title: Designer Self-Assemble Peptides Maximize the Therapeutic Benefits of Neural Stem Cell Transplantation for Alzheimer's Disease via Enhancing Neuron Differentiation and Paracrine Action.
abstract: The neuropathological hallmarks of Alzheimer's disease (AD) include the presence of extracellular amyloid-β peptide (Aβ) in the form of amyloid plaques and neuronal loss. Neural stem cell (NSC) is being scrutinized as a promising cell replacement therapy for various neurodegenerative diseases. However, the unfavorable niche at the site of degenerative disease is hostile to the survival and differentiation of transplanted cells. Here, we undertook in vitro and in vivo works to examine whether a designer self-assemble peptide (DSP), which contains one functional domain Tyr-Ile-Gly-Ser-Arg (YIGSR) derived from laminin, promotes the survival and neuronal differentiation of NSC and behavioral improvement. We found that DSP could undergo spontaneous assembly into well-ordered nanofibers, and it not only facilitated the cell viability in normal culture condition, but also decreased the number of apoptotic cells induced by Aβ in vitro. NSC seeded in DSP showed much more neuronal differentiation than that seeded in self-assemble peptide (SP) or alone. In the AD model, NSC transplantation in DSP-treated AD rats demonstrated much more obvious cognitive rescue with restoration of learning/memory function compared with NSC transplantation in SP, NSC alone, or DSP alone treated ones. Interestingly, DSP enhanced the survival and neuronal differentiation of transplanted NSC. Apoptosis levels in the CA1 region and Aβ level in the hippocampus were significantly decreased in the group of NSC transplantation in DSP. Moreover, synaptic function, indicated by the expression of pre-synaptic protein synapsin-1, was restored and the secretion of anti-inflammatory and neurotrophic factors were increased, such as IL-10, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor 1 (IGF-1), while the expression of pro-inflammatory factors were decreased, such as TNF-α and IL-1β. These data firstly unveiled that the biomaterial DSP can maximize the therapeutic benefits of NSC transplantation for AD through improving the survival and differentiation of transplanted stem cells and promoting the effects of neuroprotection, anti-neuroinflammatory and paracrine action. Our results may have important clinical implications for the design of future NSC-based strategies using the biomaterials for various neurodegenerative diseases including AD.
authors.affiliation: Department of Neurology, Shanghai No. 9 People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China.|Department of Neurology, Shanghai No. 6 People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200233, China.
authors.forename: Guo-Hong
authors.initials: GH
authors.lastname: Cui
authors.affiliation: Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China.
authors.forename: Shui-Jin
authors.initials: SJ
authors.lastname: Shao
authors.affiliation: Department of Neurology, Shanghai No. 6 People's Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200233, China.
authors.forename: Jia-Jun
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Neurology, Shanghai No. 9 People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China. liujr021@vip.163.com.
authors.forename: Jian-Ren
authors.initials: JR
authors.lastname: Liu
authors.affiliation: Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China. hdguo8@hotmail.com.
authors.forename: Hai-Dong
authors.initials: HD
authors.lastname: Guo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000503:physiopathology / Q000628:therapy; D018625:Microscopy, Atomic Force; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000637:transplantation*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D019899:Paracrine Communication / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects; D033581:Stem Cell Transplantation; D013569:Synapses / Q000187:drug effects / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D009414:Nerve Growth Factors; D010455:Peptides; D012333:RNA, Messenger
keywords: Alzheimer’s disease; Differentiation; Neural stem cell; Self-assembling peptide; Transplantation