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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 间充质干细胞（MSC）已被证明在啮齿动物模型的神经系统疾病的治疗载体的功效，但很少有研究评估其在相关的大型动物模型的安全性和有效性。以前，我们报道了MSC移植到成年恒河猴的中枢神经系统（CNS），移植量低，不会对动物健康、行为或运动功能产生不良影响。在此，我们颅内注射骨髓间充质干细胞到10个健康的婴儿猕猴和量化他们的植入水平和映射其在大脑中的解剖分布通过实时聚合酶链反应使用sry基因特异性探针。这些分析显示，与先前报道的年轻成年猕猴相比，新生儿脑中MSC植入水平平均高18倍，最大观察到的差异为180倍。此外，植入水平高出30倍后，注射低细胞剂量与高细胞剂量和移植的MSC非随机分布在整个婴儿大脑和局部特定的解剖区域。猕猴和人MSC表达已知调节中间神经元切向迁移的受体蛋白的独特亚群的鉴定可以解释它们在脑中的迁移模式。使用一组年龄合适的测试对婴儿移植受体进行广泛监测，发现移植后6个月内没有证据表明对动物的健康或社会，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的MSC递送至CNS的安全手段。此外，MSC亚群上表达的导向受体可以调节宿主脑中细胞的迁移。潜在利益冲突的披露见本文末尾。

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.