundació Marató TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014–52). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovación y Universidades (MCNU) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was supported by core support grants from the Wellcome Trust and the MRC to the Cambridge Stem Cell Institute, the Spanish Ministry of Economy and Competitiveness (SAF-2011-30308), Ramón y Cajal Program grant RYC-2009-04703, ConSEPOC-Comunidad de Madrid S2010/BMD-2542, National 427 Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 428 2020 research (ERC-2014-CoG-64765 and Marie Curie Career Integration grant FP7- 429 PEOPLE-2011-RG-294096) and a Programme Foundation Award from Cancer Research 430 UK to S.M.-F., who was also supported in part by an International Early Career Scientist 431 grant of the Howard Hughes Medical Institute.
ECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (648765)
Wellcome Trust (092738/Z/10/Z)
NHS Blood and Transplant (NHSBT) ()
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (708411)
Cancer Research UK (C61367/A26670)
Cancer Research UK (A27831)
National Cancer Institute (NCI) (R01CA153983)
European Commission (331756)
Wellcome Trust (214283/Z/18/Z)
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External DOI: https://doi.org/10.1016/j.stem.2019.06.007
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293795
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/