1. Transposon-mediated glial cell line-derived neurotrophic factor overexpression in human adipose tissue-derived mesenchymal stromal cells: A potential approach for neuroregenerative medicine?
- Author
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Rasińska J, Klein C, Stahn L, Maidhof F, Pfeffer A, Schreyer S, Gossen M, Kurtz A, Steiner B, and Hemmati-Sadeghi S
- Subjects
- Adipose Tissue cytology, Adipose Tissue metabolism, Animals, Disease Models, Animal, Follow-Up Studies, Humans, Oxidopamine pharmacology, Rats, Rats, Sprague-Dawley, Glial Cell Line-Derived Neurotrophic Factor biosynthesis, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism
- Abstract
Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects and may be a promising candidate for regenerative strategies focusing on neurodegenerative diseases. As GDNF cannot cross the blood-brain barrier to potentially regenerate damaged brain areas, continuous in situ delivery with host cells is desired. Here, a non-viral Sleeping Beauty transposon was used to achieve continuous in vitro overexpression of GDNF in immune-privileged human adipose tissue-derived mesenchymal stromal cells (GDNF-tASCs). In addition, in vivo survival, tolerance, and effectiveness of transfected cells were tested in a very mild 6-hydroxydopamine (6-OHDA)-induced dopamine depletion rat model by means of intrastriatal injection on a sample basis up to 6 months after treatment. GDNF-tASCs showed vast in vitro gene overexpression up to 13 weeks post-transfection. In vivo, GDNF was detectable 4 days following transplantation, but no longer after 1 month, although adipose tissue-derived mesenchymal stromal cells (ASCs) could be visualized histologically even after 6 months. Despite successful long-term in vitro GDNF overexpression and its in vivo detection shortly after cell transplantation, the 6-OHDA model was too mild to enable sufficient evaluation of in vivo disease improvement. Still, in vivo immunocompatibility could be further examined. ASCs initially induced a pronounced microglial accumulation at transplantation site, particularly prominent in GDNF-tASCs. However, 6-OHDA-induced pro-inflammatory immune response was attenuated by ASCs, although delayed in the GDNF-tASCs group. To further test the therapeutic potential of the generated GDNF-overexpressing cells in a disease-related context, a follow-up study using a more appropriate 6-OHDA model is needed., (© 2022 The Authors. Journal of Tissue Engineering and Regenerative Medicine published by John Wiley & Sons Ltd.) more...
- Published
- 2022
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