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TISSUE-SPECIFIC STEM CELLS

Generation of Insulin-Producing Cells from Human Bone Marrow Mesenchymal Stem Cells by Genetic Manipulation

^aDepartment of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel;
^bLaniado Medical Center, Nethanya, Israel

Key Words. β Cell replacement • Insulin secretion • Pancreatic duodenal homeobox 1 • Cell transplantation

Correspondence: Shimon Efrat, Ph.D., Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel. Telephone: 972-3-640-7701; Fax: 972-3-640-9950; e-mail: sefrat{at}post.tau.ac.il

Received March 7, 2007; accepted for publication June 26, 2007.
First published online in STEM CELLS EXPRESS   July 5, 2007.



β Cell replacement is a promising approach for treatment of type 1 diabetes; however, it is limited by a shortage of pancreas donors. The pluripotent MSC in adult bone marrow (BM) offer an attractive source of stem cells for generation of surrogate β cells. BM-MSC can be obtained with relative ease from each patient, allowing potential circumvention of allograft rejection. Here, we report a procedure for expansion of BM-MSC in vitro and their differentiation into insulin-producing cells. The pancreatic duodenal homeobox 1 (Pdx1) gene was expressed in BM-MSC from 14 human donors, and the extent of differentiation of these cells toward the β-cell phenotype was evaluated. RNA and protein analyses documented the activation of expression of all four islet hormones. However, the cells lacked expression of NEUROD1, a key transcription factor in differentiated β cells. A significant insulin content, as well as glucose-stimulated insulin release, were demonstrated in vitro. Cell transplantation into streptozotocin-diabetic immunodeficient mice resulted in further differentiation, including induction of NEUROD1, and reduction of hyperglycemia. These findings were reproducible in BM-MSC from 9 of 14 donors of both sexes, ages 19–62. These results suggest a therapeutic potential for PDX1-expressing BM-MSC in β-cell replacement in patients with type 1 diabetes.

Disclosure of potential conflicts of interest is found at the end of this article.

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