title: Human bone marrow mesenchymal stem cells differentiate into insulin-producing cells upon microenvironmental manipulation in vitro.
abstract: It was recently reported that pluripotent mesenchymal stem cells (MSCs) in rodent bone marrow (BM) have the capacity to generate insulin-producing cells (IPCs) in vitro. However, little is known about this capacity in human BM-MSCs. We developed a nongenetic method to induce human BM-MSCs to transdifferentiate into IPCs both phenotypically and functionally. BM-MSCs from 12 human donors were sequentially cultured in specially defined conditions. Their differentiation extent toward beta-cell phenotype was evaluated systemically. Specifically, after induction human BM-MSCs formed spheroid islet-like clusters containing IPCs, which was further confirmed by dithizone (DTZ) staining and electron microscopy. These IPCs expressed multiple genes related to the development or function of pancreatic beta cells (including NKX6.1, ISL-1, Beta2/Neurod, Glut2, Pax6, nestin, PDX-1, ngn3, insulin and glucagon). The coexpression of insulin and c-peptide was observed in IPCs by immunofluorescence. Moreover, they were able to release insulin in a glucose-dependent manner and ameliorate the diabetic conditions of streptozotocin (STZ)-treated nude mice. These results indicate that human BM-MSCs might be an available candidate to overcome limitations of islet transplantation.
authors.affiliation: Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, Zhejiang province 310009, PR China.
authors.forename: Qiu-Ping
authors.initials: QP
authors.lastname: Xie
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Shun-Liang
authors.initials: SL
authors.lastname: Gao
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Yu-Lian
authors.initials: YL
authors.lastname: Wu
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004230:Dithizone / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007328:Insulin / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000648:ultrastructure; D059630:Mesenchymal Stem Cells / Q000166:cytology*
chemical_list: D007328:Insulin; D004230:Dithizone