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

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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.

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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

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Acknowledgments

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

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Authors and Affiliations

  1. Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA

    Gang Ren, Melika Rezaee, Mehdi Razavi, Ahmed Taysir, Jing Wang & Avnesh S Thakor

  2. Chicago Medical School, Rosalind Franklin University, North Chicago, IL, 60064, USA

    Melika Rezaee

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  1. Gang Ren
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  2. Melika Rezaee
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Contributions

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.

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Correspondence to Avnesh S Thakor.

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Ren, G., Rezaee, M., Razavi, M. et al. Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell Tissue Res 376, 353–364 (2019). https://doi.org/10.1007/s00441-019-02997-w

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