Open AccessUM171 induces a homeostatic inflammatory-detoxification response supporting human HSC self-renewal
Author(s) -
Jalila Chagraoui,
Bernhard Lehnertz,
Simon Girard,
Jean François Spinella,
Iman Fares,
Elisa Tomellini,
Nadine Mayotte,
Sophie Corneau,
Tara MacRae,
Laura Simon,
Guy Sauvageau
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0224900
Subject(s) - downregulation and upregulation , microbiology and biotechnology , stem cell , haematopoiesis , hematopoietic stem cell , ex vivo , biology , detoxification (alternative medicine) , inflammation , proinflammatory cytokine , immunology , chemistry , in vivo , medicine , biochemistry , alternative medicine , pathology , gene
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 the hematopoietic stem cell (HSC) self-renewal agonist UM171 triggers a balanced pro- and anti-inflammatory/detoxification network that relies on NFKB activation and protein C receptor-dependent ROS detoxification, respectively. We demonstrate that within this network, EPCR serves as a critical protective component as its deletion hypersensitizes primitive hematopoietic cells to pro-inflammatory signals and ROS accumulation resulting in compromised stem cell function. Conversely, abrogation of the pro-inflammatory activity of UM171 through treatment with dexamethasone, cAMP elevating agents or NFkB inhibitors abolishes EPCR upregulation and HSC expansion. Together, these results show that UM171 stimulates ex vivo HSC expansion by establishing a critical balance between key pro- and anti-inflammatory mediators of self-renewal.