Mary Ann Liebert, Tissue Engineering Part B: Reviews, 3-4(22), p. 375-385
DOI: 10.1089/ten.tea.2015.0317
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While subcutaneous tissue has been proposed as a clinically relevant site for pancreatic islet transplantation, a major issue of concern remains its poor vascular state. In an effort to overcome this limitation, we present an efficient and reproducible method to form human composite islets (CIs) with proangiogenic cell types in a controlled manner using non-adherent agarose microwell templates. In this study, we assessed the three dimensional structure, function and angiogenic potential of composite human islets with human mesenchymal stromal cells (hMSCs), with or without human umbilical vein endothelial cells (HUVECs), and pre-conditioned hMSCs in EGM-2 medium under shear-stress (PC-hMSCs). Distinct cellular rearrangements could be observed in composite islets, but islet functionality was maintained. In vitro angiogenesis assays found significantly enhanced sprout formation in case of composite islets. In particular, the number of sprouts emanating from composite islets with PC-hMSCs was significantly increased compared to other conditions. Subsequent in vivo assessment confirmed the proangiogenic potential of composite islets. However, in contrast to our in vitro angiogenesis assays, composite islets with hMSCs and HUVECs exhibited a higher in vivo angiogenic potential compared to control islets or islets combined with hMSCs or PC-hMSCs. These findings highlight the importance and necessity of verifying in vitro studies with in vivo models to reliably predict, in this case, revascularization outcomes. Regardless, we demonstrate here the therapeutic potential of composite islets with pro-angiogenic support cells to enhance islet revascularization at a clinically relevant, though poorly vascularized transplantation site.