Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury

Liu, Shengwen; Sandner, Beatrice; Schackel, Thomas; Nicholson, LaShae; Chtarto, Abdelwahed; Tenenbaum, Liliane; Puttagunta, Radhika; Müller, Rainer; Weidner, Norbert; Blesch, Armin

doi:10.1016/j.actbio.2017.07.024

Cited by 105 publications

(101 citation statements)

References 46 publications

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“…Data were obtained from a spinal cord traumatic model and evidence significant intensification of axons using both scaffolds with cell therapy and a single injection of the BDNF virus construct [40,58,59]. It can be assumed that similar molecular processes also occur during brain tissue damage; thus, BDNF possibly induces the formation of new synapses and restores the neural network functional structure.…”

Section: Discussionmentioning

confidence: 99%

“…To date, a number of research groups are working on elaborating and testing neurotrophin therapeutic delivery systems, such as nanoparticulate carriers [33,34,35,36] and viral vector constructs for long-term BDNF overexpression in nervous system cells [37,38,39,40]. This is a promising method for ischaemia therapy, as it may avoid the need for prolonged use of drugs and have targeted effects on a strictly defined cell type.…”

Section: Introductionmentioning

confidence: 99%

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AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Митрошина

Mishchenko

Usenko

et al. 2018

IJMS

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Brain-derived neurotrophic factor (BDNF) is one of the key signaling molecules that supports the viability of neural cells in various brain pathologies, and can be considered a potential therapeutic agent. However, several methodological difficulties, such as overcoming the blood–brain barrier and the short half-life period, challenge the potential use of BDNF in clinical practice. Gene therapy could overcome these limitations. Investigating the influence of viral vectors on the neural network level is of particular interest because viral overexpression affects different aspects of cell metabolism and interactions between neurons. The present work aimed to investigate the influence of the adeno-associated virus (AAV)-Syn-BDNF-EGFP virus construct on neural network activity parameters in an acute hypobaric hypoxia model in vitro. Materials and methods. An adeno-associated virus vector carrying the BDNF gene was constructed using the following plasmids: AAV-Syn-EGFP, pDP5, DJvector, and pHelper. The developed virus vector was then tested on primary hippocampal cultures obtained from C57BL/6 mouse embryos (E18). Acute hypobaric hypoxia was induced on day 21 in vitro. Spontaneous bioelectrical and calcium activity of neural networks in primary cultures and viability tests were analysed during normoxia and during the posthypoxic period. Results. BDNF overexpression by AAV-Syn-BDNF-EGFP does not affect cell viability or the main parameters of spontaneous bioelectrical activity in normoxia. Application of the developed virus construct partially eliminates the negative hypoxic consequences by preserving cell viability and maintaining spontaneous bioelectrical activity in the cultures. Moreover, the internal functional structure, including the activation pattern of network bursts, the number of hubs, and the number of connections within network elements, is also partially preserved. BDNF overexpression prevents a decrease in the number of cells exhibiting calcium activity and maintains the frequency of calcium oscillations. Conclusion. This study revealed the pronounced antihypoxic and neuroprotective effects of AAV-Syn-BDNF-EGFP virus transduction in an acute normobaric hypoxia model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Митрошина

Mishchenko

Usenko

et al. 2018

IJMS

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“…For instance, biomaterial polymers, such as gels, may be suitable for filling for contusions or minor tears of the spinal cord (Donoghue et al, ). However, an ST, multiple channels, and numerous microchannels better serve to fill in larger defects by bridging gaps and traversing the glial scar or cystic cavities (Stokols et al, ; Moore et al, ; Novikova et al, ; Liu et al, ). An ST with a large “O” shape lumen may facilitate the migration of cells or tissue regeneration, which is especially suitable for grey matter regeneration containing neuronal somata and a complex horizontal neural network (Nomura, Katayama, Shoichet, & Tator, ).…”

Section: Discussionmentioning

confidence: 99%

Tubular scaffold with microchannels and an H‐shaped lumen loaded with bone marrow stromal cells promotes neuroregeneration and inhibits apoptosis after spinal cord injury

