MESENCHYMAL STEM CELL THERAPY FOR DIABETES

这个子项目是许多利用 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。 本申请的总体目的是使用动物模型来测试糖尿病患者可以潜在地用来自人骨髓的成体干细胞/祖细胞治疗的可能性，所述成体干细胞/祖细胞被不同地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（MSC）。 我们和其他人以前证明了MSC具有显着的特性，它们可以回到受伤的组织并修复它们。 最近，我们发现，在将人MSC输注到由链脲佐菌素（STZ）注射诱导的I型糖尿病免疫缺陷小鼠中后，人细胞归巢到胰腺，激活胰岛细胞，并增加小鼠胰岛素的分泌，足以降低血糖。 这些细胞也归巢到肾小球，并可能改善肾脏的病理变化。 因此，这些结果提出了一种可能性，即给予大量患者自身的MSC可以提供一种有效的手段来修复糖尿病中发生的胰腺和其他组织损伤。 我们的策略是研究MSC在非人灵长类动物I型糖尿病模型中的治疗潜力。本提案的具体目的是确定自体MSC，体外扩增并回输至患有I型糖尿病（T1 DM）的非人灵长类动物中是否可以改善细胞功能，降低血糖，改善葡萄糖耐量和改善肾功能。 迄今为止，已经在一只恒河猴中完成了MSC的剂量递增研究。MSC输注如下：在第0天（STZ输注后60天）输注50 × 106个MSC开始，在第7天输注100 × 106个细胞，在第30天输注200 × 106个细胞，在第50天达到峰值200 × 106个细胞。到目前为止收集的数据表明，在第二剂200 × 106细胞后，血糖水平显著降低并接近正常水平。目前，第二只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，并旨在加速转化为人类临床试验。

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.