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.
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