Journal Article

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

Gasperetti, Tracy, Himburg, Heather A., Veley, Dana, Fish, Brian L., Narayanan, Jayashree, Sharma, Guru Prasad, Frei, Anne C., Albano, Katherine, Amjad, Asma

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Agonists / Alzheimer's disease / Analysis / Animals / Antibodies / Auroral kilometric radiation / Biology and Life Sciences / Blood / Blood cells / Bone growth / Bone marrow / Brain / Brain injury / Brain stem / Brain-derived neurotrophic factor / Brain-Derived Neurotrophic Factor - pharmacology / Care and treatment / Cell survival / Chemotherapy / Cytokines / Diagnosis / Disease Models, Animal / Female / Flavones - pharmacology / Flow cytometry / Growth factors / Head injuries / Health services / Hematopoietic stem cells / Immune Reconstitution / Interleukin 6 / Interleukin-6 - metabolism / Irradiation / Kinases / Laboratory animals / Leukemia / Leukemia inhibitory factor / Leukemia Inhibitory Factor - metabolism / Long term memory / Male / Medical schools / Medicine and Health Sciences / Mesenchymal stem cells / Mesenchymal Stem Cells - drug effects / Mesenchymal Stem Cells - metabolism / Mice / Myelosuppression / Nerve growth factor / Neural stem cells / Neurodegenerative diseases / Oncology / Radiation / Radiation injuries / Radiation Injuries - metabolism / Radiation therapy / Receptor, trkB - metabolism / Regeneration / Risk factors / Signal Transduction - drug effects / Signaling / Stem cells / Thymus / Thymus Gland - drug effects / Thymus Gland - metabolism / Traumatic brain injury / TrkB receptors / Tropomyosin