Abstract
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.
Highlights
Inflammation is a well recognized mediator of hematopoietic stem and progenitor cell (HSPC) activity
We observed that upregulation of hematopoietic stem cell (HSC) specific genes, most notably PROCR or JAML [23] was highest in the primitive compartment and followed a dose dependency to UM171 (Fig 1E)
We noticed a marked increase in genes encoding MHCassociated proteins, most notably HLA-A and B, as well as beta 2-microglobulin (B2M) in all conditions compared to DMSO in all conditions compared to DMSO (S2D Fig)
Summary
Inflammation is a well recognized mediator of hematopoietic stem and progenitor cell (HSPC) activity. Examples include Toll-Like Receptors (TLR), Tumor Necrosis Factor alpha Most of these inflammation mediators promote the activation of NFkB and subsequent transcriptional induction of proinflammatory genes [3, 4]. Inflammation can either promote HSC expansion or differentiation [5,6,7,8,9,10,11,12,13,14,15,16,17,18].
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