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

• 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
• 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

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.

描述：该应用的长期目标是开发新型磁性核/壳纳米颗粒（MCNP）来递送并时空触发干细胞向少突胶质细胞的分化。对于脊髓损伤，神经干/祖细胞（NSPC）移植已被证明可以提供许多有利的治疗效果。然而，移植的 NSPC 主要分化为星形胶质细胞，这往往会阻碍移植的有效性。移植的 NSPC 引导分化为少突胶质细胞是非常理想的，因为这些细胞在轴突周围提供髓鞘，从而使神经冲动在中枢神经系统中快速传播。为此，我们的目标是开发新型 MCNP，其具有双重功能：递送编码 Olig2 的质粒，此前有报道称，Olig2 在热休克启动子的作用下诱导 NSPC 分化为少突胶质细胞，并通过磁热疗触发 Olig2 表达（即磁热疗法）。使用交变磁场）。为了应对这些挑战，提出以下具体目标： 具体目标 1. 制备磁性核/壳纳米粒子和诱导基因载体，用于递送至人诱导多能干细胞衍生的神经干/祖细胞（hiPSC衍生的NSPC）中。具体目的2. 体外测试工程化NSPCs在磁热热诱导基因表达后的少突胶质细胞分化和髓鞘再生能力。 磁性纳米粒子此前已应用于 MRI、细胞靶向和药物/基因递送。然而，现有知识与这些纳米颗粒在干细胞治疗中的临床应用之间存在着重大差距。因此，开发一种新型的基于 MCNP 的干细胞疗法将证明 MNP 在临床相关 SCI 治疗中的多功能性质。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势，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) 磁场促进基因载体递送（“磁转染”）到干细胞中，以及 iii) 磁热疗，这将用于提供激活所递送基因的机制。总体而言，所提出的 MCNP 方法将把一种方法带到最前沿，使用户能够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。这样， 科学家和临床医生可以充分利用干细胞的潜力（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

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

Multidimensional nanomaterials for the control of stem cell fate.

• DOI: 10.1186/s40580-016-0083-9
• 发表时间: 2016
• 期刊: Nano convergence
• 影响因子: 11.7
• 作者: Chueng SD;Yang L;Zhang Y;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

Real-Time Monitoring of ATP-Responsive Drug Release Using Mesoporous-Silica-Coated Multicolor Upconversion Nanoparticles.

• DOI: 10.1021/acsnano.5b00641
• 发表时间: 2015-05-26
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Lai J;Shah BP;Zhang Y;Yang L;Lee KB
• 通讯作者: Lee KB