Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Cell Stem Cell. 2019 Sep 5;25(3):407-418.e6. doi: 10.1016/j.stem.2019.06.007. Epub 2019 Jul 11.


Hematopoietic stem cells (HSCs) residing in the 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 or 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 β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR 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.

Keywords: Hutchinson-Gilford progeria; aging; hematopoietic stem cell; lymphoid; microenvironment; myeloid; niche.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Agonists / administration & dosage
  • Aging / metabolism
  • Aging / physiology*
  • Aging, Premature / metabolism
  • Aging, Premature / pathology*
  • Animals
  • Bone Marrow / physiology*
  • Cell Differentiation
  • Cell Encapsulation
  • Cell Proliferation
  • Disease Models, Animal
  • Hematopoietic Stem Cells / physiology*
  • Humans
  • Interleukin-6 / metabolism
  • Megakaryocytes / physiology*
  • Mice
  • Myeloid Cells / physiology*
  • Nitric Oxide Synthase Type I / metabolism
  • Progeria / metabolism
  • Progeria / pathology*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Signal Transduction
  • Stem Cell Niche


  • ADRB2 protein, mouse
  • Adrenergic Agonists
  • Interleukin-6
  • Receptors, Adrenergic, beta-2
  • Nitric Oxide Synthase Type I