Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Abstract

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are important in modulating neuroplasticity and promoting recovery after spinal cord injury. Intrathecal delivery of BDNF enhances functional recovery following unilateral spinal cord hemisection (SH) at C2, a well-established model of incomplete cervical spinal cord injury. We hypothesized that localized delivery of BDNF-expressing mesenchymal stem cells (BDNF-MSCs) would promote functional recovery of rhythmic diaphragm activity after SH. In adult rats, bilateral diaphragm electromyographic (EMG) activity was chronically monitored to determine evidence of complete SH at 3 days post-injury, and recovery of rhythmic ipsilateral diaphragm EMG activity over time post-SH. Wild-type, bone marrow-derived MSCs (WT-MSCs) or BDNF-MSCs (2 · 10 5 cells) were injected intraspinally at C2 at the time of injury. At 14 days post-SH, green fluorescent protein (GFP) immunoreactivity confirmed MSCs presence in the cervical spinal cord. Functional recovery in SH animals injected with WT-MSCs was not different from untreated SH controls (n = 10; overall, 20% at 7 days and 30% at 14 days). In contrast, functional recovery was observed in 29% and 100% of SH animals injected with BDNF-MSCs at 7 days and 14 days post-SH, respectively (n = 7). In BDNF-MSCs treated SH animals at 14 days, root-mean-squared EMG amplitude was 63 -16% of the pre-SH value compared with 12 -9% in the control/WT-MSCs group. We conclude that localized delivery of BDNF-expressing MSCs enhances functional recovery of diaphragm muscle activity following cervical spinal cord injury. MSCs can be used to facilitate localized delivery of trophic factors such as BDNF in order to promote neuroplasticity following spinal cord injury.

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…Neurorestoration requires long-term therapeutic intervention [50][51][52] so from a clinical perspective, achieving sustained gene/protein expression can significantly reduce costs and time by reducing the need for repeat administration of therapeutic proteins/cells. Notably, a sustained yet tapered profile of therapeutic biomolecule expression may be beneficial as it mirrors the temporal pattern of molecular expression profiles that are associated with regenerative processes in pathology sites [22].…”

Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors

“…However, others have reported spontaneous recovery as early as 14 d after the injury in the same animal model Gransee et al, 2015). We performed a control set of experiments and observed minimal spontaneous recovery occurring during the first 4 weeks following C2Hx.…”

“…Indeed, there are no available reports on duration of recovery lasting longer than several days, other than from our own laboratory (Nantwi and Goshgarian, 2002;present paper). Furthermore, cellbased approaches targeting brain-derived neurotrophic factor and tropomyosin related kinase receptor 2subtype B or choindritinase ABC inhibition were able to demonstrate recovery of respiratory function after SCI (Mantilla et al, 2013;Gransee et al, 2015); however, further studies are needed to address the potential for translation of such methods to clinical use. Finally, some reports suggest that diaphragm pacing and abdominal binder placement improved respiratory-related function after SCI (Tedde et al, 2012;Wadsworth et al, 2012;Posluszny et al, 2014).…”

Progress in the study of stem cell transplantation for the repair of spinal cord injury

“…The most recent studies have shown that the mechanism of spinal cord injury repair by MSC transplantation is related to the transplanted cells significantly inhibiting the expression of TNFα, interleukin (IL)-4, IL-1β, IL-2, IL-6 and IL-12 and other inflammatory factors at the injury site and up-regulating the expression of macrophage inflammatory proteins (MIP)-1α and the chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES), which provides a good internal environment for nerve regeneration. In addition, to further improve the efficacy of MSC transplantation, Gransee et al generated MSCs with a high expression of brain-derived neurotrophic factor (BDNF) through transfection and used them on rats with spinal cord injury, and the results showed that these enhanced MSCs had an improved efficacy compared with traditional MSCs [20].…”