Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

• Published in: Cell stem cell Vol. 25; no. 3; pp. 407 - 418.e6
• Main Authors: Ho, Ya-Hsuan, del Toro, Raquel, Rivera-Torres, José, Rak, Justyna, Korn, Claudia, García-García, Andrés, Macías, David, González-Gómez, Cristina, del Monte, Alberto, 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.09.2019; Cambridge, MA : Cell Press; Cell Press
• Subjects: Adrenergic Agonists - administration & dosage; aging; Aging - metabolism; Aging - physiology; Aging, Premature - metabolism; Aging, Premature - pathology; Animals; Bone Marrow - physiology; Cell Differentiation; Cell Encapsulation; Cell Proliferation; Cellular Biology; Disease Models, Animal; hematopoietic stem cell; Hematopoietic Stem Cells - physiology; Humans; Hutchinson-Gilford progeria; Interleukin-6 - metabolism; Life Sciences; lymphoid; Medicin och hälsovetenskap; Megakaryocytes - physiology; Mice; microenvironment; myeloid; Myeloid Cells - physiology; niche; Nitric Oxide Synthase Type I - metabolism; Progeria - metabolism; Progeria - pathology; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction; Stem Cell Niche; Subcellular Processes; microenvironment; myeloid; hematopoietic stem cell; niche; aging; lymphoid; Hutchinson-Gilford progeria
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2019.06.007

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. [Display omitted] •Reduction of endosteal BM and expansion of non-endosteal BM occurs with age•β2/β3-ARs exhibit opposite and niche-dependent regulation of myelopoiesis•β2-AR overriding β3-AR promotes myeloid expansion during physiological aging•Premature HSC aging in HGPS can be improved by targeting the microenvironment Recent studies have suggested a microenvironmental contribution to stem-cell aging, but the mechanisms are largely unexplored. Méndez-Ferrer et al. report anatomical remodeling of blood-stem-cell-supporting niches and functional switch of β adrenergic signals, leading to myeloid expansion during aging. Targeting the microenvironment can improve pathological, premature, niche-dependent hematopoietic aging in mice.