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


Autoři: Jalila Chagraoui aff001;  Bernhard Lehnertz aff001;  Simon Girard aff001;  Jean Francois Spinella aff001;  Iman Fares aff002;  Elisa Tomellini aff001;  Nadine Mayotte aff001;  Sophie Corneau aff001;  Tara MacRae aff001;  Laura Simon aff001;  Guy Sauvageau aff001
Působiště autorů: Molecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada aff001;  Department of Molecular, Cell and Developmental Biology, UCLA, LA, United States of America aff002;  Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada aff003;  Department of Medicine, Faculty of Medicine, University de Montreal, Montreal, QC, Canada aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224900

Souhrn

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.

Klíčová slova:

Blood cells – Cytokines – Flow cytometry – Gene expression – Inflammation – Nitric oxide – Hematopoietic stem cells – Detoxification


Zdroje

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