{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T22:46:51Z","timestamp":1777416411363,"version":"3.51.4"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T00:00:00Z","timestamp":1635120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI138331"],"award-info":[{"award-number":["U01AI138331"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI133594"],"award-info":[{"award-number":["U01AI133594"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>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 PDGFR\u03b1<jats:sup>+<\/jats:sup>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.<\/jats:p>","DOI":"10.1371\/journal.pone.0259042","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T17:25:52Z","timestamp":1635182752000},"page":"e0259042","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3197-4396","authenticated-orcid":true,"given":"Guru Prasad","family":"Sharma","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anne C.","family":"Frei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jayashree","family":"Narayanan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-0543","authenticated-orcid":true,"given":"Tracy","family":"Gasperetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dana","family":"Veley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Asma","family":"Amjad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine","family":"Albano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian L.","family":"Fish","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9676-6371","authenticated-orcid":true,"given":"Heather A.","family":"Himburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,10,25]]},"reference":[{"issue":"8","key":"pone.0259042.ref001","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1038\/nm.3647","article-title":"Hematopoietic stem cell niche maintenance during homeostasis and regeneration","volume":"20","author":"A Mendelson","year":"2014","journal-title":"Nature medicine"},{"issue":"1","key":"pone.0259042.ref002","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1667\/RR15361.1","article-title":"Dickkopf-1 Treatment Stimulates Hematopoietic Regenerative Function in Infused Endothelial Progenitor Cells","volume":"192","author":"MM Kim","year":"2019","journal-title":"Radiat Res"},{"issue":"7","key":"pone.0259042.ref003","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1161\/STROKEAHA.106.477331","article-title":"Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis","volume":"38","author":"WR Schabitz","year":"2007","journal-title":"Stroke"},{"issue":"6","key":"pone.0259042.ref004","first-page":"3185","article-title":"Intravenous administration of DPSCs and BDNF improves neurological performance in rats with focal cerebral ischemia","volume":"41","author":"X Zhang","year":"2018","journal-title":"Int J Mol Med"},{"issue":"5","key":"pone.0259042.ref005","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.bbadis.2015.01.018","article-title":"Flavonoid derivative 7,8-DHF attenuates TBI pathology via TrkB activation","volume":"1852","author":"R Agrawal","year":"2015","journal-title":"Biochim Biophys Acta"},{"issue":"3","key":"pone.0259042.ref006","doi-asserted-by":"crossref","first-page":"e91453","DOI":"10.1371\/journal.pone.0091453","article-title":"7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss","volume":"9","author":"NA Castello","year":"2014","journal-title":"PLoS One"},{"issue":"6","key":"pone.0259042.ref007","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1073\/pnas.0913572107","article-title":"A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone","volume":"107","author":"SW Jang","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0259042.ref008","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.neulet.2014.02.058","article-title":"7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis","volume":"566","author":"OT Korkmaz","year":"2014","journal-title":"Neurosci Lett"},{"issue":"2","key":"pone.0259042.ref009","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s10735-013-9539-y","article-title":"7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats","volume":"45","author":"B Wang","year":"2014","journal-title":"J Mol Histol"},{"issue":"3","key":"pone.0259042.ref010","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/npp.2013.243","article-title":"7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer\u2019s disease","volume":"39","author":"Z Zhang","year":"2014","journal-title":"Neuropsychopharmacology"},{"issue":"1","key":"pone.0259042.ref011","doi-asserted-by":"crossref","first-page":"7","DOI":"10.4103\/1673-5374.198964","article-title":"Therapeutic potential of brain-derived neurotrophic factor (BDNF) and a small molecular mimics of BDNF for traumatic brain injury","volume":"12","author":"M Wurzelmann","year":"2017","journal-title":"Neural