Generation of insulin-producing cells from PDX-1 gene-modified human mesenchymal stem cells.
Islet cell replacement is considered as the optimal treatment for type I diabetes. However, the availability of human pancreatic islets for transplantation is limited. Here, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) could be induced to differentiate into functional insulin-producing cells by introduction of the pancreatic duodenal homeobox-1 (PDX-1). Recombinant adenoviral vector was used to deliver PDX-1 gene into hMSCs. After being infected with Ad-PDX-1, hMSCs were successfully induced to differentiate into insulin-secreting cells. The differentiated PDX-1+ hMSCs expressed multiple islet-cell genes including neurogenin3 (Ngn3), insulin, GK, Glut2, and glucagon, produced and released insulin/C-peptide in a weak glucose-regulated manner. After the differentiated PDX-1+ hMSCs were transplanted into STZ-induced diabetic mice, euglycemia can be obtained within 2 weeks and maintained for at least 42 days. These findings validate the hMSCs model system as a potential basis for enrichment of human beta cells or their precursors, and a possible source for cell replacement therapy in diabetes.
Li
Yanhua
Y
Department of Stem Cells and Regenerative Medicine, Beijing Institute of Transfusion Medicine, Beijing, China.
Zhang
Rui
R
Qiao
Haifa
H
Zhang
Heping
H
Wang
Yunfang
Y
Yuan
Hongfeng
H
Liu
Qinbin
Q
Liu
Daqing
D
Chen
Lin
L
Pei
Xuetao
X
D000256:Adenoviridae; D000328:Adult; D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015221:Potassium Channels / Q000378:metabolism; D013311:Streptozocin; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
D002096:C-Peptide; D018398:Homeodomain Proteins; D007328:Insulin; D015221:Potassium Channels; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D013311:Streptozocin; D005947:Glucose