title: GDF-15 secreted from human umbilical cord blood mesenchymal stem cells delivered through the cerebrospinal fluid promotes hippocampal neurogenesis and synaptic activity in an Alzheimer's disease model.
abstract: Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.
authors.affiliation: 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.|2 Department of Biotechnology and Bioengineering, Sungkyunkwan University , Suwon, Republic of Korea.
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.
authors.forename: Dahm
authors.initials: D
authors.lastname: Lee
authors.affiliation: 3 Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology , Samsung Electronics Co., Ltd., Seoul, Republic of Korea.|4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea.
authors.forename: Eun Hyuk
authors.initials: EH
authors.lastname: Chang
authors.affiliation: 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.|4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea.
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: 4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea.|5 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University , Seoul, Republic of Korea.
authors.forename: Jung Won
authors.initials: JW
authors.lastname: Hwang
authors.affiliation: 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.
authors.forename: Ju-Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: 6 Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Kyung
authors.affiliation: 6 Department of Neuroscience, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 2 Department of Biotechnology and Bioengineering, Sungkyunkwan University , Suwon, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Oh
authors.affiliation: 7 Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul, Republic of Korea.
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shim
authors.affiliation: 4 Department of Neurology, Samsung Medical Center, School of Medicine, Sungkyunkwan University , Seoul, Republic of Korea.
authors.forename: Duk Lyul
authors.initials: DL
authors.lastname: Na
authors.affiliation: 1 Biomedical Research Institute , MEDIPOST Co., Ltd., Gyeonggi-Do, Republic of Korea.
authors.forename: Wonil
authors.initials: W
authors.lastname: Oh
authors.affiliation: 5 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University , Seoul, Republic of Korea.|8 Stem Cell & Regenerative Medicine Center (SCRMC), Research Institute for Future Medicine , Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Chang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D023902:Chromosome Pairing / Q000502:physiology*; D004195:Disease Models, Animal; D005312:Fetal Blood; D055436:Growth Differentiation Factor 15 / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology
chemical_list: C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15