Generation of Insulin-producing Cells From Human Bone Marrow Mesenchymal Stem Cells By Genetic Manipulation

¹ Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel, and
² Laniado Medical Center, Nethanya, Israel
³ Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel, and

^* To whom correspondence should be addressed. E-mail: sefrat{at}post.tau.ac.il.

	Abstract

Beta-cell replacement is a promising approach for treatment of type 1 diabetes, however it is limited by shortage of pancreas donors. The pluripotent mesenchymal stem cells (MSC) in adult bone marrow (BM) offer an attractive source of stem cells for generation of surrogate beta 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 factor 1 (Pdx1) gene was expressed in BM-MSC from 14 human donors, and the extent of differentiation of these cells towards the beta-cell phenotype was evaluated. RNA and protein analyses documented the activation of expression of all 4 islet hormones. However, the cells lacked expression of NEUROD1, a key transcription factor in differentiated beta 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 cells from 9/14 donors of both sexes, aged 19-62. These results suggest a therapeutic potential for PDX1-expressing BM-MSC in beta-cell replacement in patients with type 1 diabetes.

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