Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes defines survival threshold in erythroid progenitor cells

Cell Rep. 2021 Aug 10;36(6):109507. doi: 10.1016/j.celrep.2021.109507.

Abstract

Survival or apoptosis is a binary decision in individual cells. However, at the cell-population level, a graded increase in survival of colony-forming unit-erythroid (CFU-E) cells is observed upon stimulation with erythropoietin (Epo). To identify components of Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5) signal transduction that contribute to the graded population response, we extended a cell-population-level model calibrated with experimental data to study the behavior in single cells. The single-cell model shows that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of Epo receptor (EpoR):JAK2 complexes and of SHP1, as well as the extent of nuclear import because of the large variance in the cytoplasmic volume of CFU-E cells. 24-118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes is sufficient to convert a switch-like behavior at the single-cell level to a graded population-level response.

Keywords: CFU-E cells; Epo; JAK/STAT; apoptosis; cell fate decision; heterogeneity; mathematical modeling; signal transduction; single-cell modeling; transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calibration
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Computer Simulation
  • Cytoplasm / metabolism*
  • Erythroid Precursor Cells / cytology*
  • Erythroid Precursor Cells / metabolism*
  • Erythropoietin / pharmacology
  • Janus Kinase 2 / metabolism*
  • Mice, Inbred BALB C
  • Models, Biological
  • Phosphorylation / drug effects
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction* / drug effects

Substances

  • STAT5 Transcription Factor
  • Erythropoietin
  • Janus Kinase 2