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

PLoS One. 2019 Nov 8;14(11):e0224900. doi: 10.1371/journal.pone.0224900. eCollection 2019.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell Differentiation
  • Cell Proliferation
  • Cell Self Renewal / drug effects*
  • Gene Expression Profiling
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism*
  • Homeostasis / drug effects*
  • Humans
  • Indoles / pharmacology*
  • Metabolic Detoxication, Phase I
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species
  • Signal Transduction / drug effects
  • Transcriptome

Substances

  • Biomarkers
  • Indoles
  • Pyrimidines
  • Reactive Oxygen Species
  • UM171 compound

Grant support