title: Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells into Insulin-Producing Cells: Evidence for Further Maturation In Vivo.
abstract: The aim of this study was to provide evidence for further in vivo maturation of insulin-producing cells (IPCs) derived from human bone marrow-derived mesenchymal stem cells (HBM-MSCs). HBM-MSCs were obtained from three insulin-dependent type 2 diabetic volunteers. Following expansion, cells were differentiated according to a trichostatin-A/GLP protocol. One million cells were transplanted under the renal capsule of 29 diabetic nude mice. Blood glucose, serum human insulin and c-peptide levels, and glucose tolerance curves were determined. Mice were euthanized 1, 2, 4, or 12 weeks after transplantation. IPC-bearing kidneys were immunolabeled, number of IPCs was counted, and expression of relevant genes was determined. At the end of in vitro differentiation, all pancreatic endocrine genes were expressed, albeit at very low values. The percentage of IPCs among transplanted cells was small (≤3%). Diabetic animals became euglycemic 8 ± 3 days after transplantation. Thereafter, the percentage of IPCs reached a mean of ~18% at 4 weeks. Relative gene expression of insulin, glucagon, and somatostatin showed a parallel increase. The ability of the transplanted cells to induce euglycemia was due to their further maturation in the favorable in vivo microenvironment. Elucidation of the exact mechanism(s) involved requires further investigation.
authors.affiliation: Department of Biotechnology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Gabr
authors.affiliation: Department of Biotechnology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Zakaria
authors.affiliation: Department of Nephrology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Ayman F
authors.initials: AF
authors.lastname: Refaie
authors.affiliation: Department of Pathology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Sherry M
authors.initials: SM
authors.lastname: Khater
authors.affiliation: Department of Pathology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Ashamallah
authors.affiliation: Department of Immunology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Amani M
authors.initials: AM
authors.lastname: Ismail
authors.affiliation: Department of Biotechnology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Sawsan M
authors.initials: SM
authors.lastname: El-Halawani
authors.affiliation: Department of Urology, Urology and Nephrology Center, Mansoura 35516, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Ghoneim
mesh_terms: D000818:Animals; D001786:Blood Glucose; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation / Q000235:genetics*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy*; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D001786:Blood Glucose; D007328:Insulin; D005934:Glucagon