MESENCHYMAL STEM CELL THERAPY FOR DIABETES

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。 这项应用的总体目标是使用动物模型来测试来自人骨髓的成人干细胞/祖细胞潜在地治疗糖尿病的可能性，这些细胞被称为成纤维细胞样集落形成单位、间充质干细胞或多能间充质基质细胞(MSCs)。我们和其他人之前证明了骨髓间充质干细胞具有非凡的特性，即它们可以容纳并修复受损组织。最近，我们发现，将人MSCs注入链脲佐菌素(STZ)诱导的免疫缺陷的I型糖尿病小鼠体内后，人类细胞归巢于胰腺，激活细胞，并增加小鼠胰岛素的分泌，足以降低血糖。这些细胞也归巢于肾小球，可能改善了肾脏的病理变化。因此，这一结果提出了一种可能性，即大量注射患者自己的骨髓间充质干细胞可能提供一种有效的手段来修复糖尿病对胰腺和其他组织的损害。我们的策略是在I型糖尿病的非人类灵长类动物模型中检查MSCs的治疗潜力。这项建议的具体目的是确定自体骨髓间充质干细胞、体外扩增和回输到患有I型糖尿病(T1 DM)的非人类灵长类动物中是否可以改善细胞功能、降低血糖、改善糖耐量和改善肾功能。到目前为止，MSCs的剂量递增研究已经在一只恒河猴身上完成。骨髓间充质干细胞的输注顺序为：第0天(注射STZ后60天)开始输注50×106个MSCs，第7天输注100×106个细胞，第30天输注200×106个细胞，第50天达到200×106个细胞的峰值。到目前为止收集的数据表明，在第二次注射200X106细胞后，血糖水平显着下降，并接近正常水平。目前，另一种动物正在开始这项研究。这些实验将把小鼠模型研究的结果扩展到与人类关系更密切的动物物种，并旨在加快向人类临床试验的转化。

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 this application is to use animal models to test the possibility that patients with diabetes can potentially be treated with the adult stem/progenitor cells from human bone marrow variously referred to as fibroblastoid colony forming units, mesenchymal stem cells, or multipotent mesenchymal stromal cells (MSCs). We and others previously demonstrated that MSCs have the remarkable property that they home to injured tissues and repair them. Recently, we found that after human MSCs were infused into immunodeficient mice with Type I diabetes, induced by streptozotocin (STZ)-injection; the human cells homed to the pancreas, activated ¿-cells, and increased secretion of mouse insulin sufficiently to lower blood glucose. The cells also homed to renal glomeruli and perhaps improved the pathological changes in the kidneys. The results therefore raised the possibility that administration of a large number of a patient's own MSCs may provide an effective means of repairing the damage to pancreatic and other tissues that occurs in diabetes. Our strategy is to examine the therapeutic potential of MSCs in a non-human primate model of Type I diabetes. The Specific Aim for this proposal is to determine whether autologous MSCs, expanded ex vivo and reinfused into non-human primates with Type I diabetes mellitus (T1DM) can improve ¿-cell function, lower blood glucose, improve glucose tolerance, and improve renal function. To date, a dose escalation study of MSCs has been completed in one rhesus macaque. MSCs were infused as follows: starting at 50X106 MSCs infused on Day 0 (60 days after STZ infusion), 100X106 cells on Day 7, 200x106 cells on Day 30 and peaking at 200x106 cells on Day 50. Data collected so far indicate that after the second dose of 200X106 cells blood glucose levels have decreased markedly and approached nromal levels. Currently, a second animal is beginning on this study. These experiments will extend the results of the mouse model studies to an animal species more closely related to humans, and have been designed to accelerate the translation to human clinical trials.