BIOLOGY OF NON-HUMAN PRIMATE MARROW STROMAL CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的总体目标是开发程序，使来自骨髓基质的成年干细胞可以用于非人类灵长类动物的基因治疗试验。成体干细胞，称为间充质干细胞或骨髓基质细胞(MSCs)，对细胞和基因治疗感兴趣，因为它们可以很容易地从患者那里获得，在培养中扩增，使用或不使用病毒进行基因工程，然后返回治疗同一患者。它们也是令人感兴趣的，因为它们是受损组织的家园，并分化以取代组织中受损的细胞。这些细胞目前正在许多人类疾病的小动物模型中进行测试，几项有希望的临床试验已经启动，用于治疗儿童罕见疾病。然而，在非人类灵长类动物中进行广泛的细胞试验，显然对于目前提出的一些用于常见疾病的应用是必不可少的，例如骨质疏松症、心力衰竭、帕金森氏症、脑白质营养不良和阿尔茨海默病。该提案的目标是： 明确目标。比较灵长类MSCs和体内人类MSCs在全身或颅内输注给免疫缺陷小鼠后植入多个组织的能力。这些研究目前正在进行中。我们已经使用立体定位的方法将人和恒河猴的骨髓和脂肪组织来源的MSCs注射到NIHIII和Twitcher(Krabbe感染)小鼠的中枢神经系统中。我们目前正在评估这些细胞在中枢神经系统的植入和分化。来自免疫缺陷小鼠的数据表明，细胞植入后可持续180天，并沿神经谱系经历适度分化。目前正在收集将骨髓间充质干细胞(来自骨髓和脂肪组织)直接注射到Twitcher小鼠侧脑室的方法。到目前为止，我们已经证明了受Krabbe影响的动物的寿命在统计上显著延长。细胞似乎通过抑制与疾病相关的炎症途径来调节这一效应的主要机制。

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. The overall aim of the project is to develop procedures whereby adult stem cells from the bone marrow stroma can be used for trials of gene therapy in non-human primates. The adult stem cells, referred to as mesenchymal stem cells or marrow stromal cells (MSCs), are of interest for cell and gene therapy because they can readily be obtained from a patient, expanded in culture, genetically engineered with or without the use of viruses, and then returned for therapy of the same patient. They are also of interest because they home to damaged tissues and differentiate to replace the damaged cells in the tissues. The cells are currently being tested in many small animal models of human diseases and several promising clinical trials with the cells have been initiated in rare diseases in children. However, extensive trials of the cells in non-human primates are clearly essential for some of the currently proposed applications to common diseases such as osteoporosis, cardiac failure, Parkinsonism, leukodystrophies, and Alzheimer's disease. The goals of the proposal are: Specific Aim. Compare the primate MSCs to human MSCs in vivo in their ability to engraft into multiple tissues after systemic or intracranial infusion into immunodeficient mice. These studies are currently ongoing. We have injected human and rhesus bone marrow and adipose tissue derived MSCs into the CNS of NIHIII and Twitcher (Krabbe-affected) mice, using stereotaxic delivery. We are currently assessing engraftment and differentiation of these cells in the CNS. Data from the immune deficient mice indicate the cells engraft, persist for as long as 180 days and undergo moderate differentiation along neural lineages. Direct injection of MSCs (derived from bone marrow and adipose tissue) into the lateral ventricles of the brains of Twitcher mice is currently being collected. To date, we have demonstrated a statistically significant increase in life span in Krabbe-affected animals. The primary mechanisms by which the cells appear to mediate the effect is through suppression of the inflammatory pathways associated with the disease.