Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties
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A significant proportion of islets are lost following transplantation due to hypoxia and inflammation. We hypothesize that adipose tissue-derived mesenchymal stem cells (AD-MSCs) can rescue a sub-therapeutic number of transplanted islets by helping them establish a new blood supply and reducing inflammation. Diabetic mice received syngeneic transplantation with 75 (minimal), 150 (sub-therapeutic), or 225 (therapeutic) islets, with or without 1 × 106 mouse AD-MSCs. Fasting blood glucose (FBG) values were measured over 6 weeks with tissue samples collected for islet structure and morphology (H&E, insulin/glucagon staining). Histological and immunohistochemical analyses of islets were also performed at 2 weeks in animals transplanted with a sub-therapeutic number of islets, with and without AD-MSCs, to determine new blood vessel formation, the presence of pro-angiogenic factors facilitating revascularization, and the degree of inflammation. AD-MSCs had no beneficial effect on FBG values when co-transplanted with a minimal or therapeutic number of islets. However, AD-MSCs significantly reduced FBG values and restored glycemic control in diabetic animals transplanted with a sub-therapeutic number of islets. Islets co-transplanted with AD-MSCs preserved their native morphology and organization and exhibited less aggregation when compared to islets transplanted alone. In the sub-therapeutic group, AD-MSCs significantly increased islet revascularization and the expression of angiogenic factors including hepatocyte growth factor (HGF) and angiopoietin-1 (Ang-1) while also reducing inflammation. AD-MSCs can rescue the function of islets when transplanted in a sub-therapeutic number, for at least 6 weeks, via their ability to maintain islet architecture while concurrently facilitating islet revascularization and reducing inflammation.
KeywordsIslet transplantation Islet number Mesenchymal stem cells Angiogenesis Diabetes
Administrative Panel on Laboratory Animal Care
Basic fibroblast growth factor
Fasting blood glucose
Hank’s balanced salt solution
Hepatocyte growth factor
Instant blood-mediated inflammatory reaction
Mesenchymal stem cell
Neutral buffered formalin
Tumor necrosis factor-α
Diabetes mellitus type 1
Vascular endothelial growth factor
Von Willebrand factor
This work was supported by the NIDDK/NIH award to the Stanford Diabetes Research Center (P30DK116074).
GR: Designed the study, performed the study, analyzed the data, and prepared the manuscript.
MR: Helped perform the study
MR: Helped analyze the data
AT: Helped perform the study
JW: Helped perform the study
AST: Designed the study and prepared the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Statement of animal welfare
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
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