UM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal

• DOI: 10.1371/journal.pone.0224900
• Publication Date: 2019-11-08T13:30:47Z
• Authors: Jalila Chagraoui; Bernhard Lehnertz; Simon Girard; Jean Francois Spi...; Iman Fares; Elisa Tomellini; Nadine Mayotte; Sophie Corneau; Tara MacRae; Laura Simon; Guy Sauvageau
• Keywords: Hematopoietic stem cell; Ex vivo; Detoxification; Proinflammatory cytokine

Elucidation of the molecular cues required to balance adult stem cell self-renewal and differentiation is critical for advancing cellular therapies. Herein, we report that hematopoietic (HSC) agonist UM171 triggers a balanced pro- anti-inflammatory/detoxification network relies on NFKB activation protein C receptor-dependent ROS detoxification, respectively. We demonstrate within this network, EPCR serves as protective component its deletion hypersensitizes primitive cells pro-inflammatory signals accumulation resulting in compromised function. Conversely, abrogation activity through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes upregulation HSC expansion. Together, these results show stimulates ex vivo expansion by establishing between key anti-inflammatory mediators self-renewal.