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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.

Original publication




Journal article


Cell Stem Cell

Publication Date





407 - 418.e6


Hutchinson-Gilford progeria, aging, hematopoietic stem cell, lymphoid, microenvironment, myeloid, niche, Adrenergic Agonists, Aging, Aging, Premature, Animals, Bone Marrow, Cell Differentiation, Cell Encapsulation, Cell Proliferation, Disease Models, Animal, Hematopoietic Stem Cells, Humans, Interleukin-6, Megakaryocytes, Mice, Myeloid Cells, Nitric Oxide Synthase Type I, Progeria, Receptors, Adrenergic, beta-2, Signal Transduction, Stem Cell Niche