Evaluation of Multi-Layered Pancreatic Islets and Adipose-Derived Stem Cell Sheets Transplanted on Various Sites for Diabetes Treatment

Abstract

Islet cell transplantation is considered an ideal treatment for insulin-deficient diabetes, but implantation sites are limited and show low graft survival. Cell sheet technology and adipose-derived stem cells (ADSCs) can be useful tools for improving islet cell transplantation outcomes since both can increase implantation efficacy and graft survival. Herein, the optimal transplantation site in diabetic mice was investigated using islets and stem cell sheets. We constructed multi-layered cell sheets using rat/human islets and human ADSCs. Cell sheets were fabricated using temperature-responsive culture dishes. Islet/ADSC sheet (AI sheet) group showed higher viability and glucose-stimulated insulin secretion than islet-only group. Compared to islet transplantation alone, subcutaneous AI sheet transplantation showed better blood glucose control and CD31+ vascular traits. Because of the adhesive properties of cell sheets, AI sheets were easily applied on liver and peritoneal surfaces. Liver or peritoneal surface grafts showed better glucose control, weight gain, and intraperitoneal glucose tolerance test (IPGTT) profiles than subcutaneous site grafts using both rat and human islets. Stem cell sheets increased the therapeutic efficacy of islets in vivo because mesenchymal stem cells enhance islet function and induce neovascularization around transplanted islets. The liver and peritoneal surface can be used more effectively than the subcutaneous site in future clinical applications.

Decellularized Whole-Organ Pre-vascularization: A Novel Approach for Organogenesis

“…In comparison to diabetic rats, AUC was significantly lower (p 0.002) in the treatment group with functioning graft, while it was significantly higher (p < 0.001) in comparison to values from normal rats. 2021)) and their ability to improve the islet function (Jung et al, 2011;Chen et al, 2013;Lee et al, 2020;Yamashita et al, 2021). One study demonstrated a better vascularization after ADSC implantation than with BM-MSCs in a myocardial infarction (MI) model (Paul et al, 2013).…”

“…Several studies have demonstrated the angiogeneic potential of both ADSCs and BM-derived mesenchymal stem cells (BM-MSCs) (reviewed in ( Mazini et al, 2019 ; Liu and Holmes, 2021 )) and their ability to improve the islet function ( Jung et al, 2011 ; Chen et al, 2013 ; Lee et al, 2020 ; Yamashita et al, 2021 ). One study demonstrated a better vascularization after ADSC implantation than with BM-MSCs in a myocardial infarction (MI) model ( Paul et al, 2013 ).…”

“…While a direct comparison between BM-MSCs and ADSCs was not the target of the present study, with these cells instead compared to an acellular scaffold, our findings suggest that ADSCs did not offer any particular advantage over fresh BM (MSCs ≈0.004–0.009% of nucleated cells in murine BM ( Meirelles and Nardi, 2003 )) with regard to the islet function or number of newly formed vessels. Co-transplantation of either cell type alone without a pre-vascularization device was not reported to be successful in allowing the islet function in the subcutaneous tissue, although transplantation with ADSC-sheets showed promising results ( Lee et al, 2020 ; Yamashita et al, 2021 ). In vitro, ADSC-sheet + islets co-culture media showed significantly higher concentration of IL-8 compared to control ( Yamashita et al, 2021 ).…”

“…In addition to improving islet revascularization, BM-MSCs ( Chen et al, 2013 ; Wang et al, 2017 ; He et al, 2018 ) and ADSCs ( Lee et al, 2020 ; Yamashita et al, 2021 ) were shown to improve islet viability and stimulated insulin secretion in vitro . BM-MSCs also significantly upregulated insulin 1 (Ins1) and pancreatic and duodenal homeobox 1 (Pdx1) expression in islets ( Wang et al, 2017 ).…”

Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes

“…The mouse islet sheet did not correct serum hyperglycemia in diabetic recipient mice in our study, although other researchers have reported that multi-layered cell sheets boost glycemic stability and insulin function[ 144 - 146 ]. Lee et al [ 147 ] constructed multilayered cell sheets using rat/human islets and human adipose tissue-derived stem cells. We have successfully generated islet sheets from Tg pigs with a pancreas-specific expression of green fluorescent protein ( PDX1-Venus Tg Pig) and transplanted them onto the liver surface (Figure 2 ).…”