Regen Res"},{"issue":"21","key":"pone.0259042.ref012","doi-asserted-by":"crossref","first-page":"4531","DOI":"10.1242\/dev.127.21.4531","article-title":"Brain derived neurotrophic factor is an endothelial cell survival factor required for intramyocardial vessel stabilization","volume":"127","author":"MJ Donovan","year":"2000","journal-title":"Development"},{"issue":"4","key":"pone.0259042.ref013","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.tcm.2007.03.002","article-title":"Brain-derived neurotrophic factor: a newly described mediator of angiogenesis","volume":"17","author":"P Kermani","year":"2007","journal-title":"Trends Cardiovasc Med"},{"issue":"3","key":"pone.0259042.ref014","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1172\/JCI200522655","article-title":"Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors","volume":"115","author":"P Kermani","year":"2005","journal-title":"J Clin Invest"},{"issue":"32","key":"pone.0259042.ref015","doi-asserted-by":"crossref","first-page":"33538","DOI":"10.1074\/jbc.M404115200","article-title":"Paracrine and autocrine functions of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in brain-derived endothelial cells","volume":"279","author":"H Kim","year":"2004","journal-title":"J Biol Chem"},{"issue":"10","key":"pone.0259042.ref016","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1038\/s41556-020-0569-x","article-title":"STAT3-BDNF-TrkB signalling promotes alveolar epithelial regeneration after lung injury","volume":"22","author":"AJ Paris","year":"2020","journal-title":"Nat Cell Biol"},{"issue":"2","key":"pone.0259042.ref017","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/S0002-9440(10)65287-X","article-title":"Expression of neurotrophins and their receptors in human bone marrow","volume":"154","author":"E Labouyrie","year":"1999","journal-title":"Am J Pathol"},{"issue":"1","key":"pone.0259042.ref018","first-page":"151","article-title":"Expression of neurotrophins and their receptors in human CD34+ bone marrow cells","volume":"67","author":"E Paczkowska","year":"2016","journal-title":"J Physiol Pharmacol"},{"issue":"10","key":"pone.0259042.ref019","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1634\/stemcells.2004-0284","article-title":"Human umbilical cord blood progenitors: the potential of these hematopoietic cells to become neural","volume":"23","author":"N Chen","year":"2005","journal-title":"Stem Cells"},{"issue":"1\u20132","key":"pone.0259042.ref020","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.jneuroim.2005.01.023","article-title":"A role for brain-derived neurotrophic factor in B cell development","volume":"163","author":"B Schuhmann","year":"2005","journal-title":"J Neuroimmunol"},{"issue":"1\u20132","key":"pone.0259042.ref021","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0165-5728(02)00166-2","article-title":"Massive lymphocyte apoptosis in the thymus of functionally deficient TrkB mice","volume":"129","author":"O Garcia-Suarez","year":"2002","journal-title":"J Neuroimmunol"},{"issue":"1","key":"pone.0259042.ref022","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cell.2016.08.028","article-title":"Warm-Sensitive Neurons that Control Body Temperature","volume":"167","author":"CL Tan","year":"2016","journal-title":"Cell"},{"issue":"1","key":"pone.0259042.ref023","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput Cre reporting and characterization system for the whole mouse brain","volume":"13","author":"L Madisen","year":"2010","journal-title":"Nat Neurosci"},{"issue":"4","key":"pone.0259042.ref024","doi-asserted-by":"crossref","DOI":"10.1093\/ijnp\/pyu077","article-title":"Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation","volume":"18","author":"JC Zhang","year":"2014","journal-title":"Int J Neuropsychopharmacol"},{"issue":"73","key":"pone.0259042.ref025","first-page":"e50062","article-title":"An in vivo assay to test blood vessel permeability","author":"M Radu","year":"2013","journal-title":"Journal of visualized experiments: JoVE"},{"key":"pone.0259042.ref026","doi-asserted-by":"crossref","first-page":"e05521","DOI":"10.7554\/eLife.05521","article-title":"Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1","volume":"4","author":"BO Zhou","year":"2015","journal-title":"eLife"},{"issue":"5","key":"pone.0259042.ref027","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1002\/eji.201444985","article-title":"Thymocyte-derived BDNF influences T-cell maturation at the DN3\/DN4 transition stage","volume":"45","author":"RA Linker","year":"2015","journal-title":"Eur J Immunol"},{"issue":"3","key":"pone.0259042.ref028","doi-asserted-by":"crossref","first-page":"e9690","DOI":"10.1371\/journal.pone.0009690","article-title":"Neurotrophins regulate bone marrow stromal cell IL-6 expression through the MAPK