title: Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells' homeostasis.
abstract: Hematopoietic stem and progenitor cell (HSPC) homeostasis declines with age, leading to impaired hematopoiesis. Mesenchymal stromal cells (MSC) are critical components of the bone marrow niche and key regulators of the balance between HSPC proliferation and quiescence. Accrual of DNA damage, a hallmark of cellular aging, occurs in aged MSC. Whether MSC aging alters the bone marrow niche triggering HSPC dysfunction is unknown. Using a human MSC-HSPC co-culture system, we demonstrated that DNA damaged MSC have impaired capacity to maintain CD34+CD38- HSPC quiescence. Furthermore, human MSC from adult donors display some hallmarks of cellular senescence and have a decreased capacity to maintain HSPC quiescence and the most primitive CD34+CD38- subset compared to MSC from pediatric donors. IL-6 neutralization restores the MSC-HPSC crosstalk in senescent and adult MSC-HSPC co-cultures highlighting the relevance of the local microenvironment in maintaining HSPC homeostasis. These results provide new evidence implicating components of the MSC secretome in HSPC aging.
authors.affiliation: Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Kelsey
authors.initials: K
authors.lastname: O'Hagan-Wong
authors.affiliation: CRCHUM and Institut du Cancer de Montréal, Montreal, QC, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Nadeau
authors.affiliation: CRCHUM and Institut du Cancer de Montréal, Montreal, QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Carrier-Leclerc
authors.affiliation: Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Felipe
authors.initials: F
authors.lastname: Apablaza
authors.affiliation: Shriners Hospital for Children and Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada.
authors.forename: Reggie
authors.initials: R
authors.lastname: Hamdy
authors.affiliation: Divisions of Cardiac Surgery and Surgical Research, McGill University, Montreal, QC, Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Shum-Tim
authors.affiliation: CRCHUM and Institut du Cancer de Montréal, Montreal, QC, Canada.|Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Francis
authors.initials: F
authors.lastname: Rodier
authors.affiliation: Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: Inés
authors.initials: I
authors.lastname: Colmegna
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D008875:Middle Aged
chemical_list: D018952:Antigens, CD34; D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6
keywords: Gerotarget; aging; hematopoietic stem and progenitor cells; mesenchymal stromal cells; senescence; senescence-associated secretory phenotype