Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells.
Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.
Zalzman
Michal
M
Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Gupta
Sanjeev
S
Giri
Ranjit K
RK
Berkovich
Irina
I
Sappal
Baljit S
BS
Karnieli
Ohad
O
Zern
Mark A
MA
Fleischer
Norman
N
Efrat
Shimon
S
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000628:therapy; D005260:Female; D015870:Gene Expression; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D018398:Homeodomain Proteins; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000628:therapy*; D007328:Insulin / Q000096:biosynthesis*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D019098:Telomerase / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D001786:Blood Glucose; D002096:C-Peptide; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D019098:Telomerase