D. Horkan1, B. Wang1, Y. Li1, Z. Liu1, O. Velazquez1 1University Of Miami,Division Of Vascular And Endovascular Surgery, Department Of Surgery, Leonard M. Miller School Of Medicine,Miami, FL, USA
Introduction: Diabetes mellitus (diabetes) is the most common metabolic disorder in the United States affecting an estimated 29 million Americans. In diabetes, pancreatic islet injury results in disordered glucose metabolism leading to ischemic heart disease, peripheral arterial disease, and renal damage which are responsible for morbidity and mortality. Current therapies show promise for cure, but are limited due to emphasis on replacement of or compensation for the dysfunctional pancreatic islet rather than repair of damaged islet tissue. Mesenchymal stem cells (MSC) carry high therapeutic potential for tissue regeneration and are ideal therapeutic tools for repairing damaged pancreatic islet. Herein, we tested the effect on hyperglycemia of a novel stem cells-based therapy using nanocarrier-modified MSC for targeted repair of injured pancreatic islet in a mouse model of type 1 diabetes.
Methods: Bone marrow cells were harvested from C57BL6 mice and cultured in MesenCult™ medium to selectively enrich MSC. Cultured MSC were modified with a cell membrane-bound nanocarrier composed of poly(amidoamine) (PAMAM) dendrimer coupled with either a specific adhesion molecule or albumin as control. These nanocarrier–modified MSC selectively associate with counterpart adhesion molecules highly or selectively expressed on the inflamed islet endothelium of recipient diabetic mice, which are streptozocin-induced C57BL6. Low-dose intraperitoneal injection of streptozocin induces type 1 diabetes with concurrent islet inflammation. 1 x 10^6 nanocarrier (PAMAM-adhesion molecule)- versus control nanocarrier (PAMAM-albumin)-modified MSC were infused into recipient diabetic mice via the tail vein (N=5/group) at two and five weeks post-streptozocin induction. For each group, blood glucose levels (BG) were measured at baseline and weekly thereafter.
Results: At baseline, mean BG values for control and experimental groups were euglycemic with no statistically significant difference (98 mg/dL vs 101, ρ = 0.35). One week post-streptozocin induction, mean BG for both groups showed hyperglycemia with no statistical difference (456 vs 444, ρ = 0.36). At seven weeks post-streptozocin induction, control group mice showed statistically significant higher mean BG compared to experiment group (548 vs 362, ρ = 0.02).
Conclusion: In our murine model of type 1 diabetes, systemic administration of nanocarrier-modified MSC showed significantly improved hyperglycemia compared to administration of control MSC. Our results revealed a promising therapeutic effect of nanocarrier-modified MSC on improving hyperglycemia, which is presumably achieved through targeted repair of inflamed/injured pancreatic islet. Notably, however, this therapy failed to normalize blood glucose levels after eight weeks of follow-up. It may be that administration of nanocarrier-modified MSC earlier in the inflammatory process could lead to repair of islet and normalization of glucose levels in diabetes.