Ho, Ya-HsuanDel Toro, RaquelRivera-Torres, JoséRak, JustynaKorn, ClaudiaGarcía-García, AndrésMacías, DavidGonzález-Gómez, CristinaDel Monte, AlbertoWittner, MonikaWaller, Amie KFoster, Holly RLópez-Otín, CarlosJohnson, Randall SNerlov, ClausGhevaert, CedricVainchenker, WilliamLouache, FawziaAndrés, VicenteMéndez-Ferrer, Simón2025-01-072025-01-072019-07-11https://hdl.handle.net/10668/27543Hematopoietic 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Hutchinson-Gilford progeriaaginghematopoietic stem celllymphoidmicroenvironmentmyeloidnicheAdrenergic AgonistsAgingAging, PrematureAnimalsBone MarrowCell DifferentiationCell EncapsulationCell ProliferationDisease Models, AnimalHematopoietic Stem CellsHumansInterleukin-6MegakaryocytesMiceMyeloid CellsNitric Oxide Synthase Type IProgeriaReceptors, Adrenergic, beta-2Signal TransductionStem Cell Nicheresearch article31303548open access10.1016/j.stem.2019.06.0071875-9777PMC6739444http://www.cell.com/article/S1934590919302711/pdfhttps://pmc.ncbi.nlm.nih.gov/articles/PMC6739444/pdf