title: Effective endothelial cell and human pluripotent stem cell interactions generate functional insulin-producing beta cells.
abstract: Endothelial cells (ECs) play an essential role in pancreatic organogenesis. We hypothesise that effective in vitro interactions between human microvascular endothelial cells (HMECs) and human pluripotent stem cells (hPSCs) results in the generation of functional pancreatic beta cells.
  
  
  
  Embryoid bodies (EBs) derived from hPSCs were cultured alone (controls) or with ECs in collagen gels. Subsequently, cells were analysed for pancreatic beta cell markers, and then isolated and expanded. Insulin secretion in response to glucose was evaluated in vitro by static and dynamic (perifusion) assays, and in vivo by EB transplantation into immunodeficient mice.
  
  
  
  Co-cultured EBs had a higher expression of mature beta cells markers and enhanced insulin secretion in vitro, compared with controls. In mice, transplanted EBs had higher levels of human C-peptide secretion with a significant reduction in hyperglycaemia after the selective destruction of native pancreatic beta cells. In addition, there was significant in vitro upregulation of bone morphogenetic proteins 2 and 4 (BMP-2, 4) in co-cultured cells, compared with controls.
  
  
  
  ECs provide essential signalling in vitro, such as activation of the BMP pathway, for derivation of functional insulin-producing beta cells from hPSCs.
authors: Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, 251E, Los Angeles, CA, 90048, USA. Talaverad@cshs.org.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Talaverad@cshs.org.
authors: Dodanim
authors: D
authors: Talavera-Adame
authors: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Orison O
authors: OO
authors: Woolcott
authors: Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Joseph
authors: J
authors: Ignatius-Irudayam
authors: Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, 251E, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Vaithilingaraja
authors: V
authors: Arumugaswami
authors: Pediatric Endocrinology, Children's Hospital, Los Angeles, CA, USA.
authors: David H
authors: DH
authors: Geller
authors: Comprehensive Transplant Center, Department of Surgery, Cedars-Sinai Medical Center, 8900 Beverly Boulevard, 251E, Los Angeles, CA, 90048, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Donald C
authors: DC
authors: Dafoe
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D002460:Cell Line; D058732:Embryoid Bodies / Q000166:cytology / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*
chemical_list: C525718:BMP2 protein, human; C525809:BMP4 protein, human; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D007328:Insulin
keywords: Endothelium; Insulin secretion in vitro; Stem cells