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Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties

  • Gang Ren
  • Melika Rezaee
  • Mehdi Razavi
  • Ahmed Taysir
  • Jing Wang
  • Avnesh S ThakorEmail author
Regular Article
  • 67 Downloads

Abstract

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.

Keywords

Islet transplantation Islet number Mesenchymal stem cells Angiogenesis Diabetes 

Abbreviations

AD

Adipose tissue

Ang-1

Angiopoietin-1

APLAC

Administrative Panel on Laboratory Animal Care

bFGF

Basic fibroblast growth factor

BM

Bone marrow

DTZ

Dithizone

FBG

Fasting blood glucose

FDA

Fluorescein diacetate

HBSS

Hank’s balanced salt solution

HGF

Hepatocyte growth factor

HIF-1α

Hypoxia-inducible factor-1α

IBMIR

Instant blood-mediated inflammatory reaction

IDO

Indoleamine 2,3-dioxygenase

ITX

Islet transplantation

MSC

Mesenchymal stem cell

NBF

Neutral buffered formalin

PGE2

Prostaglandin E2

PI

Propidium iodide

STZ

Streptozotocin

TNF-α

Tumor necrosis factor-α

T1DM

Diabetes mellitus type 1

UC

Umbilical cord

VEGF

Vascular endothelial growth factor

vWF

Von Willebrand factor

Notes

Acknowledgments

This work was supported by the NIDDK/NIH award to the Stanford Diabetes Research Center (P30DK116074).

Authors’ contribution

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Gang Ren
    • 1
  • Melika Rezaee
    • 1
    • 2
  • Mehdi Razavi
    • 1
  • Ahmed Taysir
    • 1
  • Jing Wang
    • 1
  • Avnesh S Thakor
    • 1
    Email author
  1. 1.Interventional Regenerative Medicine and Imaging LaboratoryStanford University, Department of RadiologyPalo AltoUSA
  2. 2.Chicago Medical SchoolRosalind Franklin UniversityNorth ChicagoUSA

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