Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/8331
Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging
Ho, Ya-Hsuan | Del Toro, Raquel CNIC | Rivera-Torres, Jose CNIC | Rak, Justyna | Korn, Claudia | Garcia-Garcia, Andres CNIC | Macías, David | Gonzalez-Gomez, Cristina CNIC | del Monte, Alberto CNIC | Wittner, Monika | Waller, Amie K | Foster, Holly R | López-Otín, Carlos | Johnson, Randall S | Nerlov, Claus | Ghevaert, Cedric | Vainchenker, William | Louache, Fawzia | Andres, Vicente CNIC | Mendez-Ferrer, Simon CNIC
Cell Stem Cell. 2019; 25(3):407-18
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.
Hutchinson-Gilford progeria | Aging | Hematopoietic stem cell | Lymphoid | Microenvironment | Myeloid | Niche