title: Insulin-Producing Cells Differentiated from Human Bone Marrow Mesenchymal Stem Cells In Vitro Ameliorate Streptozotocin-Induced Diabetic Hyperglycemia.
abstract: BACKGROUND
  The two major obstacles in the successful transplantation of islets for diabetes treatment are inadequate supply of insulin-producing tissue and immune rejection. Induction of the differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) into insulin-producing cells (IPCs) for autologous transplantation may alleviate those limitations.
  
  
  METHODS
  hMSCs were isolated and induced to differentiate into IPCs through a three-stage differentiation protocol in a defined media with high glucose, nicotinamide, and exendin-4. The physiological characteristics and functions of IPCs were then evaluated. Next, about 3 × 10(6) differentiated cells were transplanted into the renal sub-capsular space of streptozotocin (STZ)-induced diabetic nude mice. Graft survival and function were assessed by immunohistochemistry, TUNEL staining and measurements of blood glucose levels in the mice.
  
  
  RESULTS
  The differentiated IPCs were characterized by Dithizone (DTZ) positive staining, expression of pancreatic β-cell markers, and human insulin secretion in response to glucose stimulation. Moreover, 43% of the IPCs showed L-type Ca2+ channel activity and similar changes in intracellular Ca2+ in response to glucose stimulation as that seen in pancreatic β-cells in the process of glucose-stimulated insulin secretion. Transplantation of functional IPCs into the renal subcapsular space of STZ-induced diabetic nude mice ameliorated the hyperglycemia. Immunofluorescence staining revealed that transplanted IPCs sustainably expressed insulin, c-peptide, and PDX-1 without apparent apoptosis in vivo.
  
  
  CONCLUSIONS
  IPCs derived from hMSCs in vitro can ameliorate STZ-induced diabetic hyperglycemia, which indicates that these hMSCs may be a promising approach to overcome the limitations of islet transplantation.
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.|Department of Pediatrics, Division of Endocrinology, University of Louisville, Wendy L. Novak Diabetes Care Center, Louisville, Kentucky, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Yishu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Xuejin
authors.initials: X
authors.lastname: Su
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Meiyu
authors.initials: M
authors.lastname: Sun
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Division of Endocrinology, University of Louisville, Wendy L. Novak Diabetes Care Center, Louisville, Kentucky, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Department of Pediatrics, Division of Endocrinology, University of Louisville, Wendy L. Novak Diabetes Care Center, Louisville, Kentucky, United States of America.
authors.forename: Kupper A
authors.initials: KA
authors.lastname: Wintergerst
authors.affiliation: Department of Orthopedic Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000166:cytology; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology*; D015220:Calcium Channels / Q000378:metabolism; D002454:Cell Differentiation; D019902:Chondrocytes / Q000166:cytology; D003470:Culture Media / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000628:therapy*; D004230:Dithizone / Q000737:chemistry; D000077270:Exenatide; D005947:Glucose / Q000737:chemistry; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000628:therapy*; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology; D007621:Karyotyping; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000737:chemistry; D010012:Osteogenesis; D010455:Peptides / Q000737:chemistry; D010641:Phenotype; D013311:Streptozocin; D014183:Transplantation, Heterologous; D014688:Venoms / Q000737:chemistry
chemical_list: D015220:Calcium Channels; D003470:Culture Media; D007328:Insulin; D010455:Peptides; D014688:Venoms; D009536:Niacinamide; D013311:Streptozocin; D004230:Dithizone; D000077270:Exenatide; D005947:Glucose