Induction of insulin-producing cells derived from endometrial mesenchymal stem-like cells.
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.
Li
Hsin-Yang
HY
Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan.
Chen
Yi-Jen
YJ
Chen
Shih-Jen
SJ
Kao
Chung-Lan
CL
Tseng
Ling-Ming
LM
Lo
Wen-Liang
WL
Chang
Chia-Ming
CM
Yang
Der-Ming
DM
Ku
Hung-Hai
HH
Twu
Nae-Fang
NF
Liao
Chen-Yi
CY
Chiou
Shih-Hwa
SH
Chang
Yuh-Lih
YL
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
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