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Title

Remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging

AuthorsHo, Ya-Hsuan; Toro, Raquel del; Rivera-Torres, José; Rak, Justyna; Korn, Claudia; García-García, Andrés; Macías, David; González-Gómez, Cristina; Monte, Alberto del; Wittner, Monika; Waller, Amie K.; Foster, Holly R.; López-Otín, Carlos; Johnson, Randall S.; Nerlov, Claus; Ghevaert, Cedric; Vainchenker, William; Louache, Fawzia; Andrés, Vicente; Méndez-Ferrer, Simón
KeywordsHematopoietic stem cell
Niche
Aging
Microenvironment
Hutchinson-Gilford progeria
Myeloid
Lymphoid
Issue Date2019
PublisherElsevier
CitationCell Stem Cell 25(3): 407-418.e6 (2019)
AbstractHematopoietic 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.
Publisher version (URL)https://doi.org/10.1016/j.stem.2019.06.007
URIhttp://hdl.handle.net/10261/212670
DOI10.1016/j.stem.2019.06.007
Identifiersdoi: 10.1016/j.stem.2019.06.007
issn: 1934-5909
e-issn: 1875-9777
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