title: Inducible VEGF expression by human embryonic stem cell-derived mesenchymal stromal cells reduces the minimal islet mass required to reverse diabetes.
abstract: Islet transplantation has been hampered by loss of function due to poor revascularization. We hypothesize that co-transplantation of islets with human embryonic stem cell-derived mesenchymal stromal cells that conditionally overexpress VEGF (hESC-MSC:VEGF) may augment islet revascularization and reduce the minimal islet mass required to reverse diabetes in mice. HESC-MSCs were transduced by recombinant lentiviruses that allowed conditional (Dox-regulated) overexpression of VEGF.
  VEGF were characterized by tube formation assay. After co-transplantation of hESC-MSC:VEGF with murine islets in collagen-fibrin hydrogel in the omental pouch of diabetic nude mice, we measured blood glucose, body weight, glucose tolerance and serum C-peptide. As control, islets were transplanted alone or with non-transduced hESC-MSCs. Next, we compared functional parameters of 400 islets alone versus 200 islets co-transplanted with hESC-MSC:VEGF. As control, 200 islets were transplanted alone. Metabolic function of islets transplanted with hESC-MSC:VEGF significantly improved, accompanied by superior graft revascularization, compared with control groups. Transplantation of 200 islets with hESC-MSC:VEGF showed superior function over 400 islets alone. We conclude that co-transplantation of islets with VEGF-expressing hESC-MSCs allowed for at least a 50% reduction in minimal islet mass required to reverse diabetes in mice. This approach may contribute to alleviate the need for multiple donor organs per patient.
authors.affiliation: 1] National Cell Bank, Pasteur Institute of Iran, Tehran, Iran [2] Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: E
authors.initials: E
authors.lastname: Hajizadeh-Saffar
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: Y
authors.initials: Y
authors.lastname: Tahamtani
authors.affiliation: Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
authors.forename: N
authors.initials: N
authors.lastname: Aghdami
authors.affiliation: Department of Molecular Virology, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: K
authors.initials: K
authors.lastname: Azadmanesh
authors.affiliation: National Cell Bank, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: M
authors.initials: M
authors.lastname: Habibi-Anbouhi
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Heremans
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: De Leu
authors.affiliation: Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: H
authors.initials: H
authors.lastname: Heimberg
authors.affiliation: Biotechnology and Biotherapy Laboratory, University Pierre et Marie Curie, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Ravassard
authors.affiliation: National Cell Bank, Pasteur Institute of Iran, Tehran, Iran.
authors.forename: M A
authors.initials: MA
authors.lastname: Shokrgozar
authors.affiliation: 1] Department of Stem Cells and Developmental Biology at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran [2] Department of Developmental Biology, University of Science and Culture, ACECR, Tehran, Iran.
authors.forename: H
authors.initials: H
authors.lastname: Baharvand
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015870:Gene Expression; D000066449:Human Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D007515:Islets of Langerhans / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
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