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

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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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 co-expressed 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.

Original languageEnglish
Pages (from-to)997-1009
Number of pages13
JournalCell Transplantation
Volume21
Issue number5
DOIs
Publication statusPublished - 2012

Fingerprint

Mesenchymal Stem Cell Transplantation
Insulin
Streptozocin
Stem cells
Glucose
Blood Glucose
Cell Differentiation
Hepatocytes
Homeostasis
Blood
Transplantation
Sugars
Liver
Oxidative stress
Medical problems
Therapeutic Uses
Diabetes Mellitus
Oxidative Stress
Cholesterol
Hyperglycemia

Keywords

  • β-cell depletion
  • Blood glucose homeostasis
  • Liver engraftment
  • Mesenchymal stem cells (MSCs)
  • Multiple intravenous transplantations

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation
  • Biomedical Engineering

Cite this

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. / Ho, Jennifer H.; Tseng, Tzu Ching; Ma, Wei Hsien; Ong, Wei Kee; Chen, Yu Fan; Chen, Ming Hsiang; Lin, Ming Wei; Hong, Chuang Ye; Lee, Oscar K.

In: Cell Transplantation, Vol. 21, No. 5, 2012, p. 997-1009.

Research output: Contribution to journalArticle

Ho, Jennifer H. ; Tseng, Tzu Ching ; Ma, Wei Hsien ; Ong, Wei Kee ; Chen, Yu Fan ; Chen, Ming Hsiang ; Lin, Ming Wei ; Hong, Chuang Ye ; Lee, Oscar K. / 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. In: Cell Transplantation. 2012 ; Vol. 21, No. 5. pp. 997-1009.
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