title: Spontaneous in vivo differentiation of embryonic stem cell-derived pancreatic endoderm-like cells corrects hyperglycemia in diabetic mice.
abstract: BACKGROUND
  Whole pancreas and islet transplantation are currently used for the treatment of type 1 diabetes. However, the major limitations of this potentially curative approach are an inadequate supply of cadaveric pancreata, lifelong immunosuppression, and chronic graft rejection. Therefore, there is an urgent need to develop new sources of insulin-producing cells (IPCs). Here, we investigated whether embryonic stem (ES) cells can be exploited for the derivation of IPCs, and whether their transplantation can correct hyperglycemia in diabetic mice.
  
  
  METHODS
  ES cells engineered to express pancreatic and duodenal homeobox 1 (Pdx1), a critical pancreatic transcription factor, were differentiated into pancreatic endoderm-like cells (PELCs) and evaluated for their potential to correct hyperglycemia after transplantation in diabetic mice.
  
  
  RESULTS
  After systemic injection, PELCs localized to the pancreas, liver, and kidney. They then spontaneously differentiated into IPCs that corrected hyperglycemia in diabetic mice. When transplanted under the kidney capsule, PELC-derived IPCs were equally efficient at correcting hyperglycemia. Real-time noninvasive in vivo bioluminescence imaging (BLI) of rat insulin promoter (RIP)-driven luciferase was used to monitor the fate of the transplanted PELCs. To confirm that the transplanted cells were responsible for the correction of hyperglycemia, kidneys containing the transplanted cells were nephrectomized, causing rapid hyperglycemia. Interestingly, none of the animals transplanted with PELCs developed tumors, a potential consequence of the differentiation and purification procedures.
  
  
  CONCLUSIONS
  Our data suggest that Pdx1-expressing PELCs are capable of spontaneously undergoing differentiation in vivo into IPCs and leading to a sustained correction of hyperglycemia in diabetic mice.
authors: Division of Immunology, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA, USA. sudhanshu-raikwar@uiowa.edu
authors: Sudhanshu P
authors: SP
authors: Raikwar
authors: Nicholas
authors: N
authors: Zavazava
mesh_terms: D028341:Activins / Q000378:metabolism; D000818:Animals; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D004707:Endoderm / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006943:Hyperglycemia / Q000628:therapy*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D051379:Mice; D010179:Pancreas / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019718:Receptors, CXCR4 / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C514936:CXCR4 protein, mouse; D018398:Homeodomain Proteins; D019718:Receptors, CXCR4; D015534:Trans-Activators; C422405:activin A; C084010:pancreatic and duodenal homeobox 1 protein; D028341:Activins