Increased IL-6 secretion by aged human mesenchymal stromal cells disrupts hematopoietic stem and progenitor cells' homeostasis

// Kelsey O’Hagan-Wong 1 , Stéphanie Nadeau 2 , Audrey Carrier-Leclerc 2 , Felipe Apablaza 1 , Reggie Hamdy 3 , Dominique Shum-Tim 4 , Francis Rodier 2,5 and Inés Colmegna 1 1 Division of Rheumatology, Department of Medicine, McGill University, Montreal, QC, Canada 2 CRCHUM and Institut du Cancer de Montréal, Montreal, QC, Canada 3 Shriners Hospital for Children and Division of Orthopedic Surgery, McGill University, Montreal, QC, Canada 4 Divisions of Cardiac Surgery and Surgical Research, McGill University, Montreal, QC, Canada 5 Department of Radiology, Radio-Oncology and Nuclear Medicine, Université de Montréal, Montreal, QC, Canada Correspondence to: Inés Colmegna, email: // Francis Rodier, email: // Keywords : mesenchymal stromal cells, hematopoietic stem and progenitor cells, aging, senescence(definition), senescence-associated secretory phenotype, Gerotarget Received : January 06, 2016 Accepted : January 30, 2016 Published : February 24, 2016 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.