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


  • Ho, Ya-Hsuan
  • del Toro, Raquel
  • Rivera-Torres, José
  • Rak, Justyna
  • Korn, Claudia
  • García-García, Andrés 
  • Macías, David
  • González-Gómez, Cristina
  • del Monte, Alberto
  • Wittner, Monika
  • Waller, Amie K.
  • Foster, Holly R.
  • López-Otín, Carlos
  • Johnson, Randall S.
  • Nerlov, Claus
  • Ghevaert, Cedric
  • Vainchenker, William
  • Louache, Fawzia
  • Méndez-Ferrer, Simón

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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.

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Published by Cell Stem Cell