title: Coculturing Human Islets with Proangiogenic Support Cells to Improve Islet Revascularization at the Subcutaneous Transplantation Site.
abstract: While subcutaneous tissue has been proposed as a clinically relevant site for pancreatic islet transplantation, a major issue of concern remains, which is 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 nonadherent agarose microwell templates. In this study, we assessed the three-dimensional structure, function, and angiogenic potential of human CIs with human mesenchymal stromal cells (hMSCs), with or without human umbilical vein endothelial cells (HUVECs), and preconditioned hMSCs (PC-hMSCs) in EGM-2 under shear stress. Distinct cellular rearrangements could be observed in CIs, but islet functionality was maintained. In vitro angiogenesis assays found significantly enhanced sprout formation in case of CIs. In particular, the number of sprouts emanating from CIs with PC-hMSCs was significantly increased compared to other conditions. Subsequent in vivo assessment confirmed the proangiogenic potential of CIs. However, in contrast to our in vitro angiogenesis assays, CIs 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 CIs with proangiogenic support cells to enhance islet revascularization at a clinically relevant, although poorly vascularized, transplantation site.
authors.affiliation: 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Mijke
authors.initials: M
authors.lastname: Buitinga
authors.affiliation: 2 Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Karolina
authors.initials: K
authors.lastname: Janeczek Portalska
authors.affiliation: 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Cornelissen
authors.affiliation: 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Plass
authors.affiliation: 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .
authors.forename: Maaike
authors.initials: M
authors.lastname: Hanegraaf
authors.affiliation: 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .
authors.forename: Françoise
authors.initials: F
authors.lastname: Carlotti
authors.affiliation: 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .|4 Department of Endocrinology, Leiden University Medical Center , Leiden, The Netherlands .|5 Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht , Utrecht, The Netherlands .
authors.forename: Eelco
authors.initials: E
authors.lastname: de Koning
authors.affiliation: 3 Department of Nephrology, Leiden University Medical Center , Leiden, The Netherlands .
authors.forename: Marten
authors.initials: M
authors.lastname: Engelse
authors.affiliation: 6 Department of Complex Tissue Regeneration, Institute for Technology Inspired Regenerative Medicine (MERLN), Maastricht University , Maastricht, The Netherlands .
authors.forename: Clemens
authors.initials: C
authors.lastname: van Blitterswijk
authors.affiliation: 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Marcel
authors.initials: M
authors.lastname: Karperien
authors.affiliation: 1 Department of Developmental BioEngineering, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente , Enschede, The Netherlands .
authors.forename: Aart
authors.initials: A
authors.lastname: van Apeldoorn
authors.affiliation: 7 Laboratory for Cell Biology-Inspired Tissue Engineering, Institute for Technology Inspired Regenerative Medicine (MERLN) , Maastricht, The Netherlands .
authors.forename: Jan
authors.initials: J
authors.lastname: de Boer
mesh_terms: D018920:Coculture Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000098:blood supply* / Q000166:cytology* / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D018919:Neovascularization, Physiologic