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Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and beta cell differentiation in streptozosin-induced diabetic mice
Authors: Jennifer H. Ho, Tzu-Ching Tseng, Wei-Hsien Ma, Wei-Kee Ong, Yu-Fan Chen, Ming-Hsiang Chen, Ming-Wei Lin, Chuang-Ye Hong, Oscar K Lee
Source: Cell Transplantation
Publisher: Cognizant Communication Corporation
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Abstract:
Depletion of pancreatic beta cells results in insulin insufficiency and diabetes mellitus (DM). Single transplantation of mesenchymal stem cells exhibits short-term effects in some pre-clinical studies. Here, we further investigated the long-term therapeutic effects of multiple intravenous MSCs transplantations. In this study, multiple human MSC transplantations (4.2 x 10⁷ cells/kg each time) were performed intravenously at two-week intervals into streptozocin (STZ)-induced diabetic mice for 6 months. Blood sugar, insulin, renal function, cholesterol and triglyceride levels were monitored. We demonstrated that compared to single intravenous transplantation, which only transiently decreased hyperglycemia, multiple MSC transplantations effectively restored blood glucose homeostasis. Systemic oxidative stress levels were reduced from the 7th week of treatment. From the 11th week, production of human insulin was markedly increased. When MSC transplantation was skipped after blood sugar level returned to normal at the end of 15th week, a sharp rebound of blood sugar occurred, and was then controlled by subsequent transplantations. At the end of 6 months, histopathology examination revealed MSCs specifically engrafted into liver tissues of the recipients. Fifty-one percent of human cells in the recipient liver co-expressed human insulin, especially those surrounding the central veins. Taken together, intravenous MSCs delivery was safe and effective for blood glucose stabilization in this pre-clinical DM model. Multiple transplantations were essential to restore and maintain glucose homeostasis through decreasing systemic oxidative stress in the early stage and insulin production in the late stage. Liver engraftment and differentiation into insulin-producing cells account for the long-term therapeutic effects of MSCs.Document Type:
DOI: http://dx.doi.org/10.3727/096368911X603611
Appeared or available online: October 14, 2011
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