Ho, Ya-HsuanDel Toro, RaquelRivera-Torres, JoseRak, JustynaKorn, ClaudiaGarcia-Garcia, AndresMacías, DavidGonzalez-Gomez, Cristinadel Monte, AlbertoWittner, MonikaWaller, Amie KFoster, Holly RLópez-Otín, CarlosJohnson, Randall SNerlov, ClausGhevaert, CedricVainchenker, WilliamLouache, FawziaAndres, VicenteMendez-Ferrer, Simon2019-09-112019-09-112019-09-05Cell Stem Cell. 2019; 25(3):407-1819345909http://hdl.handle.net/20.500.12105/8331Hematopoietic 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.engVoRhttp://creativecommons.org/licenses/by/4.0/Hutchinson-Gilford progeriaAgingHematopoietic stem cellLymphoidMicroenvironmentMyeloidNicheAtribución 4.0 Internacional31303548253407-418.e610.1016/j.stem.2019.06.0071875-9777Cell stem cellopen access