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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-014-9069-y) contains supplementary material, which is available to authorized users.

Peptide‐modified, hyaluronic acid‐based hydrogels as a 3D culture platform for neural stem/progenitor cell engineering

“…In vitro , IKVAV‐bearing hydrogels are reported to promote differentiation of neurons while reducing differentiation of astrocytes . YIGSR has also been reported to support survival and neurogenesis of transplanted NS/PCs and has been widely found to promote neurite extension . YIGSR and IKVAV are known to synergistically improve neurite attachment and outgrowth .…”

Regenerative therapy for hippocampal degenerative diseases: lessons from preclinical studies

“…This has enabled the creation of biomaterials with microarchitecture resembling the in vivo stem cell milieu (Edalat et al ., , ), thus facilitating graft survival, and directed differentiation into appropriate phenotypes and successful functional integration into host tissue. In line with this, Cui et al () demonstrated that neural stem cells seeded on designer self‐assembled peptide (DSP) with Tyr–Ile–Gly–Ser–Arg (YIGSR), a functional domain derived from laminin, led to enhanced neural differentiation as compared to neural stem cells seeded on self‐assembled peptide or neural stem cells alone, indicating that the functionalized peptide with the YIGSR amino acid sequence interacted with neural stem cells and guided them towards appropriate differentiation. Moreover, transplantation of neural stem cells with DSP into the hippocampus of AD rats survived for a longer duration, as opposed to non‐DSP neural stem cells, and conferred significant neuroprotection, enhanced synaptic connections, decreased amyloid deposition, increased the secretion of growth factors and improved cognitive function, thus providing proof‐of‐concept that the therapeutic effects of cell therapy can be improved with a biomaterial‐based approach.…”

<p>Targetting Exosomes as a New Biomarker and Therapeutic Approach for Alzheimer’s Disease</p>

“…89 In another study, MSC-derived exosomes were shown to improve learning and memory function in APP/PS1 transgenic mice, reduce Aβ accumulation, and increase the expression of synaptic protein in the brains of APP/PS1 transgenic mice. 90,91 Furthermore, treatment with exosomes derived from MSCs were shown to reduce the activation of glial cells, and the levels of inflammatory factors involved in the regulation of the STAT3 and NF-kB pathways. 91 A very recent study further showed that the injection of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) into the brain could repair cognitive dysfunction and facilitate the clearance of Aβ deposition in the AβPP/PS1 transgenic mouse model.…”

“…Binding extracellular Aβ and promoting its degradation 70,92 Neutralizing Aβ induced disruption in synaptic plasticity 71 Carrying nucleic acids with gene expression regulating abilities 90,[100][101][102] Serving as therapeutic vehicles of drug delivery for AD [108][109][110] Abbreviations: AD, Alzheimer's disease; APP, amyloid precursor protein; oAß, ßamyloid oligomers.…”