Abstract
Viral gene carriers are being widely used as gene transfer systems in (trans)differentiation and reprogramming strategies. Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine pancreatic differentiation. While several viral vector systems have been employed in such studies, the results reported with adenovirus vectors have been the most promising in vitro and in vivo. In this study, we examined whether the viral vector system itself could impact the differentiation capacity of human bone-marrow derived mesenchymal stem cells (hMSCs) toward the endocrine lineage. Lentivirus-mediated expression of Pdx-1, Ngn-3, and Maf-A alone or in combination does not lead to robust expression of any of the endocrine hormones (i.e. insulin, glucagon and somatostatin) in hMSCs. Remarkably, subsequent transduction of these genetically modified cells with an irrelevant early region 1 (E1)-deleted adenoviral vector potentiates the differentiation stimulus and promotes glucagon gene expression in hMSCs by affecting the chromatin structure. This adenovirus stimulation was observed upon infection with an E1-deleted adenovirus vector, but not after exposure to helper-dependent adenovirus vectors, pointing at the involvement of genes retained in the E1-deleted adenovirus vector in this phenomenon. Lentivirus mediated expression of the adenovirus E4-ORF3 mimics the adenovirus effect. From these data we conclude that E1-deleted adenoviral vectors are not inert gene-transfer vectors and contribute to the modulation of the cellular differentiation pathways.
Highlights
The use of adult stem cells in regenerative medicine procedures is appealing
Bone marrow-derived human mesenchymal stem cells (hMSCs) represent an attractive source of stem cells to be used in regenerative medicine since they are relatively easy to isolate, purify, and expand ex vivo
The use of these primary adult stem cells is generally considered as safe. This has led to a large number of clinical studies involving administration of hMSCs
Summary
The use of adult stem cells in regenerative medicine procedures is appealing. In this respect the use of human mesenchymal stem cells (hMSCs) is attractive since these cells can be isolated with relative ease from living donors. The endocrine pancreas contains the Islets of Langerhans These islets consist of cell clusters, which contain the major pancreatic hormone-producing cells, such as the a-cells, producing glucagon, the b-cells, which synthesize insulin, the d-cells, producing somatostatin, and the PP cells that generate pancreatic polypeptide. These hormones are involved in, among others, the regulation of glucose homeostasis. In diabetes type 1 the glucose homeostasis is disturbed as a result of the immune-mediated destruction of the insulin-producing cells
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