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Heterotypic Cell-Cell Interactions in Hybrid Human Stem Cell Microtissues during Neural Differentiation

神经分化过程中杂交人类干细胞微组织的异型细胞间相互作用

基本信息

批准号：
9111161
负责人：
Yan Li
金额：
$ 7.06万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111161
关键词：
3-Dimensional Acute Anti-Inflammatory Agents Anti-inflammatory Apoptotic Biological Assay Cell Communication Cell Death Cell Differentiation process Cell Survival Cell Therapy Cell physiology Cell secretion Cells Cessation of life Complex Demyelinations Development Engraftment Environment Enzyme-Linked Immunosorbent Assay Enzymes Equilibrium Event Extracellular Matrix Extracellular Matrix Degradation Extracellular Matrix Proteins Free Radicals Genes Goals Hemorrhage Human Hybrids In Vitro Inflammation Inflammatory Injury Ischemia Lesion Ligand Binding Lipid Peroxidation Liquid Chromatography Longevity Mechanics Mesenchymal Stem Cells Modeling Molecular Morphogenesis Neurons Oligodendroglia Organ Oxidative Stress Pattern Play Predisposition Production Progenitor Cell Engraftment Proteins Reactive Oxygen Species Role Science Secondary to Series Signal Transduction Site Source Spinal Cord Spinal cord injury Spinal cord injury patients Structure Surface TNF gene Testing Tissues Western Blotting Work autocrine base brain-derived growth factor cytotoxic cytotoxicity extracellular functional loss human stem cells improved in vitro Assay in vivo induced pluripotent stem cell innovation nerve injury nerve stem cell nervous system disorder neurogenesis neuron loss novel paracrine public health relevance receptor relating to nervous system response self assembly stem cell therapy tandem mass spectrometry

项目摘要

DESCRIPTION (provided by applicant): Despite the promising results from stem cell therapy in spinal cord injury, mesenchymal stem cells (MSCs) present an intermediate solution with short in vivo life span. Neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) provide an alternative source for novel cell therapy, but the engraftment of hiPSC-NPCs needs to be improved. The formation of microtissues of hiPSC-NPCs and MSCs could up-regulate the secretion of trophic factors from MSCs and NPCs, and the secretion of anti-apoptotic and anti-inflammatory factors from MSCs to enhance NPC engraftment at injury site. However, the complex heterotypic interactions of MSCs with hiPSC-NPCs and their secretory activities during neurogenesis have not been well understood.} The objective of this proposal is to construct 3-D microtissues composed of human MSCs and hiPSC-derived NPCs, and investigate the impact of heterotypic cell-cell interactions on the secretion of extracellular matrices and trophic factors during neural differentiation in vitro. The central hypothesis is that the heterotypic cell-cell interactions and the secretion of endogenous extracellular matrices are modulated by the structure of microtissues of MSCs and hiPSC- derived NPCs which promote trophic factor section and functional neural differentiation. Specifically, the following aims are proposed: 1) Aim 1 will test the hypothesis that the composition and structure of microtissues differentially regulates the secretion of trophic factors, NPC differentiation, and cell survival under oxidative stress. 2) Aim 2 will test the hypothesis that the structure of microtissues regulates the secretion of endogenous ECMs to stimulate neurogenesis. {Neural microtissue self-assembly from hiPSCs in vitro was chosen by Science's editors as a runner-up for 2013 Breakthrough of the Year. By their unique ability to coordinate the dictatorial signals and to form tissue or mini-organ like structures reminiscent of cell organization in vivo, hiPSCs and their derivatives provide a novel platform to advance our understanding on tissue morphogenesis for the treatment of neurological disorders. The most innovative feature of this project is to evaluate microtissue-based neural differentiation by fabricating hybrid MSC-NPC microtissues with tunable structure to achieve the enhanced cellular function and neurogenesis. If successful, the proposed study will advance our understanding on the actions of hiPSC-derived NPCs and MSCs in treating neural injury and on the modulation of extracellular microenvironment during neurogenesis.

描述（由申请人提供）：尽管干细胞疗法在脊髓损伤中取得了有希望的结果，但间充质干细胞（MSC）提供了一种体内寿命较短的中间解决方案。源自人诱导多能干细胞 (hiPSC) 的神经祖细胞 (NPC) 为新型细胞疗法提供了替代来源，但 hiPSC-NPC 的植入需要改进。 hiPSC-NPCs和MSCs微组织的形成可以上调MSCs和NPCs营养因子的分泌，以及MSCs抗凋亡和抗炎因子的分泌，从而增强NPC在损伤部位的植入。然而，MSCs与hiPSC-NPCs复杂的异型相互作用及其在神经发生过程中的分泌活动尚未得到很好的理解。}本提案的目的是构建由人类MSCs和hiPSC衍生的NPCs组成的3D微组织，并研究异型细胞间相互作用对体外神经分化过程中细胞外基质和营养因子分泌的影响。中心假设是异型细胞间相互作用和内源性细胞外基质的分泌受到MSC和hiPSC衍生的NPC的微组织结构的调节，促进营养因子部分和功能性神经分化。具体而言，提出以下目标：1）目标1将检验微组织的组成和结构差异调节营养因子的分泌、NPC分化和氧化应激下细胞存活的假设。 2）目标2将检验微组织结构调节内源性ECM的分泌以刺激神经发生的假设。 {《Science》杂志编辑将 hiPSC 体外神经微组织自组装评为 2013 年度突破奖亚军。凭借他们协调独裁信号并形成 hiPSC 及其衍生物具有让人想起体内细胞组织的组织或微型器官样结构，为增进我们对治疗神经系统疾病的组织形态发生的理解提供了一个新的平台。该项目最具创新性的特点是评估通过制造具有可调节结构的混合 MSC-NPC 微组织来实现基于微组织的神经分化，以实现增强的细胞功能和神经发生。如果成功，拟议的研究将增进我们对 hiPSC 衍生的 NPC 和 MSC 在治疗神经损伤中的作用以及神经发生过程中细胞外微环境的调节的理解。