caa a22 4500 445311916 CHVBK 20180317142633.0 cr unu---uuuuu 170323e20110901xx s 000 0 eng 10.1007/s11095-011-0434-5 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0434-5 Mesenchymal Stem Cells as a Gene Delivery Vehicle for Successful Islet Transplantation [Elektronische Daten] [Hao Wu, Wenli Lu, Ram Mahato] ABSTRACT: Purpose: To evaluate the efficacy of human bone marrow-derived mesenchymal stem cells (hBMSCs) as gene delivery vehicles to simultaneously express human hepatocyte growth factor (HGF) and interleukin 1 receptor antagonist (IL-1Ra) to improve the outcome of islet transplantation. Methods: Morphology and islet-binding affinity of hBMSCs were checked by microscope. The expression of target genes and endogenous genes was determined by ELISA. Protection of islets by hBMSCs was evaluated in vitro by Calcein-AM/Propidium Iodide staining and in vivo by allogeneic islet transplantation study. Function and revascularization of islets was evaluated by immune fluorescence study. Results: Non-donor-specific hBMSCs showed strong binding affinity to human islets and protected viability and function. Transduction of hBMSCs with adenovirus encoding human HGF and human IL-1Ra (Adv-hHGF-hIL-1Ra) prior to co-culturing with islets further protected from apoptotic cell death, helped maintain 3D structures and morphology, and enhanced insulin secretion. Transplantation of human islets reconstituted with Adv-hHGF-hIL-1Ra transduced hBMSCs under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice reversed diabetes by reducing blood glucose levels to ≤200mg/dL for up to 15weeks and reduced the number of islets required to achieving normoglycemia. Blood glucose levels of mice transplanted with islets alone reversed to ≥500mg/dL 4weeks post-transplantation. Conclusions: Results indentified hBMSCs as effective gene delivery vehicles to improve the outcome of islet transplantation. Springer Science+Business Media, LLC, 2011 adenovirus nationallicence gene therapy nationallicence islet transplantation nationallicence mesenchymal stem cells nationallicence Adv : adenoviral vector nationallicence DAPI : 6-diamidino-2-phenylindole nationallicence GFP : green fluorescent protein nationallicence hBMSCs : human bone marrow derived mesenchymal stem cells nationallicence HGF : hepatocyte growth factor nationallicence IL-1β : interleukin-1 beta nationallicence IL-1Ra : interleukin 1 receptor antagonist nationallicence MHC : major histocompatibility complex nationallicence MMP : matrix metalloproteinases nationallicence MOI : multiplicity of infection nationallicence NOD-SCID : non-obese diabetic/severe combined immunodeficient nationallicence PBS : phosphate-buffered solution nationallicence PGE : prostaglandin E nationallicence SCF : stem cell factor nationallicence STZ : streptozotocin nationallicence TGF-β1 : transforming growth factor-beta 1 nationallicence VEGF : vascular endothelial growth factor nationallicence vWF : von-willebrand factor nationallicence Wu Hao Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut Lu Wenli Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut Mahato Ram Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/9(2011-09-01), 2098-2109 0724-8741 28:9<2098 2011 28 11095 https://doi.org/10.1007/s11095-011-0434-5 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0434-5 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Wu Hao Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut NATIONALLICENCE 700 1- Lu Wenli Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut NATIONALLICENCE 700 1- Mahato Ram Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, 19 S. Manassas, RM 224, 38103-3308, Memphis, Tennessee, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/9(2011-09-01), 2098-2109 0724-8741 28:9<2098 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer