Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells

PLoS One. 2021 Oct 25;16(10):e0259042. doi: 10.1371/journal.pone.0259042. eCollection 2021.


Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFRα+ bone marrow mesenchymal stem cells (MSCs) which increase secretion of hematopoietic cytokines interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in response to TrkB activation. These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Disease Models, Animal
  • Female
  • Flavones / pharmacology*
  • Immune Reconstitution*
  • Interleukin-6 / metabolism
  • Leukemia Inhibitory Factor / metabolism
  • Male
  • Mesenchymal Stem Cells / drug effects*
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Radiation Injuries / metabolism*
  • Receptor, trkB / metabolism
  • Signal Transduction / drug effects*
  • Thymus Gland / drug effects*
  • Thymus Gland / metabolism


  • 6,7-dihydroxyflavone
  • Brain-Derived Neurotrophic Factor
  • Flavones
  • Interleukin-6
  • Leukemia Inhibitory Factor
  • Receptor, trkB