Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

Michal Zalzman, Sanjeev Gupta, Ranjit K. Giri, Irina Berkovich, Baljit S. Sappal, Ohad Karnieli, Mark A Zern, Norman Fleischer, Shimon Efrat

Research output: Contribution to journalArticle

242 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7253-7258
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number12
DOIs
StatePublished - Jun 10 2003

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Hyperglycemia
Stem Cells
Insulin
Liver
Cell Transplantation
Type 1 Diabetes Mellitus
Obese Mice
C-Peptide
Homeobox Genes
Telomerase
Genes
Glucose
Serum

ASJC Scopus subject areas

  • Genetics
  • General

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Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. / Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K.; Berkovich, Irina; Sappal, Baljit S.; Karnieli, Ohad; Zern, Mark A; Fleischer, Norman; Efrat, Shimon.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 12, 10.06.2003, p. 7253-7258.

Research output: Contribution to journalArticle

Zalzman, Michal ; Gupta, Sanjeev ; Giri, Ranjit K. ; Berkovich, Irina ; Sappal, Baljit S. ; Karnieli, Ohad ; Zern, Mark A ; Fleischer, Norman ; Efrat, Shimon. / Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 12. pp. 7253-7258.
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