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Novel magnetic core/shell nanoparticle-based stem cell therapy to direct neural s

新型磁核/壳纳米颗粒干细胞疗法可指导神经系统

基本信息

批准号：
8737987
负责人：
Kibum Lee
金额：
$ 22.93万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8737987
关键词：
Address Astrocytes Attention Axon Biological Assay Cell Differentiation process Cell Therapy Cells Development Devices Disease Drug Targeting Effectiveness Engineering Environment Exposure to Gene Activation Gene Delivery Gene Expression Genes Goals Gold Heat shock proteins Heat-Shock Response Heating Human Human Engineering Hyperthermia Image In Vitro Induced Hyperthermia Inflammation Injury Knowledge Label Magnetic Resonance Imaging Magnetism Methodology Methods Microfluidics Modeling Myelin Sheath Natural regeneration Nature Nerve Neurons Oligodendroglia Plasmids Property Rattus Reporter Genes Reporting Route Scientist Signal Transduction Spinal cord injury Stem cell transplant Stem cells Testing Therapeutic Therapeutic Effect Transcription factor genes Transfection Transplantation Zinc axon growth base cell fate specification clinical application clinically relevant culture plates expression vector gene therapy improved iron oxide magnetic field myelination nanomaterials nanoparticle neural graft neuronal circuitry neuroregulation novel novel strategies overexpression precursor cell promoter public health relevance relating to nervous system remyelination stem stem cell differentiation stem cell therapy tissue culture transcription factor transmission process vector white matter

项目摘要

DESCRIPTION: The long-term goal of this application represents the development of novel magnetic core/shell nanoparticles (MCNPs) to deliver and spatiotemporally trigger the differentiation of stem cells to oligodendrocytes. With regard to spinal cord injury, neural stem/progenitor cell (NSPCs) transplantation has been shown to afford a number of favorable therapeutic effects. However, grafted NSPCs were found to differentiate primarily into astrocytes, which tend to hinder the effectiveness of transplantation. The guided differentiation of the grafted NSPCs into oligodendrocytes is highly desirable since these cells provide myelin sheaths around axons and thus enable fast propagation of nerve impulses in the CNS. To this end, the objective is to develop novel MCNPs, which have the dual functions of delivering a plasmid encoding Olig2, which has previously been reported to induce NSPC differentiation to oligodendrocytes, under a heat shock promoter and triggering Olig2 expression through magnetic hyperthermia (i.e. using an alternating magnetic field). To address these challenges, the following specific aims are proposed: Specific Aim 1. To prepare magnetic core/shell nanoparticles and inducible gene vectors for delivery into human induced pluirpotent stem cell-derived neural stem/progenitor cells (hiPSC-derived NSPCs). Specific Aim 2. To test the oligodendrocyte differentiation and remyelination ability of the engineered NSPCs in vitro after magnetic hyperthermia-induced gene expression. Magnetic nanoparticles have previously been applied for MRI, cell targeting, and drug/gene delivery. However, there is a critical gap between the existing knowledge and the clinical application of these nanoparticles to stem cell-based therapy. Therefore, the development of a novel MCNP-based stem cell therapy will demonstrate the multifunctional nature of MNPs for a clinically-relevant SCI treatment. In particular, compared to conventional gene therapies and cellular labeling methodologies, a MCNP-based approach would offer many advantages including: i) non-invasive magnetic resonance imaging (due to magnetic core) and Raman imaging (due to the gold shell) capabilities, ii) magnetic field-facilitated delivery ('magnetofection') of gene vectors into the stem cells, and iii) magnetic hyperthermia, which will be used to provide a mechanism for the activation of the delivered gene. Overall, the proposed MCNP approach will bring a methodology to the forefront that can allow the user to achieve spatial and temporal control over cellular differentiation, while potentially maintaining the neuroprotective properties innate to stem/precursor cells. In this way, scientists and clinicians can harness the full potential of stem cells (i.e. intrinsic therapeutic properties and controlled cell fate specification) for an enhanced SCI treatment.

产品说明：本申请的长期目标是开发新型磁性核/壳纳米颗粒（MCNP），以递送并时空触发干细胞向少突胶质细胞的分化。关于脊髓损伤，神经干/祖细胞（NSPCs）移植已被证明提供了许多有利的治疗效果。然而，移植的NSPCs被发现主要分化成星形胶质细胞，这往往会阻碍移植的有效性。移植的NSPCs被引导分化为少突胶质细胞是非常期望的，因为这些细胞提供轴突周围的髓鞘，从而使得神经冲动能够在CNS中快速传播。为此，目的是开发新的MCNP，其具有在热休克启动子下递送编码Olig 2的质粒和通过磁热疗（即使用交变磁场）触发Olig 2表达的双重功能，Olig 2先前已被报道诱导NSPC分化为少突胶质细胞。为了应对这些挑战，提出了以下具体目标：具体目标1。目的制备磁性核壳纳米粒子和诱导基因载体，用于人诱导多能干细胞衍生的神经干/祖细胞（hiPSC衍生的NSPCs）。具体目标2。检测基因工程化的NSPCs在体外经磁场诱导表达后的少突胶质细胞分化和髓鞘再生能力。磁性纳米颗粒以前已被应用于MRI，细胞靶向和药物/基因递送。然而，现有的知识和这些纳米颗粒在干细胞治疗中的临床应用之间存在着关键的差距。因此，开发一种新的基于MCNP的干细胞疗法将证明MNP用于临床相关SCI治疗的多功能性质。特别是，与传统的基因疗法和细胞标记方法相比，基于MCNP的方法将提供许多优点，包括：i）非侵入性磁共振成像（由于磁芯）和拉曼成像（由于金壳）能力，ii）磁场促进的递送iii）磁热疗，其将用于提供用于激活递送的基因的机制。总的来说，所提出的MCNP方法将使一种方法走在前列，可以允许用户实现对细胞分化的空间和时间控制，同时可能保持干细胞/前体细胞固有的神经保护特性。通过这种方式，科学家和临床医生可以利用干细胞的全部潜力（即内在的治疗特性和受控的细胞命运规范）来增强SCI治疗。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering Stem Cells for Biomedical Applications.

DOI：
10.1002/adhm.201400842
发表时间：
2016-01-07
期刊：
Advanced healthcare materials
影响因子：
10
作者：
Yin PT;Han E;Lee KB
通讯作者：
Lee KB

Nanotechnology-Based Approaches for Guiding Neural Regeneration.

DOI：
10.1021/acs.accounts.5b00345
发表时间：
2016-01-19
期刊：
Accounts of chemical research
影响因子：
18.3
作者：
Shah S;Solanki A;Lee KB
通讯作者：
Lee KB

Core-shell nanoparticle-based peptide therapeutics and combined hyperthermia for enhanced cancer cell apoptosis.

DOI：
10.1021/nn503431x
发表时间：
2014-09-23
期刊：
ACS NANO
影响因子：
17.1
作者：
Shah, Birju P.;Pasquale, Nicholas;De, Gejing;Tan, Tao;Ma, Jianjie;Lee, Ki-Bum
通讯作者：
Lee, Ki-Bum

Multidimensional nanomaterials for the control of stem cell fate.

用于控制干细胞命运的多维纳米材料。