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

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 in...

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Detalles Bibliográficos
Autores: Ho, 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/212670
Acceso en línea:http://hdl.handle.net/10261/212670
Access Level:acceso abierto
Palabra clave:Hematopoietic stem cell
Niche
Aging
Microenvironment
Hutchinson-Gilford progeria
Myeloid
Lymphoid
Descripción
Sumario: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.

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