pathway","volume":"5","author":"F Rezaee","year":"2010","journal-title":"PLoS One"},{"issue":"4","key":"pone.0259042.ref029","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s11596-013-1146-3","article-title":"Role of brain-derived neurotrophic factor in bone marrow angiogenesis in multiple myeloma","volume":"33","author":"ZB Chu","year":"2013","journal-title":"J Huazhong Univ Sci Technolog Med Sci"},{"issue":"6","key":"pone.0259042.ref030","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.ijdevneu.2005.05.009","article-title":"Neurotrophins in murine viscera: a dynamic pattern from birth to adulthood","volume":"23","author":"M Lommatzsch","year":"2005","journal-title":"Int J Dev Neurosci"},{"issue":"7","key":"pone.0259042.ref031","doi-asserted-by":"crossref","first-page":"2864","DOI":"10.4049\/jimmunol.157.7.2864","article-title":"Expression of trKB neurotrophin receptor during T cell development. Role of brain derived neurotrophic factor in immature thymocyte survival","volume":"157","author":"M Maroder","year":"1996","journal-title":"J Immunol"},{"issue":"8","key":"pone.0259042.ref032","first-page":"3983","article-title":"BDNF: An Oncogene or Tumor Suppressor?","volume":"37","author":"DP Radin","year":"2017","journal-title":"Anticancer Res"},{"issue":"2","key":"pone.0259042.ref033","first-page":"2031","article-title":"Targeting the BDNF\/TrkB pathway for the treatment of tumors","volume":"17","author":"L Meng","year":"2019","journal-title":"Oncol Lett"},{"issue":"9","key":"pone.0259042.ref034","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1182\/blood-2008-05-155200","article-title":"High-affinity neurotrophin receptors and ligands promote leukemogenesis","volume":"113","author":"Z Li","year":"2009","journal-title":"Blood"},{"key":"pone.0259042.ref035","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3389\/fncel.2015.00249","article-title":"Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities","volume":"9","author":"AJ Salgado","year":"2015","journal-title":"Front Cell Neurosci"},{"issue":"1\u20132","key":"pone.0259042.ref036","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jns.2010.09.003","article-title":"Enhancing trophic support of mesenchymal stem cells by ex vivo treatment with trophic factors","volume":"298","author":"YJ Choi","year":"2010","journal-title":"J Neurol Sci"},{"issue":"5","key":"pone.0259042.ref037","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1007\/s00592-015-0735-y","article-title":"Co-transplantation of autologous MSCs delays islet allograft rejection and generates a local immunoprivileged site","volume":"52","author":"M Ben Nasr","year":"2015","journal-title":"Acta Diabetol"},{"issue":"6","key":"pone.0259042.ref038","doi-asserted-by":"crossref","first-page":"1892","DOI":"10.1002\/stem.1986","article-title":"PI3kalpha and STAT1 Interplay Regulates Human Mesenchymal Stem Cell Immune Polarization","volume":"33","author":"M Mounayar","year":"2015","journal-title":"Stem Cells"},{"issue":"3","key":"pone.0259042.ref039","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1182\/blood.V77.3.472.472","article-title":"Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression","volume":"77","author":"ML Patchen","year":"1991","journal-title":"Blood"},{"issue":"8","key":"pone.0259042.ref040","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1182\/blood.V84.8.2515.2515","article-title":"Therapeutic efficacy of recombinant interleukin-6 (IL-6) alone and combined with recombinant human IL-3 in a nonhuman primate model of high-dose, sublethal radiation-induced marrow aplasia","volume":"84","author":"TJ MacVittie","year":"1994","journal-title":"Blood"},{"issue":"11","key":"pone.0259042.ref041","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1182\/blood.V84.11.3675.bloodjournal84113675","article-title":"Therapeutic efficacy of recombinant human leukemia inhibitory factor in a primate model of radiation-induced marrow aplasia","volume":"84","author":"AM Farese","year":"1994","journal-title":"Blood"},{"issue":"4","key":"pone.0259042.ref042","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1016\/j.stem.2019.06.003","article-title":"Stress-Induced Changes in Bone Marrow Stromal Cell Populations Revealed through Single-Cell Protein Expression Mapping","volume":"25","author":"N Severe","year":"2019","journal-title":"Cell Stem Cell"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0259042","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T19:29:42Z","timestamp":1673638182000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0259042"}},"subtitle":[],"editor":[{"given":"Paolo","family":"Fiorina","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,10,25]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0259042","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,25]]}}}