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β-MSCs: Successful fusion of MSCs with β-cells results in a β-cell like phenotype

Azizi, Zahra; Lange, Claudia; Paroni, Federico; Ardestani, Amin; Meyer, Anke; Wu, Yonghua; Zander, Axel R.; Westenfelder, Christof; Maedler, Kathrin

Authors

Zahra Azizi

Claudia Lange

Federico Paroni

Anke Meyer

Yonghua Wu

Axel R. Zander

Christof Westenfelder

Kathrin Maedler



Abstract

Bone marrow mesenchymal stromal cells (MSC) have anti-inflammatory, antiapoptotic and immunosuppressive properties and are a potent source for cell therapy. Cell fusion has been proposed for rapid generation of functional new reprogrammed cells. In this study, we aimed to establish a fusion protocol of bone marrow-derived human MSCs with the rat beta-cell line (INS-1E) as well as human isolated pancreatic islets in order to generate insulin producing beta-MSCs as a cell-based treatment for diabetes. Human eGFP+ puromycin+ MSCs were co-cultured with either stably mCherryexpressing rat INS-1E cells or human dispersed islet cells and treated with phytohemagglutinin (PHA-P) and polyethylene glycol (PEG) to induce fusion. MSCs and fused cells were selected by puromycin treatment. With an improved fusion protocol, 29.8 ± 2.9% of all MSCs were β-MSC heterokaryons based on double positivity for mCherry and eGFP. After fusion and puromycin selection, human NKX6.1 and insulin as well as rat Neurod1, Nkx2.2, MafA, Pdx1 and Ins1 mRNA were highly elevated in fused human MSC/INS-1E cells, compared to the mixed control population. Such induction of betacell markers was confirmed in fused human MSC/human dispersed islet cells, which showed elevated NEUROD1, NKX2.2, MAFA, PDX1 and insulin mRNA compared to the mixed control. Fused cells had higher insulin content and improved insulin secretion compared to the mixed control and insulin positive beta-MSCs also expressed nuclear PDX1. We established a protocol for fusion of human MSCs and beta cells, which resulted in a beta cell like phenotype. This could be a novel tool for cell-based therapies of diabetes.

Citation

Azizi, Z., Lange, C., Paroni, F., Ardestani, A., Meyer, A., Wu, Y., …Maedler, K. (2016). β-MSCs: Successful fusion of MSCs with β-cells results in a β-cell like phenotype. Oncotarget, 7(31), 48963-48977. https://doi.org/10.18632/oncotarget.10214

Journal Article Type Article
Acceptance Date Apr 19, 2016
Online Publication Date Jun 21, 2016
Publication Date Aug 2, 2016
Deposit Date Jan 4, 2024
Publicly Available Date Jan 8, 2024
Journal Oncotarget
Print ISSN 1949-2553
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 7
Issue 31
Pages 48963-48977
DOI https://doi.org/10.18632/oncotarget.10214
Keywords MSCs; Cell fusion; Beta-cells; Islets; Diabetes; Pathology Section
Public URL https://hull-repository.worktribe.com/output/4461703

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