title: Substrate-mediated nanoparticle/gene delivery to MSC spheroids and their applications in peripheral nerve regeneration.
abstract: Substrate-derived mesenchymal stem cell (MSC) spheroids show greater differentiation capacities than dispersed single cells in vitro. During spheroid formation, nanoparticles (NPs)/genes may be delivered into the cells. In this study, MSCs were conveniently labeled with superparamagnetic Fe3O4 NPs, or transfected with brain-derived neurotrophic factor (BDNF) gene, by the substrate-mediated NP/gene uptake. With the promising in vitro data showing the beneficial effect on neural development and neurotrophic factor expression, MSCs were combined with a polymeric nerve conduit to bridge a 10 mm transection gap of rat sciatic nerve. High-resolution (7-T) magnetic resonance imaging (MRI) was used to track the transplanted cells. Nerve regeneration was assessed by functional recovery and histology. Results revealed that Fe3O4 NP-labeled MSCs were successfully visualized by MRI in vivo. Animals receiving BDNF-transfected MSC spheroids demonstrated the shortest gap bridging time (<21 days), the largest regenerated nerve, and the thickest myelin sheath at 31 days. Compared to MSC single cells, the pristine or BDNF-transfected MSC spheroids significantly promoted the functional recovery of animals, especially for the BDNF-transfected MSC spheroids. The transplanted MSCs were incorporated in the regenerated nerve and differentiated into non-myelinating Schwann cells after 31 days. This study suggests that the substrate-mediated gene delivery and NP labeling may provide extra values for MSC spheroids to carry therapeutic/diagnostic agents in cell-based therapy.
authors.affiliation: Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan.
authors.forename: Ting-Chen
authors.initials: TC
authors.lastname: Tseng
authors.affiliation: Institute of Polymer Science and Engineering, National Taiwan University, Taipei, Taiwan; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan. Electronic address: shhsu@ntu.edu.tw.
authors.forename: Shan-hui
authors.initials: SH
authors.lastname: Hsu
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053758:Nanoparticles / Q000737:chemistry*; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D019707:Receptors, Chemokine / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013194:Staining and Labeling
chemical_list: D018925:Chemokines; D005290:Ferric Compounds; D005904:Glial Fibrillary Acidic Protein; D009414:Nerve Growth Factors; D019707:Receptors, Chemokine; C000499:ferric oxide
keywords: Brain-derived neurotrophic factor (BDNF); MSC spheroids; Peripheral nerve regeneration; Superparamagnetic iron oxide nanoparticles