Xue

Sun

et al. 2020

J Tissue Eng Regen Med

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As a result of its complex histological structure, regeneration patterns of grey and white matter are quite different in the spinal cord. Therefore, tissue engineering scaffolds for repairing spinal cord injury must be able to adapt to varying neural regeneration patterns. The aim of the present study was to improve a previously reported spinal cord‐mimicking partition‐type scaffold by adding microchannels on a single tubular wall along its longitudinal axis, thus integrating the two architectures of a single H‐shaped central tube and many microchannels. Next, the integrated scaffold was loaded with bone marrow stromal cells (BMSCs) and transplanted to bridge the 5‐mm defect of a complete transverse lesion in the thoracic spinal cord of rats. Subsequently, effects on nerve regeneration, locomotion function recovery, and early neuroprotection were observed. After 1 year of repair, the integrated scaffold could guide the regeneration of axons appearing in the debris of degraded microchannels, especially serotonin receptor 1A receptor‐positive axonal tracts, which were relatively orderly arranged. Moreover, a network of nerve fibres was present, and a few BMSCs expressed neuronal markers in tubular lumens. Functionally, electrophysiological and locomotor functions of rats were partially recovered. In addition, we found that BMSCs could protect neurons and oligodendrocytes from apoptosis during the early stage of implantation. Taken together, our results demonstrate the potential of this novel integrated scaffold loaded with BMSCs to promote spinal cord regeneration through mechanical guidance and neuroprotective mechanisms.

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“…Neurotrophins such as BDNF and NT‐3 play a significant role in modulating functional neuroplasticity after SCI. BDNF plays an essential role in neuronal structure and can promote the regeneration of injured neurons and improve the pathological state of neurons . It has also been established that BDNF can reduce neuronal apoptosis and enhance the remyelination of injured axons and neuronal regeneration in SCI .…”

Section: Discussionmentioning

confidence: 99%

HIF‐1α promotes bone marrow stromal cell migration to the injury site and enhances functional recovery after spinal cord injury in rats

Han

Chen

Liu

et al. 2018

The Journal of Gene Medicine

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Background Spinal cord injury (SCI) is a severe health problem worldwide, and efficacious strategies to properly repair SCI have not yet been developed. Recently, gene and cell therapies as alternative treatments for SCI have been proposed to comprise safe and promising strategies. Methods The present study investigated the therapeutic effects and underlying mechanisms of hypoxia‐inducible factor‐1α carried in recombinant adenovirus (Adv‐HIF‐1α), as administered immediately after SCI in adult rats. Results Adv‐HIF‐1α‐treated animals showed better functional recovery and smaller cavity volume than those in the vehicle‐treated control group. Both the numbers of green fluorescent protein‐labeled bone marrow stromal cells (GFP‐BMSCs) and cells double‐positive for GFP and a cell lineage marker (NeuN) in the injured spinal cord were larger in the Adv‐HIF‐1α‐treated group. The expression levels of neurotrophins such as neurotrophin‐3 and brain‐derived neurotrophic factor were also higher in the Adv‐HIF‐1α‐treated group. Conclusions Adv‐HIF‐1α improves functional recovery in rats with SCI, and the underlying mechanism may be related to the mobilization of BMSCs to the injured area and higher expression levels of neurotrophin‐3 and brain‐derived neurotrophic factor.

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Regulated viral BDNF delivery in combination with Schwann cells promotes axonal regeneration through capillary alginate hydrogels after spinal cord injury

Cited by 105 publications

References 46 publications

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

AAV-Syn-BDNF-EGFP Virus Construct Exerts Neuroprotective Action on the Hippocampal Neural Network during Hypoxia In Vitro

Tubular scaffold with microchannels and an H‐shaped lumen loaded with bone marrow stromal cells promotes neuroregeneration and inhibits apoptosis after spinal cord injury

HIF‐1α promotes bone marrow stromal cell migration to the injury site and enhances functional recovery after spinal cord injury in rats

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