title: Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells.
abstract: Studies have demonstrated that mesenchymal stem-like cells can be isolated from endometrium. However, the potential of endometrial-derived stem cells to differentiate into insulin-positive cells and functionally secrete insulin remains undetermined. We isolated endometrial mesenchymal stem-like cells (EMSCs) from human endometrial tissue from six donors. The insulin-secreting function of EMSCs was further analyzed in vitro and in transplanted grafts in vivo. We successfully isolated EMSCs from human endometrium, and our results showed that EMSCs expressed high levels of stemness genes (Nanog, Oct-4, Nestin). Under specific induction conditions for 2 weeks, EMSCs formed three-dimensional spheroid bodies (SBs) and secreted C-peptide. The high insulin content of SB-EMSCs was confirmed by enzyme-linked immunosorbent assay, and glucose responsiveness was demonstrated by measuring glucose-dependent insulin secretion. Using cDNA microarrays, we found that the expression profiles of SB-EMSCs are related to those of islet tissues. Insulin and C-peptide production in response to glucose was significantly higher in SB-EMSCs than in undifferentiated EMSC controls. Furthermore, upon differentiation, SB-EMSCs displayed increased mRNA expression levels of NKx2.2, Glut2, insulin, glucagon, and somatostatin. Our results also showed that SB-EMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than fibroblasts from the same patient. It is noteworthy that SB-EMSCs xenotransplanted into immunocompromised mice with streptozotocin-induced diabetes restored blood insulin levels to control values and greatly prolonged the survival of graft cells. These data suggest that EMSCs not only play a novel role in the differentiation of pancreatic progenitors, but also can functionally enhance insulin production to restore the regulation of blood glucose levels in an in vivo transplantation model.
authors.affiliation: Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Hsin-Yang
authors.initials: HY
authors.lastname: Li
authors.forename: Yi-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Chen
authors.forename: Chung-Lan
authors.initials: CL
authors.lastname: Kao
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Lo
authors.forename: Chia-Ming
authors.initials: CM
authors.lastname: Chang
authors.forename: Der-Ming
authors.initials: DM
authors.lastname: Yang
authors.forename: Hung-Hai
authors.initials: HH
authors.lastname: Ku
authors.forename: Nae-Fang
authors.initials: NF
authors.lastname: Twu
authors.forename: Chen-Yi
authors.initials: CY
authors.lastname: Liao
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Yuh-Lih
authors.initials: YL
authors.lastname: Chang
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000628:therapy; D015536:Down-Regulation / Q000235:genetics; D004717:Endometrium / Q000166:cytology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000637:transplantation; D053583:Interleukin-1beta / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D014157:Transcription Factors; D014183:Transplantation, Heterologous; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015703:Antigens, CD; D001786:Blood Glucose; D002096:C-Peptide; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D007328:Insulin; D053583:Interleukin-1beta; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D005934:Glucagon; D005978:Glutathione; D005947:Glucose