Interleukin-8 Dedifferentiates Primary Human Luminal Cells to Multipotent Stem Cells

Mol Cell Biol. 2020 Apr 13;40(9):e00508-19. doi: 10.1128/MCB.00508-19. Print 2020 Apr 13.

Abstract

During aging, cellular plasticity and senescence play important roles in tissue regeneration and the pathogenesis of different diseases, including cancer. We have recently shown that senescent breast luminal cells can activate their adjacent stromal fibroblasts. In the present report, we present clear evidence that these senescence-related active fibroblasts can dedifferentiate proliferating primary human luminal cells to multipotent stem cells in an interleukin-8 (IL-8)-dependent manner. This was confirmed using recombinant IL-8, while the truncated protein was not active. This IL-8-related dedifferentiation of luminal cells was mediated through the STAT3-dependent downregulation of p16INK4A and the microRNA miR-141. Importantly, these in vitro-generated mammary stem cells exhibited high molecular and cellular similarities to human mammary stem cells. They have also shown a long-term mammary gland-reconstituting ability and the capacity to produce milk postdelivery. Thereby, these IL-8-generated mammary stem cells could be of great value for autologous cell therapy procedures and also for biomedical research as well as drug development.

Keywords: IL-8; STAT3; cell differentiation; stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast / cytology*
  • Breast / metabolism*
  • Cell Dedifferentiation / physiology
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cellular Senescence / physiology
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Humans
  • Interleukin-6 / metabolism
  • Interleukin-8 / metabolism*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Multipotent Stem Cells / cytology*
  • Multipotent Stem Cells / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Stromal Cells / cytology
  • Stromal Cells / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Interleukin-6
  • Interleukin-8
  • MIRN141 microRNA, human
  • MicroRNAs
  • STAT3 Transcription Factor
  • STAT3 protein, human