Induced Pluripotent Stem Cells from Neurosurgical removed tissue for Brain Repair

来自神经外科切除组织的诱导多能干细胞用于大脑修复

• 批准号: 8445546
• 负责人: RAJ Raghavendra RAO
• 金额: $ 22.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445546
• 关键词: Adult; Animals; Autologous; Biological; Bone Marrow; Brain; Cell Survival; Cell Transplants; Cells; Characteristics; Clinic; Development; Ectopic Expression; Emerging Technologies; Engineering; Environment; Epilepsy; Ethical Issues; Excision; Female; Fibroblasts; Generations; Goals; Graft Rejection; Graft Survival; Health; Healthcare; Human; Human Engineering; Immunocompetent; In Vitro; Lead; Methods; Mission; Motor; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Nude Rats; Outcome; Patients; Pluripotent Stem Cells; Population; Positioning Attribute; Property; Protocols documentation; Rattus; Replacement Therapy; Research; Research Personnel; Resources; Risk; Role; Sex Characteristics; Somatic Cell; Source; Stromal Cells; Techniques; Testing; The Sun; Tissues; Transplantation; Trauma; Traumatic Brain Injury; adult stem cell; base; brain repair; cell type; cognitive function; effective therapy; embryonic stem cell; fetal; improved; in vivo; induced pluripotent stem cell; injured; innovation; male; monolayer; nerve stem cell; nervous system disorder; neuronal replacement; novel; patch clamp; pluripotency; progenitor; relating to nervous system; repaired; research and development; self-renewal; senescence; stem; stem cell technology; tissue/cell culture; transcription factor; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The long-term goal of this project is to develop patient-specific autologous cell source from induced pluripotent stem cells (iPSC) technology as a therapy for traumatic brain injury and other neurological diseases. Many current neural transplantation approaches have encountered problems associated with the source of donor cells. The ethnic controversies, limited cell availability, poor survival, lack of functional integration of grafted cells, the risk of tumor formation and immunological rejection in vivo are prominent issues need to be overcome before neural transplantation as a therapy to be used in clinic. It is essential, therefore, to identify optimal cell sources that are more conducive for cel replacement therapies. The emerging technology of human iPSCs generation, followed by directed differentiation into uniform populations of neural progenitor cells (hNPs) and neurons, holds great promise as an approach to reverse engineer human cells obtained from TBI patients. In this project, we are focusing our efforts on reprogramming adult human neural cells isolated from neurosurgical resection tissues. The specific hypothesis of this proposal is that functional iPSC-derived neural progenitor cells can be generated from neurosurgical resection tissues and utilized as cell replacement therapy for TBI. The hypothesis is based on our observations and research developments that (a) iPSCs can be generated from patients with specific neurodegenerative disorders, (b) directed differentiation of pluripotent stem cells can lead to uniform populations of hNPs, and (c) adult human stem-like cells can be isolated from neurosurgical resection tissues and successfully cultured as neurospheres and monolayers. To test the hypothesis, in this proposal, we will first generate iPSCs from adult human neural cells isolated from neurosurgical resection tissues and evaluate their pluripotent characteristics, directed differentiation capabilities in vitro. We will then assess the transplantation potential o these iPSC-derived hNPs in vivo in the brain in both intact immunodeficient animals and injured immunocompetent animals. The two proposed specific aims are: (1) Generate and characterize iPSCs from adult human neural cells isolated from neurosurgical resection tissues. (2) Evaluate the survival, differentiation and functionality of iPSC-derived NPs in the injured environment and assess the role of gender differences on cell survival. Results from the proposed study will have significant impact in the development of patient-specific hiPSCs as autologous cell replacement strategies for TBI and other neurological disorders. PUBLIC HEALTH RELEVANCE: Traumatic brain injury is fundamentally untreatable and clinically devastating. Generating induced pluripotent stem cells will significantly advance our strategies towards developing patient-specific cells for cell replacement therapy for TBI. The results from this proposal will provide positive impact on the development of autologous cell replacement therapies for TBI and other neurological diseases.

描述（由申请人提供）：该项目的长期目标是从诱导的多能干细胞（IPSC）技术中开发患者特异性的自体细胞来源，以作为脑损伤和其他神经系统疾病的疗法。许多当前的神经移植方法遇到了与供体细胞来源有关的问题。种族争议，有限的细胞可用性，存活不良，缺乏移植细胞的功能整合，体内肿瘤形成和免疫学排斥的风险是显着的问题，在神经移植作为一种疗法以在临床中使用之前，需要克服重大问题。因此，必须识别更有利于CEL替代疗法的最佳细胞来源。人类IPSC的新兴技术随后将分化为神经祖细胞（HNP）和神经元均匀种群，具有巨大的希望，是一种从TBI患者获得的反向工程人类细胞的方法。在这个项目中，我们将精力集中在重编程从神经外科切除组织中分离的成年人类神经细胞。该提案的具体假设是功能性IPSC衍生的神经祖细胞可以由神经外科切除组织产生，并用作TBI的细胞替代疗法。该假设是基于我们的观察结果和研究的发展，即（a）IPSC可以是由患有特定神经推导疾病的患者产生的，（（b）多能干细胞的定向分化可以导致HNP统一的HNPS，（C）与成年人类干细胞相比，可以从神经神经神经外神经手术切除术和成功培训中隔离为Neurosistricals Neurosed Neurostrics Neurossed和Neurossed。为了检验该假设，在此提案中，我们将首先从神经外科切除组织分离的成年人类神经细胞中产生IPSC，并评估其多能特征，并在体外定向分化能力。然后，我们将在完整的免疫缺陷动物和受伤的免疫能力动物的大脑中评估这些IPSC衍生的HNP的移植潜力。提出的两个特定目的是：（1）从神经外科切除组织分离的成年人类神经细胞中产生和表征IPSC。 （2）评估IPSC衍生的NP在受伤环境中的生存，分化和功能，并评估性别差异在细胞存活中的作用。拟议研究的结果将对患者特异性HIPSC的发展产生重大影响，作为TBI和其他神经系统疾病的自体细胞置换策略。 公共卫生相关性：创伤性脑损伤从根本上是无法治疗的，并且在临床上是毁灭性的。产生诱导的多能干细胞将显着推动我们开发患者特异性细胞的策略，以用于TBI的细胞替代疗法。该提案的结果将对TBI和其他神经系统疾病的自体细胞替代疗法的发展产生积极影响。