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

doi:10.1073/pnas.1136854100

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

^*Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel; ^†Department of Medicine, ^‡Marion Bessin Liver Research Center, and ^¶Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and ^§Transplant Research Institute, University of California, Davis Medical Center, Sacramento, CA 95817

Edited by Donald F. Steiner, University of Chicago, Chicago, IL (received for review November 11, 2002)

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.

Footnotes

↵ ∥ To whom correspondence should be addressed. E-mail: sefrat{at}post.tau.ac.il.
Abbreviations: Pdx1, pancreatic duodenal homeobox 1; FH, fetal hepatocyte; ES, embryonic stem; TGF, transforming growth factor; DPPIV, dipeptidyl peptidase IV; STZ, streptozotocin; HNF, hepatocyte nuclear factor; PC, prohormone convertase; PP, pancreatic polypeptide; GK, glucokinase.
This paper was submitted directly (Track II) to the PNAS office.