Publication — IRIC

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

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.

Publication date
November 17, 2019
Principal Investigators
Chagraoui J, Lehnertz B, Girard S, Spinella JF, Fares I, Tomellini E, Mayotte N, Corneau S, MacRae T, Simon L, Sauvageau G
PubMed reference
PLoS ONE 2019;14(11):e0224900
PubMed ID
31703090
Affiliation
Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada.