Abstract
Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. While transplanted bone marrow-derived mesenchymal stem/stromal cells (BMMSCs) have been explored as an alternative therapeutic approach for diseases, the choice of delivery route may be a critical factor determining their sustainability. This study evaluated the effects of intrapancreatic and intravenous injection of human BMMSCs (hBMMSCs) in streptozotocin (STZ)-induced type 1 diabetic mouse model. C57/BL6 mice were intraperitoneally injected with 115 mg/kg STZ on day 0. hBMMSCs (1 × 106 cells) or vehicle were injected into the pancreas or jugular vein on day 7. Intrapancreatic, but not intravenous, hBMMSC injection significantly reduced blood glucose levels on day 28 compared with vehicle injection by the same route. This glucose-lowering effect was not induced by intrapancreatic injection of human fibroblasts as the xenograft control. Intrapancreatically injected fluorescence-labeled hBMMSCs were observed in the intra- and extra-lobular spaces of the pancreas, and intravenously injected cells were in the lung region, although the number of cells mostly decreased within 2 weeks of injection. For hBMMSCs injected twice into the pancreatic region on days 7 and 28, the injected mice had further reduced blood glucose to borderline diabetic levels on day 56. Animals injected with hBMMSCs twice exhibited increases in the plasma insulin level, number and size of islets, insulin-positive proportion of the total pancreas area, and intensity of insulin staining compared with vehicle-injected animals. We found a decrease of Iba1-positive cells in islets and an increase of CD206-positive cells in both the endocrine and exocrine pancreas. The hBMMSC injection also reduced the number of CD40-positive cells merged with glucagon immunoreactions in the islets. These results suggest that intrapancreatic injection may be a better delivery route of hBMMSCs for the treatment of type 1 diabetes mellitus.
Highlights
Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia
We found that the CD40-positive area, which overlapped with α-cells, was increased after STZ treatment and reduced by intrapancreatic injection of human BMMSCs (hBMMSCs)
We demonstrated that intrapancreatic injection of hBMMSCs prevents hyperglycemia and restores body weight compared with intravenous injection into STZinduced diabetic mice
Summary
Type 1 diabetes mellitus is a progressive disease caused by the destruction of pancreatic β-cells, resulting in insulin dependency and hyperglycemia. Patients with the disease, who require exogenous insulin treatment, are at risk of blood glucose fluctuations and hypoglycemia. Pancreas or pancreatic islet transplantation is a promising treatment for patients who lack endogenous insulin secretion, those who experience recurrent episodes of severe hypoglycemia [1, 2]. Stem cell-based therapies have been explored as an alternative therapeutic approach for type 1 diabetes mellitus because of the relatively high availability of stem cells [6]. Carlsson et al have recently shown that hBMMSC transplantation preserves β-cell functions in patients with type 1 diabetes mellitus [15]. Further improvements in treatment outcomes might be facilitated by a better understanding of how hBMMSCs function and how they can be applied to treatment of type 1 diabetes mellitus
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