Secreted factors from dental pulp stem cells improve glucose intolerance in streptozotocin-induced diabetic mice by increasing pancreatic ß-cell function.

OBJECTIVE: Many studies have reported that stem cell transplantation promotes propagation and protection of pancreatic ß-cells in streptozotocin (STZ)-induced diabetic mice without the differentiation of transplanted cells into pancreatic ß-cells, suggesting that the improvement is due to a paracrine effect of the transplanted cells. We investigated the effects of factors secreted by dental pulp stem cells from human exfoliated deciduous teeth (SHED) on ß-cell function and survival. RESEARCH DESIGN AND METHODS: Conditioned medium from SHED (SHED-CM) was collected 48 h after culturing in serum-free Dulbecco's modified Eagle's medium (DMEM). The insulin levels in SHED-CM and serum-free conditioned media from human bone marrow-derived mesenchymal stem cells (BM-CM) were undetectable. STZ-induced diabetic male C57B/6J mice were injected with DMEM as a control, SHED-CM, exendin-4 (Ex-4), or BM-CM for 14 days. Mouse pancreatic ß-cell line MIN6 cells were incubated with different concentrations of STZ with SHED-CM, DMEM, Ex-4, or BM-CM for 6 h. RESULTS: Administration of 1 mL of SHED-CM twice a day improved glucose intolerance in STZ-induced diabetic mice and the effect continued for 20 days after the end of treatment. SHED-CM treatment increased pancreatic insulin content and ß-cell mass through proliferation and an intraperitoneal glucose tolerance test revealed enhanced insulin secretion. Incubation of MIN6 cells (a mouse pancreatic ß-cell line) with SHED-CM enhanced insulin secretion in a glucose concentration-dependent manner and reduced STZ-induced cell death, indicating that the amelioration of hyperglycemia was caused by the direct effects of SHED-CM on ß-cell function and survival. These effects were more pronounced than with the use of Ex-4, a conventional incretin-based drug, and BM-CM, which is a medium derived from other stem cells. CONCLUSIONS: These findings suggest that SHED-CM provides direct protection and encourages the propagation of ß-cells, and has potential as a novel strategy for treatment of diabetes.