Intrapancreatic injection of human bone marrow-derived mesenchymal stem/stromal cells alleviates hyperglycemia and modulates the macrophage state in streptozotocin-induced type 1 diabetic mice

PLoS One

Kazumichi Yagura¹  Hirokazu Ohtaki²  Shoichiro Nagasaka²  Kazuho Honda²  Shun Sasaki²  Zhifang Xu²  Seiji Shioda²  Norimitsu Murai³  Jun Watanabe⁴  Masahiko Izumizaki⁵ 

[1] Center for Biotechnology, Showa University, Tokyo, Japan;Department of Anatomy, Showa University School of Medicine, Tokyo, Japan;Department of Physiology, Showa University School of Medicine, Tokyo, Japan;Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan;Peptide Drug Innovation, Global Research Center for Innovative Life Science, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan

关键词: Pancreas;    Blood sugar;    Diabetes mellitus;    Insulin;    Intravenous injections;    Macrophages;    Body weight;    Mouse models;   

DOI  :  10.1371/journal.pone.0186637

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY