title: In vitro reprogramming of rat bone marrow-derived mesenchymal stem cells into insulin-producing cells by genetically manipulating negative and positive regulators.
abstract: Islet cell replacement therapy represents the most promising approach for the cure of type 1 diabetes if autoimmunity to β cells is under control. However, this potential is limited by a shortage of pancreas donors. To address the donor shortage problem, we determined whether bone marrow-derived mesenchymal stem cells (bmMSCs) can be directly reprogrammed to islet lineages by simultaneously forced suppression and over-expression of key regulator genes that play critical roles during pancreas development. Here, we report that rat bmMSCs were converted in vitro into insulin-producing cells by suppressing two-repressor genes repressor element-1 silencing transcription factor/neuronal restrictive silencing factor (Rest/Nrsf) and sonic hedgehog (Shh) and by over-expressing pancreas and duodenal transcription factor 1 (Pdx1). The reprogrammed bmMSCs expressed both genes and proteins specific for islet cells. These converted cells were capable of releasing insulin in a glucose-responsive manner. Our study suggests that bmMSCs may ultimately be reprogrammed to functional insulin-secreting cells.
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology of Ministry of Public Health, China Medical University, Shenyang 110001, China.
authors.forename: Hong-Tu
authors.initials: HT
authors.lastname: Li
authors.forename: Fang-Xu
authors.initials: FX
authors.lastname: Jiang
authors.forename: Ping
authors.initials: P
authors.lastname: Shi
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Liu
authors.forename: Xue-Wen
authors.initials: XW
authors.lastname: Lin
authors.forename: Xi-Ning
authors.initials: XN
authors.lastname: Pang
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002469:Cell Separation; D065150:Cellular Reprogramming / Q000235:genetics*; D020868:Gene Silencing; D053823:Hedgehog Proteins / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000166:cytology*; D016086:Lentivirus; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics*; D013489:Suppression, Genetic; D015534:Trans-Activators / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D000099229:RE1-Silencing Transcription Factor; C546888:Shh protein, rat; C084010:pancreatic and duodenal homeobox 1 protein