SAFETY OF MESENCHYMAL STEM CELL ADMINISTRATION TO THE CNS OF RHESUS MACAQUES

间充质干细胞对恒河猴中枢神经系统给药的安全性

• 批准号: 7958586
• 负责人: Donald G Phinney
• 金额: $ 5.57万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958586
• 关键词: Adult; Adverse effects; Affect; Age; Animal Model; Animals; Behavioral; Brain; Cells; Cognitive; Computer Retrieval of Information on Scientific Projects Database; Conflict of Interest; Disclosure; Dose; Engraftment; Funding; Grant; Health; Health behavior; Human; Infant; Injection of therapeutic agent; Institution; Interneurons; Macaca; Macaca mulatta; Maps; Mesenchymal Stem Cells; Motor; Neuraxis; Pattern; Polymerase Chain Reaction; Primates; Reporting; Research; Research Personnel; Resources; Rodent Model; Safety; Source; Stem cell transplant; Testing; Therapeutic; Time; Transplant Recipients; Transplantation; United States National Institutes of Health; cell motility; infant monitoring; migration; neonate; nervous system disorder; receptor; social; sry Genes; vector; young adult

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mesenchymal stem cells (MSCs) have demonstrated efficacy as therapeutic vectors in rodent models of neurological diseases, but few studies have evaluated their safety and efficacy in a relevant large animal model. Previously, we reported that MSCs transplanted to the central nervous systems (CNS) of adult rhesus macaques engrafted at low levels without adversely affecting animal health, behavior, or motor function. Herein, we injected MSCs intracranially into 10 healthy infant macaques and quantified their engraftment levels and mapped their anatomical distribution in brain by real-time polymerase chain reaction using an sry gene-specific probe. These analyses revealed that MSC engraftment levels in brain were on average 18-fold higher with a maximal observed difference of 180-fold in neonates as compared with that reported previously for young adult macaques. Moreover, engraftment levels were 30-fold higher after injection of a low versus high cell dose and engrafted MSCs were nonrandomly distributed throughout the infant brain and localized to specific anatomical regions. Identification of unique subpopulations of macaque and human MSCs that express receptor proteins known to regulate tangential migration of interneurons may explain their migration patterns in brain. Extensive monitoring of infant transplant recipients using a battery of age appropriate tests found no evidence of any long-term adverse effects on the health or social, behavioral, cognitive, or motor abilities of animals up to 6 months post-transplant. Therefore, direct intracranial injection represents a safe means to deliver therapeutic levels of MSCs to the CNS. Moreover, expressed guidance receptors on MSC subpopulations may regulate migration of cells in the host brain. Disclosure of potential conflicts of interest is found at the end of this article.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 间充质干细胞（MSC）在神经系统疾病的啮齿动物模型中表现出作为治疗载体的功效，但是很少有研究评估其在相关大型动物模型中的安全性和有效性。以前，我们报道了将嗜猕猴移植到成年恒河猕猴的中枢神经系统（CNS）的MSC植入低水平而不会不利影响动物健康，行为或运动功能的情况下。本文中，我们将颅内注入了10个健康的婴儿猕猴，并通过实时聚合酶链反应使用SRY基因特异性探针量化了其植入水平，并量化了其植入水平，并绘制了其在大脑中的解剖学分布。这些分析表明，与先前报道的年轻成人猕猴相比，新生儿的最大差异为180倍，大脑中的MSC植入水平平均高出180倍。此外，在注射低细胞剂量和植入的MSC后，植入水平高30倍，非随机分布在整个婴儿大脑中，并定位于特定的解剖区域。鉴定已知的调节中间神经元切向迁移的猕猴和人类MSC的独特亚群可以解释其在大脑中的迁移模式。使用适当年龄的测试对婴儿移植接受者进行广泛的监测，没有证据表明在移植后长达6个月，对动物的健康，社会，行为，认知或运动能力有任何长期不良影响。因此，直接颅内注射代表了将治疗水平提供给CNS的安全手段。此外，对MSC亚群的表达引导受体可能调节宿主大脑中细胞的迁移。在本文末尾发现了潜在利益冲突的披露。