title: Multiple intravenous transplantations of mesenchymal stem cells effectively restore long-term blood glucose homeostasis by hepatic engraftment and β-cell differentiation in streptozocin-induced diabetic mice.
abstract: Depletion of pancreatic β-cells results in insulin insufficiency and diabetes mellitus (DM). Single transplantation of mesenchymal stem cells exhibits short-term effects in some preclinical studies. Here, we further investigated the long-term therapeutic effects of multiple intravenous  MSC transplantations. In this study, multiple human MSC transplantations (4.2 × 10(7) cells/kg each time) were performed intravenously at 2-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 seventh 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 coexpressed human insulin, especially those surrounding the central veins. Taken together, intravenous MSC delivery was safe  and effective for blood glucose stabilization in this preclinical 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.
authors: Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors: Jennifer H
authors: JH
authors: Ho
authors: Tzu-Ching
authors: TC
authors: Tseng
authors: Wei-Hsien
authors: WH
authors: Ma
authors: Wei-Kee
authors: WK
authors: Ong
authors: Yu-Fan
authors: YF
authors: Chen
authors: Ming-Hsiang
authors: MH
authors: Chen
authors: Ming-Wei
authors: MW
authors: Lin
authors: Chuang-Ye
authors: CY
authors: Hong
authors: Oscar K
authors: OK
authors: Lee
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D002454:Cell Differentiation; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D006801:Humans; D007275:Injections, Intravenous; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008099:Liver / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D014280:Triglycerides / Q000097:blood
chemical_list: D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides; D002784:Cholesterol