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Neurogenic Potential of Engineered Mesenchymal Stem Cells Overexpressing VEGF

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Abstract

Numerous signaling molecules are altered following nerve injury, serving as a blueprint for drug delivery approaches that promote nerve repair. However, challenges with achieving the appropriate temporal duration of recombinant protein delivery have limited the therapeutic success of this approach. Genetic engineering of mesenchymal stem cells (MSCs) to enhance the secretion of proangiogenic molecules such as vascular endothelial growth factor (VEGF) may provide an alternative. We hypothesized that the administration of VEGF-expressing human MSCs would stimulate neurite outgrowth and proliferation of cell-types involved in neural repair. When cultured with dorsal root ganglion explants in vitro, control and VEGF-expressing MSCs (VEGF–MSCs) increased neurite extension and proliferation of Schwann cells (SCs) and endothelial cells, while VEGF–MSCs stimulated significantly greater proliferation of endothelial cells. When embedded within a 3D fibrin matrix, VEGF–MSCs maintained overexpression and expressed detectable levels over 21 days. After transplantation into a murine sciatic nerve injury model, VEGF–MSCs maintained high VEGF levels for 2 weeks. This study provides new insight into the role of VEGF on peripheral nerve injury and the viability of transplanted genetically engineered MSCs. The study aims to provide a framework for future studies with the ultimate goal of developing an improved therapy for nerve repair.

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Acknowledgements

This work was partially supported by R03DE021704 (to JKL) and CIRM Disease Team Grant DR2A-05423 for Critical Limb Ischemia (to FAF). The authors acknowledge Dr. Tony Passerini for providing HAECs.

Conflicts of Interest

Alan Man, Gregory Kujawski, Travis Burns, Elaine Miller, Fernando Fierro, Kent Leach, and Peter Bannerman declare that they have no conflicts of interest.

Ethical Standards

Treatment of all experimental animals was in accordance with UC Davis animal care guidelines and all National Institutes of Health animal-handling procedures and was approved by the appropriate institutional committees. No human subject research was performed.

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Authors and Affiliations

  1. Institute for Pediatric Regenerative Medicine, Shriners Hospital for Children Northern California, Sacramento, CA, 95817, USA

    Alan J. Man, Gregory Kujawski, Travis S. Burns, Elaine N. Miller & Peter Bannerman

  2. Institute of Regenerative Cures, University of California, Davis, Sacramento, CA, 95817, USA

    Fernando A. Fierro

  3. Department of Biomedical Engineering, University of California, Davis, 451 Health Sciences Dr., GBSF 2303, Davis, CA, 95616, USA

    Alan J. Man & J. Kent Leach

  4. Department of Cell Biology, UC Davis School of Medicine, Shriners Hospital for Children Northern California, 2425 Stockton Blvd., Sacramento, CA, 95817, USA

    Peter Bannerman

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  1. Alan J. Man
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Correspondence to J. Kent Leach or Peter Bannerman.

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Associate Editor Michael R. King oversaw the review of this article.

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Man, A.J., Kujawski, G., Burns, T.S. et al. Neurogenic Potential of Engineered Mesenchymal Stem Cells Overexpressing VEGF. Cel. Mol. Bioeng. 9, 96–106 (2016). https://doi.org/10.1007/s12195-015-0425-4

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  • DOI: https://doi.org/10.1007/s12195-015-0425-4

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