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: 8623454
• 负责人: Kibum Lee
• 金额: $ 19.22万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623454
• 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; 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; stem cells; 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：本应用的长期目标代表了新型磁芯/壳纳米颗粒（MCNP）的发展，以传递和时空触发干细胞分化为少突胶质细胞。关于脊髓损伤，已证明神经茎/祖细胞（NSPC）移植具有许多有利的治疗作用。然而，发现移植的NSPC主要分化为星形胶质细胞，这倾向于阻碍移植的有效性。非常需要移植的NSPC分化为少突胶质细胞，因为这些细胞在轴突周围提供髓鞘，因此可以在中枢神经系统中快速传播神经冲动。为此，目标是开发新型MCNP，其具有传递编码Olig2的质粒的双重功能，以前据报道，在热冲击启动子下，它诱导NSPC与少突胶质细胞的分化，并通过磁性高（即使用交替的磁场）触发OLIG2表达。为了应对这些挑战，提出了以下特定目的：特定目的1。准备磁芯/壳纳米颗粒和诱导型基因载体，以将其传递到人类诱导的pluirpotent pluirpotent pluirpotent的干细胞衍生的神经干/祖细胞（HIPSC衍生的NSPC）。具体目的2。测试磁性高热诱导的基因表达后，在体外工程NSPC的少突胶质细胞分化和再髓鞘能力。 先前已将磁性纳米颗粒用于MRI，细胞靶向和药物/基因递送。但是，这些纳米颗粒在基于干细胞的治疗中的现有知识与临床应用之间存在危险差异。因此，基于MCNP的新型干细胞疗法的发展将证明MNP的多功能性质用于临床上的SCI治疗。 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活化基因的机制。总体而言，所提出的MCNP方法将使方法成为最前沿的方法，使用户能够实现对细胞分化的空间和时间控制，同时有可能维持神经保护性质与茎/前体细胞的先天性。这样， 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细胞命运规格）来增强SCI治疗。