title: Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats.
abstract: Mesenchymal stem cell (MSC) transplantation protects against neonatal severe intraventricular hemorrhage (IVH)-induced brain injury by a paracrine rather than regenerative mechanism; however, the paracrine factors involved and their roles have not yet been delineated. This study aimed to identify the paracrine mediator(s) and to determine their role in mediating the therapeutic effects of MSCs in severe IVH. We first identified significant upregulation of brain-derived neurotrophic factor (BDNF) in MSCs compared with fibroblasts, in both DNA and antibody microarrays, after thrombin exposure. We then knocked down BDNF in MSCs by transfection with small interfering (si)RNA specific for human BDNF. The therapeutic effects of MSCs with or without BDNF knockdown were evaluated in vitro in rat neuronal cells challenged with thrombin, and in vivo in newborn Sprague-Dawley rats by injecting 200 μl of blood on postnatal day 4 (P4), and transplanting MSCs (1 × 105 cells) intraventricularly on P6. siRNA-induced BDNF knockdown abolished the in vitro benefits of MSCs on thrombin-induced neuronal cell death. BDNF knockdown also abolished the in vivo protective effects against severe IVH-induced brain injuries such as the attenuation of posthemorrhagic hydrocephalus, impaired behavioral test performance, increased astrogliosis, increased number of TUNEL cells, ED-1+ cells, and inflammatory cytokines, and reduced myelin basic protein expression. Our data indicate that BDNF secreted by transplanted MSCs is one of the critical paracrine factors that play a seminal role in attenuating severe IVH-induced brain injuries in newborn rats.
authors.forename: So Yoon
authors.initials: SY
authors.lastname: Ahn
authors.forename: Yun Sil
authors.initials: YS
authors.lastname: Chang
authors.forename: Dong Kyung
authors.initials: DK
authors.lastname: Sung
authors.forename: Se In
authors.initials: SI
authors.lastname: Sung
authors.forename: Jee-Yin
authors.initials: JY
authors.lastname: Ahn
authors.forename: Won Soon
authors.initials: WS
authors.lastname: Park
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D000074042:Cerebral Intraventricular Hemorrhage / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D006849:Hydrocephalus / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007231:Infant, Newborn; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D004676:Myelin Basic Protein / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D004676:Myelin Basic Protein; D034741:RNA, Small Interfering; D013917:Thrombin