title: Pancreatic insulin-producing cells differentiated from human embryonic stem cells correct hyperglycemia in SCID/NOD mice, an animal model of diabetes.
abstract: BACKGROUND
  Human pancreatic islet transplantation is a prospective curative treatment for diabetes. However, the lack of donor pancreases greatly limits this approach. One approach to overcome the limited supply of donor pancreases is to generate functional islets from human embryonic stem cells (hESCs), a cell line with unlimited proliferative capacity, through rapid directed differentiation. This study investigated whether pancreatic insulin-producing cells (IPCs) differentiated from hESCs could correct hyperglycemia in severe combined immunodeficient (SCID)/non-obese diabetic (NOD) mice, an animal model of diabetes.
  
  
  METHODS
  We generated pancreatic IPCs from two hESC lines, YT1 and YT2, using an optimized four-stage differentiation protocol in a chemically defined culture system. Then, about 5-7 × 10(6) differentiated cells were transplanted into the epididymal fat pad of SCID/NOD mice (n = 20). The control group were transplanted with undifferentiated hESCs (n = 6). Graft survival and function were assessed using immunohistochemistry, and measuring serum human C-peptide and blood glucose levels.
  
  
  RESULTS
  The pancreatic IPCs were generated by the four-stage differentiation protocol using hESCs. About 17.1% of differentiated cells expressed insulin, as determined by flow cytometry. These cells secreted insulin/C-peptide following glucose stimulation, similarly to adult human islets. Most of these IPCs co-expressed mature β cell-specific markers, including human C-peptide, GLUT2, PDX1, insulin, and glucagon. After implantation into the epididymal fat pad of SCID/NOD mice, the hESC-derived pancreatic IPCs corrected hyperglycemia for ≥ 8 weeks. None of the animals transplanted with pancreatic IPCs developed tumors during the time. The mean survival of recipients was increased by implanted IPCs as compared to implanted undifferentiated hESCs (P<0.0001).
  
  
  CONCLUSIONS
  The results of this study confirmed that human terminally differentiated pancreatic IPCs derived from hESCs can correct hyperglycemia in SCID/NOD mice for ≥8 weeks.
authors.affiliation: Department of Endocrinology, Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Xiu-feng
authors.initials: XF
authors.lastname: Hua
authors.affiliation: Research Center of Stem Cell Engineering of Shandong, Central Laboratory of Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Yan-wei
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Yu-xiao
authors.initials: YX
authors.lastname: Tang
authors.affiliation: Department of Urology, Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Sheng-qiang
authors.initials: SQ
authors.lastname: Yu
authors.affiliation: Department of clinical laboratory, Yuhuangding Hospital, Yantai, Shangdong Province, China.
authors.forename: Shao-hua
authors.initials: SH
authors.lastname: Jin
authors.affiliation: Department of Endocrinology, Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Meng
authors.affiliation: Department of Endocrinology, Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Hua-feng
authors.initials: HF
authors.lastname: Li
authors.affiliation: Research Center of Stem Cell Engineering of Shandong, Central Laboratory of Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Fu-jun
authors.initials: FJ
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, Chinese people's Liberation Army Navy 407 hospital, Yantai, Shandong Province, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Research Center of Stem Cell Engineering of Shandong, Central Laboratory of Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Hai-yan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Research Center of Stem Cell Engineering of Shandong, Central Laboratory of Yuhuangding Hospital, Yantai, Shandong Province, China.
authors.forename: Jian-yuan
authors.initials: JY
authors.lastname: Li
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002096:C-Peptide / Q000097:blood; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000637:transplantation*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000378:metabolism / Q000473:pathology
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin